+ MODEL

Genes & Diseases xxx (xxxx) xxx

Available online at www.sciencedirect.com

ScienceDirect

journal homepage: http://ees.elsevier.com/gendis/default.asp

REVIEW ARTICLE

Cancer chemotherapy and beyond: Current

status, drug candidates, associated risks and
progress in targeted therapeutics
Uttpal Anand a, Abhijit Dey b,1, Arvind K. Singh Chandel c,1,
Rupa Sanyal d, Amarnath Mishra e,**, Devendra Kumar Pandey f,
Valentina De Falco g, Arun Upadhyay h, Ramesh Kandimalla i,j,
Anupama Chaudhary k, Jaspreet Kaur Dhanjal l,
Saikat Dewanjee m, Jayalakshmi Vallamkondu n,
José M. Pérez de la Lastra o,*

a
Department of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel
b
Department of Life Sciences, Presidency University, Kolkata, West Bengal 700073, India
c
Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo,
Tokyo 113-0033, Japan
d
Department of Botany, Bhairab Ganguly College (affiliated to West Bengal State University), Kolkata,
West Bengal 700056, India
e
Faculty of Science and Technology, Amity Institute of Forensic Sciences, Amity University Uttar
Pradesh, Noida 201313, India
f
Department of Biotechnology, School of Bioengineering and Biosciences, Lovely Professional
University, Phagwara, Punjab 144411, India
g
Institute of Endocrinology and Experimental Oncology (IEOS), National Research Council (CNR),
Department of Molecular Medicine and Medical Biotechnology (DMMBM), University of Naples Federico
II, Naples 80131, Italy
h
Department of Biochemistry, School of Life Sciences, Central University of Rajasthan, Bandar Sindari,
Kishangarh Ajmer, Rajasthan 305817, India
i
CSIR-Indian Institute of Chemical Technology, Hyderabad, Telangana 500007, India
j
Department of Biochemistry, Kakatiya Medical College, Warangal, Telangana 506007, India
k
Orinin-BioSystems, LE-52, Lotus Road 4, CHD City, Karnal, Haryana 132001, India
l
Department of Computational Biology, Indraprastha Institute of Information Technology Delhi (IIIT-
D), Okhla Industrial Estate, Phase III, New Delhi 110020, India

* Corresponding author.
** Corresponding author.

Peer review under responsibility of Chongqing Medical University.

https://doi.org/10.1016/j.gendis.2022.02.007
2352-3042/Copyright ª 2022, Chongqing Medical University. Production and hosting by Elsevier B.V. This is an open access article under the
CC BY license (http://creativecommons.org/licenses/by/4.0/).

Please cite this article as: U. Anand, A. Dey, A.K.S. Chandel et al., Cancer chemotherapy and beyond: Current status, drug candidates,
associated risks and progress in targeted therapeutics, Genes & Diseases, https://doi.org/10.1016/j.gendis.2022.02.007
 + MODEL
U. Anand, A. Dey, A.K.S. Chandel et al.

m
Advanced Pharmacognosy Research Laboratory, Department of Pharmaceutical Technology, Jadavpur
University, Kolkata 700032, India
n
Department of Physics, National Institute of Technology-Warangal, Warangal, Telangana 506004, India
o
Biotechnology of Macromolecules Research Group, Instituto de Productos Naturales y Agrobiologı´a,
IPNA-CSIC, San Cristóbal de La Laguna 38206, Tenerife, Spain

Received 4 July 2021; received in revised form 15 February 2022; accepted 21 February 2022

KEYWORDS Abstract Cancer is an abnormal state of cells where they undergo uncontrolled proliferation
Antimicrobial and produce aggressive malignancies that cause millions of deaths every year. With the new
peptides; understanding of the molecular mechanism(s) of disease progression, our knowledge about
Cancer therapies; the disease is snowballing, leading to the evolution of many new therapeutic regimes and their
Clinical trials; successive trials. In the past few decades, various combinations of therapies have been pro-
Combination therapy; posed and are presently employed in the treatment of diverse cancers. Targeted drug therapy,
Immunotherapy; immunotherapy, and personalized medicines are now largely being employed, which were not
Patient survival; common a few years back. The field of cancer discoveries and therapeutics are evolving fast as
Personalized cancer type-specific biomarkers are progressively being identified and several types of cancers
medicine; are nowadays undergoing systematic therapies, extending patients’ disease-free survival
Targeted drug thereafter. Although growing evidence shows that a systematic and targeted approach could
delivery be the future of cancer medicine, chemotherapy remains a largely opted therapeutic option
despite its known side effects on the patient’s physical and psychological health. Chemother-
apeutic agents/pharmaceuticals served a great purpose over the past few decades and have
remained the frontline choice for advanced-stage malignancies where surgery and/or radiation
therapy cannot be prescribed due to specific reasons. The present report succinctly reviews
the existing and contemporary advancements in chemotherapy and assesses the status of
the enrolled drugs/pharmaceuticals; it also comprehensively discusses the emerging role of
specific/targeted therapeutic strategies that are presently being employed to achieve better
clinical success/survival rate in cancer patients.
Copyright ª 2022, Chongqing Medical University. Production and hosting by Elsevier B.V. This is
an open access article under the CC BY license (http://creativecommons.org/licenses/by/
4.0/).

Introduction can suppress tumor growth through diverse mechanisms. Some

of the drugs/compounds work on crucial cellular enzymes,
Cancer is a heterogeneous and multifactorial disease in which while others may alter cell metabolism. They have also shown
a series of genomic/molecular alterations cause the uncon- the potential to interfere with some critical cellular processes,
trolled growth and proliferation of the cells, causing a rapid e.g., programmed cell death/apoptosis, drug resistance, DNA
increase in tissue mass in the affected parts of the body. Under damage, DNA replication, or immune reactions. These drugs
normal conditions, a cell gets signals to die to supplant the have distinct modes of action and selectivity for multiple
organism with a young and healthier cell. Cancer cells grow cancer types7e12; however, subtle alteration to their chemical
using the body’s oxygen and supplements, depriving other cells structure could abolish their anti-cancer potency.13,14
of regular supplements and growth factors. These cells can The idea of chemotherapy (utilizing toxic compounds
turn the microenvironment in their favor, deceive the immune and drugs to destroy cancerous cells) came into existence
system of the body, and can exploit the physiology of other after the reports of mustard gas killing lymphatic tissues
cells to accommodate their needs.1e6 Some of the biomarkers and bone marrow. The effects were later validated in mice
which are currently been used to detect cancer include human using an effective derivative of the gas (nitrogen mustard)
epididymis protein 4 (HE4), carcinoembryonic antigen (CEA), that showed effective regression of lymphoma tissues.15e17
legumain, mesothelin, osteopontin, and vitamin E-binding The first patient receiving this nitrogen mustard was forty-
plasma protein. A plethora of anti-cancer drugs and natural eight years old lymphosarcoma patient whose cancer soft-
medicinal compounds have been devised over the years, which ened and cleared initially. Unfortunately, later he died

1
Equal contribution.

2
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Genes & Diseases xxx (xxxx) xxx

after relapsing, but this secret military trial at Yale Uni- also succinctly discussed various side effects and drawbacks
versity paved the way for chemicals in treating cancers and of these treatment plans and further provided an overview
developing the field of cancer chemotherapy for treating a of recent advancements in interventional strategies by
variety of cancers.18e21 focusing on targeted drug therapy, immunotherapy,
Chemotherapy primarily works by circumventing the can- personalized and integrative medicines. Fig. 1 depicts the
cer cells from further growth and division. Cancer cells usually significant intrinsic and extrinsic cellular and molecular
divide and grow at a much-accelerated rate than normal cells events causing the transformation of a normal cell to a
and are physiologically possess very high endogenous stress. cancer cell and its distinct hallmarks.
Therefore, the drugs can destroy them rapidly and more
effectively in comparison to other surrounding cells. Some of
the promising inhibitor therapies which have been used to Cancer chemotherapeutics: what is known so
treat solid cancers are polyadenosine diphosphate-ribose po- far?
lymerase inhibitors, angiogenesis inhibitors, histone deacety-
lase (HDAC) inhibitors, mechanistic target of rapamycin The idea of cancer as a disease was known to Hippocrates,
(mTOR) inhibitors, poly (adenosine di-phosphate-ribose) po- the father of medicine, around 400 BC. He later coined the
lymerase (PARP) inhibitors, p53/mouse double minute 2 ho- term ’carcinos’ due to the similarity of cancer tissue
molog (MDM2) inhibitors, hedgehog pathway blockers, tyrosine growths with crabs. The term was later replaced with the
kinase inhibitors and proteasome inhibitors.22,23 Chemo- Latin word cancer by Celsus. Many ancient pieces of
therapy may have different variations, which can affect the literature have described several kinds of malignancies in
target cells in distinct manners.24 Some of the treatments may humans, and multiple treatment approaches were also in
directly alter the quality of cellular proteins, rendering them use in different parts of the ancient world, as found in the
non-functional and affecting major cellular physiological literature of that era.37,38 However, the progress of stra-
pathways. Major chaperone repressors, autophagy suppres- tegies to treat the disease was more or less static until the
sors, or proteasome inhibitors belong to these classes of mol- beginning of the twentieth century.39 The extract of the
ecules.25e31 Other drugs may target some essential hormones plant Colchicum autumnale was used by Greek physicians
and interfere with the body’s overall metabolism.32,33 The to dissolve the tumor mass. Interestingly, in the 1930s, the
2018 Nobel Prize attributed to immune checkpoint therapy active compound in the extract, colchicine, was reported
research has highlighted the importance of immunotherapy, that can interfere with microtubule assembly and may
which underlies the possibilities of modulating our immune work as a potential drug.40 Vincristine and vinblastine are
system in our favor to cope up with the cancer-like conditions other similar compounds that were medicinally recognized
and fight back against the disease.24,34 as possible anti-tumor agents a long time ago.41 The
The selection of chemo-preventive drugs or a combi- ancient pieces of the literature suggest that the Greek and
nation of drugs is mostly based on the type and stage of Roman physicians have contributed enormously to the
cancer. The primary objective of these drugs is to identification and characterization of disease. Arabic, In-
neutralize the cancerous cells and ameliorate the stress dian, and Chinese medicinal archives have also paved the
caused by the tumor’s growth. The dosage and timespan of way for multiple medieval and modern approaches to un-
the treatment are two important points of consideration. derstand and treat the disease. Interestingly, for cen-
It has been observed that the medications are given at turies, most of the approaches remain limited to
very high doses causing numerous side effects and harm to cauterization, bloodletting, surgery, herbal medicine,
other healthy cells.35 One major challenge is the relapse etc.42 In modern onco-medicine, which was evolved during
of the disease. During reoccurrence, it has been widely the Second World War, many active compounds were re-
observed that the cancer cells attain drug resistance ported following the detailed characterization of the dis-
following longer exposure to the drugs. Despite enormous ease at the genetic and molecular level. The initial
applications, most chemotherapies are given to prolong decades have seen enormous debate on the use of cyto-
and ease the patient’s survival, hence called palliative toxic agents as drug candidates; however, advancements
chemotherapy.21 However, prolonged exposure to these were made, and success came in the form of Eli Lily
drugs may have excessively adverse effects on a patient’s introducing Vinca alkaloids in the 1960s, which was then
physical and mental health, making it difficult to continue followed by procarbazine.43 In the following years, the
the ongoing treatment. Oncologists, for the most part, idea of combination therapy was introduced for acute
provide these medications with possible time intervals in lymphocytic leukemia and non-Hodgkin’s lymphoma pa-
between, which also gives non-transformed cells a chance tients that were also supplemented with supportive
to mend.36 In most cases, a team of specialists, including medical care to enhance the quality of life.21
radiologists, nutritionists, psychologists, and the primary In the second half of the twentieth century, a series of
consultant collectively decide the treatment plans that reports have identified numerous mutations, external
include drug combinations, dosage, duration of cycles, stimuli (toxic chemicals, viruses, etc.), metabolic alter-
and additional supplements. ations, etc. as the underlying causes of cancer.44,45 Iden-
This report mainly reviews various aspects of cancer tification of a plethora of cellular pathways that are
chemotherapy, including various applications of the drugs/ affected in various cancer types has given different mo-
chemotherapeutic agents that are already in practice. We lecular alternatives to target and develop effective drugs

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U. Anand, A. Dey, A.K.S. Chandel et al.

Figure 1 Schematic diagram showing different intrinsic and extrinsic biological/molecular events potentiating the trans-
formation of a normal cell to the cancer cell, while the lower part of this diagram showing different hallmarks of a transformed
cancer cell.

(Fig. 2).46e48 Several modes of medications have also been Nevertheless, the selectivity of most drug particles is
introduced and tried for drug administration based on the restricted, and such medications are considered one of the
types and stages of the diagnosed cancer. Here, we discuss most harmful medications utilized in the treatment.60,61
the available drug medications, following which we have Since the initial findings of modern anticancer drug dis-
revisited the chemotherapeutic agents, which have sub- coveries in the 1940s, continuous efforts are being made to
stantially pushed the field forward and extended the lives treat this life-threatening disease. Advances in scientific
of millions in the past several decades. methods and techniques have brought new treatment and
Intravenous (IV) chemotherapy requires drug infusion diagnostic tools and advanced patient care measures
straightforwardly into the patient’s veins that may take (Fig. 2).62e69 Treatment plans may have palliation as one
from minutes to a few hours. Some medications can also be strategy that may lead to shrinkage of the obvious tumor,
given either as pills or fluid regularly or at some intervals.49 easing side effects, and increasing the life quality of pa-
Intramuscular shots and intra-abdominal administration are tients. Fig. 2 describes various ways of providing anti-
other methods of giving chemotherapeutic medications to cancer medications to patients depending upon their type
target the specific locations of tumor mass.50 In addition, a and stage of the disease.
new technology called pressurized intraperitoneal aerosol Along with primary treatment, adjuvant therapy is also
chemotherapy has been developed to efficiently deliver given to the patients for additionally combating the disease
intraperitoneal chemotherapy for end-stage peritoneal through supportive strategies.70,71 Surgery and radiation
metastases patients.51 Topical treatment methods imply can be given to patients to supplement a chemotherapeutic
providing drugs through the skin surface. The anti-cancer plan to curb the disease by destroying shrouded cancer
compounds derived from either natural sources or their cells that could not be targeted otherwise.72 Sometimes
synthetic chemical analogs can kill cancer cells or stop their adjuvant chemotherapy is given to patients after surgery or
development.52e54 Notably, various other approaches are radiation or both to lessen the chances of recurrence.73e75
emerging to treat the cancer cells, including small mole- Adjuvant chemotherapy starts typically within three to five
cule inhibitors,55 a combination of anti-cancer agents and weeks of the surgical removal of a tumor and has distinctive
immunotherapy,56 nanotechnology-based drugs,57e59 and treatment lengths relying upon the disease. Although
organo-seleno compounds (Fig. 2).31 chemotherapy has significantly improved overall survival,

4
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Figure 2 Schematic diagram showing the basic principles of chemotherapy (A), different classes of chemotherapeutic agents/
drugs (B), and immunotherapeutic mechanism(s) of targeting cancer cells (C).

patients experience a wide range of physical and psycho- challenging.76,77 Designing drugs or therapeutics mainly
logical symptoms that impact their quality of life. Symp- focuses on selectivity, which can specifically kill the
toms seldom occur in isolation. Chemotherapy-induced hair cancerous cells without affecting the non-cancerous cells
loss remains greatly feared, with a negative impact on the (Fig. 2). In a way, the anti-cancer therapy may resemble
well-being of many cancer patients. Cancer- and antimicrobials, but the cancerous cells and the bacterial
chemotherapy-induced poor appetite is usually the result cells have differences in terms of the metabolic and phys-
of taste changes, mouth sores, nausea and vomiting, iological characters.78e80 For our immune cells, bacterial
increased satiety, medication side effects, pain, fatigue, cell recognition is straightforward, while our transformed
depressed mood, and anxiety. cells can hide cell surface receptors to evade the immune
system.81 Early-stage detection of cancers increases the
Basic principles of chemotherapy: years of chances of treatment and survival. Therefore, recognizing
and diagnosing those transformed cells remains one of the
research, miles to go most challenging tasks in oncological research. At early
stages, most known biomarkers remain undetectable, and
The cancer cell metabolic mechanisms functionally overlap
with the host cells, so cancer treatment is very

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U. Anand, A. Dey, A.K.S. Chandel et al.

cancer cells’ ability to hide from immune cells freezes our pyrimethamine, trimethoprim, and triamterene, act
immune responses.82,83 directly on the production of these metabolites, hindering
In a tumor subpopulation, transformed cells differ the enzyme from producing folate insufficiency.95 Metho-
drastically from the other cells in terms of physiology, trexate, an antifolate drug, is one of the exceptionally
metabolism, proliferation rate, etc.84e86 Besides that, the successful anti-cancer medications that represses dihy-
genetic diversity may pose additional challenges to drofolate reductase (DHFR) and obstructs the trans-
target all kinds of cells in a particular tissue mass owing to formation of dihydrofolic acid (DHFA) into tetrahydrofolic
the tumor heterogeneity.87,88 A combination of drug ther- acid (THFA).96 This coenzyme activity is indispensable to
apy is applied to address this challenge, and the regime is the cells as they are essential for the nucleotide synthesis
devised according to the cancer phase and type pathways. Methotrexate is an anti-inflammatory molecule
(Fig. 2).89,90 and is hence used as a medication for many other in-
In the subsequent section, we provide a comprehen- flammatory diseases, like rheumatoid arthritis and
sive overview of various chemotherapeutic agents which extreme psoriasis, apart from various cancer types. A
have served the purpose for several decades in different detailed description of common antimetabolites is
cancer types. These drugs could be classified in different comprehensively provided in Table 1.
ways based on their chemical nature/source, molecular
target, mechanism/mode of action, or effectiveness in
model systems against various malignancies/cancer types Pyrimidine-derived antimetabolites
(Table 1). (pyrimidine antagonists) and Vinca alkaloids

Alkylating agents Pyrimidine-derived antimetabolites are a group of chemo-

therapeutic agents that interrupt DNA synthesis and exert
One major class of the current drugs belongs to alkylating their cytotoxicity to cancer cells (Fig. 2). For instance,
agents, which can interfere with the formation/linkage of cytarabine also known as cytosine arabinoside or Ara C in-
DNA double strands.91 These drugs can cause it by trans- terrupts DNA as well as RNA synthesis by displacing the
ferring one alkyl group to the guanidine base in DNA cytosine with itself (that differs merely by its base sugar
(Fig. 2). Cross-linking of nucleic acids with proteins or arabinose). Cytarabine/cytosine arabinoside is enrolled
peptides can likewise affect the DNA geometry, cause frequently in clinics to treat leukemia or non-Hodgkin’s
erroneous base pairing and DNA strand breakage, and lymphoma.97 Some other notably pyrimidine-derived anti-
eventually preventing the cell division and causing irre- metabolites include fluorouracil, 5-fluorouracil (5-FU),
versible senescence.92 Mechanistically, alkylating agents capecitabine, floxuridine, gemcitabine, decitabine, ralti-
in their electrophilic forms interact with cellular DNA and trexed, and tegafur (Table 1).98e103 Being as pyrimidine or
form covalent adducts, underlying their broader utility. purine analogs having altered chemical groups, these
Therefore, alkylating drugs are the frontline chemother- drugs/compounds induce apoptosis while progressing
apeutic agents given against most of the cancer types, yet through the S phase of the cell cycle by their mis-
the greatest therapeutic value of their inhibition is known incorporation to RNA and DNA or by inhibiting the key en-
for slow-growing cancers. In Table 1, we described the zymes required for nucleic acid synthesis. Among these
common chemotherapeutic alkylating agents including enzymes, DNA polymerases, ribonucleotide reductase, and
the altretamine, chlorambucil, platinum drugs (cisplatin, thymidylate synthetase are the main intracellular targets of
carboplatin, oxaliplatin), doxorubicin, epirubicin, etopo- the pyrimidine antimetabolites. 5-FU has been a promising
side, mitoxantrone, cyclophosphamide, thiotepa, and pyrimidine analog that largely interrupts DNA and RNA
busulfan that are in clinical practice and also provided synthesis. 5-FU that dependents on its incorporation to DNA
details of their molecular targets, mode of action, and inhibits mitosis and stimulates cell death in the dividing
studied model systems in various malignancies/cancer- cells.
types. Vinca alkaloids, primarily extracted from several spe-
cies under the Vinca genus, are mainly cell division in-
hibitors, which can interact with microtubular protein
Antimetabolites tubulin to obstruct its polymerization and meddle with the
cytoskeleton, leading to stalling of mitotic division.104 The
Antimetabolites are the next class of substances that may chromosomes do not separate efficiently during cell divi-
compete, replace, or inhibit some specific metabolites sion, leading to metaphase capture. Vincristine and
inside the cells and thus meddle with the cellular meta- vinblastine are primary examples of this drug class with
bolism (Fig. 2).93 These molecules mostly possess a struc- different degrees and ranges of anti-tumor activity (Table
ture similar to a cellular metabolite or enzymeesubstrate, 1).105,106 Cancers treated with these drugs include acute
usually identified and processed by an enzyme to meet the leukemia, Hodgkin’s and non-Hodgkin’s lymphoma, rhab-
cellular needs.94 Tetrahydrofolates are formed from domyosarcoma, Ewing’s sarcoma, neuroblastoma, Wilms’
unreduced dietary folates by the enzyme dihydrofolate tumor, miscellaneous myeloma, chronic leukemia, thyroid
reductase. For example, various medications, such as cancer, brain tumors, and several blood-related
aminopterin, methotrexate (amethopterin), disorders.107

6
 Table 1 Table listing chemotherapeutic drugs/agents used in current clinical practice along with details of their molecular targets, mode of action, and investigated model
systems across diverse malignancies.
Drugs/Compound Molecular targets Mechanism of action Studied model system Reference/Source
Antineoplastic alkylating agents
278
Altretamine DNA polymerase alpha catalytic Inhibitor B-cell chronic lymphocytic,
subunit Inhibitor leukemia/prolymphocytic
Ribonucleoside-diphosphate Other/unknow leukemia/small lymphocytic
reductase large subunit lymphoma refractory, and
DNA refractory non-Hodgkin’s
lymphoma
279
Bendamustine DNA Intra- and inter-strand crosslinking Chronic lymphocytic leukaemia
(CLL), follicular non-Hodgkin’s
lymphoma refractory, refractory
Hodgkin lymphoma, refractory
Mantle cell lymphoma,
Waldenström’s macroglobulinemia

Genes & Diseases xxx (xxxx) xxx

(WM), recurrent multiple
myeloma, and refractory indolent
B cell non-Hodgkin lymphoma
279
Busulfan DNA Cross-linking/alkylation Chronic myelogenous leukemia

+
279

MODEL
Carboplatin DNA Cross-linking/alkylation Advanced cervical cancer,
advanced Endometrial Cancer,
7

advanced esophageal cancers,

advanced head and neck Cancer,
advanced melanoma, advanced
non-small cell lung cancer,
advanced ovarian carcinoma,
advanced Sarcoma, metastatic
breast cancer, neuroendocrine
carcinoma of the skin, pleural
mesothelioma, refractory Hodgkin
lymphoma, retinoblastoma,
advanced bladder cancer,
advanced small cell lung cancer,
advanced testicular cancer,
advanced thymoma, advanced
thymic carcinoma, and refractory
non-Hodgkin’s lymphoma
280
Carmustine DNA Other/unknown inhibitor Glioblastoma, brainstem glioma,
Glutathione reductase, Other/unknown medulloblastoma, astrocytoma,
mitochondrial ependymoma and metastatic brain
RNA tumors, multiple myeloma,
Hodgkin’s disease, non-Hodgkin’s
(continued on next page)
 Table 1 (continued )
Drugs/Compound Molecular targets Mechanism of action Studied model system Reference/Source
lymphomas, and may be used on
the skin (topically) for cutaneous
T-cell lymphoma
279
Chlorambucil DNA Cross-linking/alkylation Chronic lymphocytic leukemia,
lymphomas, and Hodgkin’s disease
279
Cisplatin DNA Cross-linking/alkylation Testicular cancer, ovarian cancer,
DNA-3-methyladenine glycosylase Not Available bladder cancer, head and neck
Alpha-2-macroglobulin Not Available cancer, esophagus cancer, small
Serotransferrin Not Available cell and non-small cell lung
Copper transport protein ATOX1 Not Available cancer, non-
Hodgkin’s lymphoma and
trophoblastic neoplasms
279

U. Anand, A. Dey, A.K.S. Chandel et al.

Cyclophosphamide DNA Cross-linking/alkylation Lymphoma, multiple myeloma,
Nuclear receptor subfamily 1 Not Available leukemia, ovarian cancer, breast
group I member 2 cancer, small cell lung cancer,
neuroblastoma, and sarcoma.
279
Dacarbazine DNA Cross-linking/alkylation Melanoma skin cancer, soft tissue
DNA polymerase alpha subunit B Other/unknown sarcoma, Hodgkin lymphoma

+
MODEL
6-phosphogluconate Inhibitor
dehydrogenase, decarboxylating
8

279
Daunorubicin DNA Intercalation Acute nonlymphocytic leukemia in
DNA topoisomerase 2-alpha Inhibitor adults and acute lymphocytic
DNA topoisomerase 2-beta Inhibitor leukemia in adults and children
279,281
Decitabine DNA Other/unknown Myelodysplastic syndromes, and
DNA (cytosine-5)- Inhibitor acute myeloid leukemia (AML)
methyltransferase 1 Inhibitor
DNA (cytosine-5)- Inhibitor
methyltransferase 3A
DNA (cytosine-5)-
methyltransferase 3B
279
Doxorubicin DNA Intercalation
DNA topoisomerase 2-alpha Inhibitor
Nucleolar and coiled-body Not available
phosphoprotein 1
279,282
Epirubicin DNA topoisomerase 2-alpha Inhibitor Breast cancer
DNA Intercalation
279
Etoposide DNA topoisomerase 2-alpha inhibitor Testicular cancer, lung cancer,
DNA topoisomerase 2-beta Inhibitor lymphoma, nonlymphocytic
leukemia, neuroblastoma, and
ovarian cancer, Kaposi’s sarcoma,
Ewing’s sarcoma and glioblastoma
 multiforme
279
Idarubicin DNA Intercalation Acute myelogenous, acute
DNA topoisomerase 2-alpha Inhibitor lymphoblastic and chronic
myelogenous
279
Ifosfamide DNA Other/unknown Germ cell testicular cancer, soft
Nuclear receptor subfamily 1 Not available tissue sarcoma, acute lymphocytic
group I member 2 leukemia, bladder cancer, bone
cancer, pancreatic cancer,
stomach cancer, breast cancer,
cervical cancer, endometrial
cancer, lung cancer, ovarian
cancer, neuroblastoma,
lymphoma, and Wilms’ tumor
279
Irinotecan DNA topoisomerase 1, Inhibitor Metastatic colorectal cancer,
DNA topoisomerase I, Inhibitor other colorectal cancers and non-
mitochondrial small/small lung cancers
279

Genes & Diseases xxx (xxxx) xxx

Lomustine DNA Cross-linking/alkylation Metastatic brain tumors,
Stathmin-4 Antagonist Hodgkin’s and non-Hodgkin’s
lymphoma
283
Mechlorethamine DNA Intercalation Hodgkin’s disease, chronic

+
lymphocytic leukemia, chronic

MODEL
myelogenous leukemia, small cell
9

lung cancer, medulloblastoma,

and non-Hodgkin’s lymphoma
284
Melphalan DNA Cross-linking/alkylation Multiple myeloma, ovarian cancer,
breast cancer, melanoma, and
amyloidosis
279
Mitomycin C DNA Cross-linking/alkylation Gastric cancer, anal and colon
cancer, breast cancer, non-small
cell lung cancer, head and neck
cancer, small bladder papillomas,
pancreatic cancer, cervical cancer
285
Mitoxantrone DNA Intercalation Advanced, hormone-refractory
DNA topoisomerase 2-alpha Inhibitor prostate cancer, acute
nonlymphocytic leukemia (ANLL),
breast cancer and non-Hodgkin’s
lymphoma.
286
Oxaliplatin DNA Cross-linking/alkylation Metastatic or recurrent colorectal
cancer, metastatic pancreatic
cancer and metastatic gastric
cancer.
287
Temozolomide DNA Cross-linking/alkylation Brain tumors (astrocytomas) in
adult patients,
metastatic melanoma and
(continued on next page)
 Table 1 (continued )
Drugs/Compound Molecular targets Mechanism of action Studied model system Reference/Source
glioblastoma multiforme
288
Topotecan DNA topoisomerase 1 Inhibitor Ovarian cancer, small cell lung
DNA topoisomerase I, Inhibitor cancer, and certain types of
mitochondrial DNA Intercalation cervical cancer
289
Thiotepa DNA Cross-linking/alkylation Adenocarcinoma of the breast,
adenocarcinoma of the ovary,
papillary thyroid cancer and
bladder cancer, Hodgkin’s and
non-Hodgkin’s lymphomas
290
Trabectedin DNA Binder Soft tissue sarcoma, and ovarian
cancer
Antineoplastic antimetabolites
291

U. Anand, A. Dey, A.K.S. Chandel et al.

Azathioprine Ras-related C3 botulinum toxin Modulator Leukemia and lymphomas
substrate 1
292
Cladribine Ribonucleoside-diphosphate Inhibitor Drug-resistant T-cell
reductase large subunit Inhibitor prolymphocytic leukemia
Ribonucleoside-diphosphate Inhibitor
reductase subunit M2 Other/unknown

+
MODEL
Ribonucleoside-diphosphate Inhibitor
10

reductase subunit M2 B Inhibitor

DNA Inhibitor
DNA polymerase alpha catalytic Inhibitor
subunit Inhibitor
DNA polymerase epsilon catalytic Inducer
subunit A
DNA polymerase epsilon subunit 2
DNA polymerase epsilon subunit 3
DNA polymerase epsilon subunit 4
Purine nucleoside phosphorylase
293
Clofarabine DNA polymerase alpha catalytic Inhibitor Relapsed or refractory acute
subunit Inhibitor lymphoblastic leukaemia, acute
Ribonucleoside-diphosphate Other/unknown myeloid leukaemia, juvenile
reductase large subunit myelomonocytic leukaemia, and
DNA myelodysplastic syndrome
294
Fludarabine Ribonucleoside-diphosphate Inhibitor Chronic lymphocytic leukemia,
reductase large subunit Inhibitor non-Hodgkin’s lymphoma, acute
DNA polymerase alpha catalytic Incorporation into and myeloid leukemia, and acute
subunit destabilization lymphocytic leukemia
DNA Agonist
Deoxycytidine kinase
295
Gemcitabine DNA Cross-linking/alkylation Breast cancer, ovarian cancer,
 Ribonucleoside-diphosphate Inhibitor non-small cell lung cancer,
reductase large subunit Inhibitor pancreatic cancer and bladder
Thymidylate synthase Inhibitor cancer
UMP-CMP kinase
296
Mercaptopurine Hypoxanthine-guanine Inhibitor Acute lymphocytic leukemia
phosphoribosyltransferase Inhibitor (ALL), chronic myeloid leukemia
Amidophosphoribosyltransferase Inhibitor (CML), Crohn’s disease and
Inosine-50 -monophosphate ulcerative colitis.
dehydrogenase
297
Nelarabine DNA Incorporation into and Acute T-cell lymphoblastic
DNA polymerase alpha catalytic destabilization leukemia
subunit Inhibitor
298
Pentostatin Adenosine deaminase inhibitor Hairy cell leukaemia refractory to
alpha interferon
299
Tioguanine DNA Intercalation Acute leukemia
Pyrimidine-derived antimetabolites (pyrimidine antagonists)
99

Genes & Diseases xxx (xxxx) xxx

Capecitabine Thymidylate synthase DNA Inhibitor Metastatic breast, gastric and
RNA Incorporation into and colorectal cancers
destabilization
Incorporation into and

+
destabilization

MODEL
97
Cytarabine DNA polymerase beta Inhibitor Acute myeloid leukemia (AML),
11

DNA Cross-linking/alkylation acute lymphocytic leukemia (ALL),

chronic myelogenous leukemia
(CML) and non-Hodgkin’s
lymphoma
101
Decitabine DNA Other/unknown Myelodysplastic syndromes (MDS)
DNA (cytosine-5)- Inhibitor
methyltransferase 1 Inhibitor
DNA (cytosine-5)- Inhibitor
methyltransferase 3A
DNA (cytosine-5)-
methyltransferase 3B
100
Gemcitabine DNA Cross-linking/alkylation Metastatic ovarian cancer,
Ribonucleoside-diphosphate Inhibitor metastatic non-small cell lung
reductase large subunit Inhibitor cancer, and metastatic pancreatic
Thymidylate synthase Inhibitor adenocarcinoma
UMP-CMP kinase
98
Fluorouracil Thymidylate synthase Other/unknown Actinic keratosis (AK), breast
DNA Incorporation into and cancer, malignant neoplasm of
RNA destabilization colon, malignant neoplasm of
Incorporation into and pancreas, malignant neoplasm of
destabilization stomach, rectal carcinoma,
superficial basal cell carcinoma,
(continued on next page)
 Table 1 (continued )
Drugs/Compound Molecular targets Mechanism of action Studied model system Reference/Source
and hyperkeratotic actinic
keratosis
102
Raltitrexed Thymidylate synthase Inhibitor Advanced Colorectal Cancer,
Folylpolyglutamate synthase, Antagonist Pleural Mesotheliomas
mitochondrial
103
Tegafur Thymidylate synthase Inhibitor Advanced Gastric Cancer
Other antineoplastic agents (belong to one or multiple drug classes)
300
Arsenic trioxide (Trisenox) Inhibitor of nuclear factor Kappa-B Inducer Refractory Acute Promyelocytic
kinase subunit beta Inhibitor Leukemia
Thioredoxin reductase 1, Inducer
cytoplasmic Antagonist
Transcription factor AP-1 Inducer

U. Anand, A. Dey, A.K.S. Chandel et al.

G1/S-specific cyclin-D1 Inducer
Mitogen-activated protein kinase 3 Inducer
Mitogen-activated protein kinase 1 Not available
inducer Not available
RAC-alpha serine/threonine- Not available
protein kinase

+
MODEL
Cyclin-dependent kinase inhibitor
12

1
Histone deacetylase 1
Protein PML
301
Hydroxyurea Ribonucleoside-diphosphate Inhibitor Melanoma, resistant chronic
reductase large subunit myelocytic leukemia, and
recurrent, metastatic, or
inoperable carcinoma of the ovary
and Sickle-cell anemia
302
Paclitaxel (Taxol) Tubulin beta-1 chain Inhibitor Kaposi’s sarcoma and cancer of
Apoptosis regulator Bcl-2 Inhibitor the lung, ovarian, and breast
Microtubule-associated protein 4 Not Available
Microtubule-associated protein 2 Not Available
Microtubule-associated protein Not Available
tau Inducer
Nuclear receptor subfamily 1
group I member 2
303
Docetaxel (Taxotere) Tubulin beta-1 chain Not available Locally advanced or metastatic
Apoptosis regulator Bcl-2 Not available breast cancer, locally advanced or
Microtubule-associated protein 2 Not available metastatic non-small cell lung
Microtubule-associated protein 4 Not available cancer, hormone refractory
Microtubule-associated protein Not available metastatic prostate cancer,
tau Binder gastric adenocarcinoma and head
 Nuclear receptor subfamily 1 and neck cancer
group I member 2
279
Ixabepilone (Ixempra) Tubulin beta-3 chain Inhibitor Breast cancer, head and neck
cancer, melanoma, lung cancer,
non-Hodgkin’s lymphoma,
prostate cancer, renal cell
carcinoma
304
Methotrexate Dihydrofolate reductase Inhibitor Pediatric acute lymphoblastic
Humans Inhibitor leukemia, gestational
Thymidylate synthase Inhibitor choriocarcinoma, chorioadenoma
Bifunctional purine biosynthesis destruens, breast cancer,
protein PURH epidermoid cancer of the head
and neck, lung cancer, and
advanced non-Hodgkin’s
lymphoma
305
Pemetrexed (Alimta) Thymidylate synthase Inhibitor Malignant pleural mesothelioma,

Genes & Diseases xxx (xxxx) xxx

Bifunctional purine biosynthesis Inhibitor and metastatic non-small cell lung
protein PURH Inhibitor cancer (NSCLC)
Dihydrofolate reductase Inhibitor
Trifunctional purine biosynthetic

+
protein adenosine-3

MODEL
306
Streptozocin DNA Cross-linking/alkylation Malignant neoplasms of pancreas
13

Solute carrier family 2, facilitated Ligand

glucose transporter member 2 Antagonist
O-GlcNAcase BT_4395 Not available
Bifunctional protein NCOAT
307
Vinblastine Tubulin alpha-1A chain Adduct Breast cancer, testicular cancer,
Tubulin beta chain Adduct lymphomas, neuroblastoma,
Tubulin delta chain Adduct Hodgkin’s and non-Hodgkin’s
Tubulin gamma-1 chain Adduct lymphomas and Kaposi’s sarcoma
Tubulin epsilon Adduct
Transcription factor AP-1 Other/unknown
308
Vincristine Tubulin beta-1 chain Inhibitor Acute lymphocytic leukemia
(ALL), Hodgkin lymphoma, non-
Hodgkin’s lymphomas, Wilms’
tumor, neuroblastoma,
rhabdomyosarcoma, relapsed
Philadelphia chromosome-
negative (Ph-) acute lymphoblastic
leukemia (ALL)
309
Vindesine Tubulin beta-1 chain Inhibitor Acute leukaemia, malignant
lymphoma, Hodgkin’s disease
310
Vinorelbine Tubulin beta chain Antagonist inhibitor Advanced non-small cell lung
cancer (NSCLC), relapsed or
(continued on next page)
 + MODEL
U. Anand, A. Dey, A.K.S. Chandel et al.

Other antineoplastic drugs/agents

Reference/Source
Besides these three established classes, several other
antineoplastic agents are also enrolled in the clinical
practice of cancer chemotherapy (Table 1). Given their
clinical promises, in the subsequent section, we described
the biological activities, targets, and mechanisms of key
chemotherapeutic drugs that may belong to one or multiple
drug classes and can affect more than one cellular pathway
ovarian cancer, metastatic breast

in the cancer cells and induce apoptosis by different

metastatic squamous cell head

mechanisms (Fig. 2). A succinct review of well-known anti-

refractory Hodgkin lymphoma,

cancer drugs that are in routine clinical practice is provided

and neck cancer, recurrent

as follows.
Studied model system

Paclitaxel/Taxol
cancer

It is a complex diterpene taxane ring-containing drug ac-

quired from the bark of the Western yew tree (Taxus bre-
vifolia), which induces cytotoxic activity by a novel
system.108 It increases the polymerization of tubulin,
thereby inducing a mechanism inverse to that of the
aforementioned alkaloids.109 It forestalls the microtubule’s
structural adjustment and depolymerization, bringing an
inherent cytotoxic activity to the paclitaxel due to the
significance of tubulin-microtubule dynamics.110 The
confirmed antagonistic impacts of paclitaxel are reported
Mechanism of action

on the metastatic ovarian and bosom carcinomas after the

disappointment from first-line chemotherapy and backslide
cases.111 It has also shown efficacy against the advanced
stage tumors of the head and neck disease, small cell lung
cancer, oesophageal adenocarcinoma, and prostate cancer
(Table 1).112,113 Docetaxel is a more potent relative of
paclitaxel with a comparable activity. It has been shown to
provide benefits against the bosom and ovarian cancers,
which get resistant to first-line chemotherapeutic drugs.114
Unfortunately, many side effects have been reported from
the long exposure to these drugs, which mainly include
neutropenia, arrhythmia, neuropathy, and cardiovascular
breakdown (Table 2).115,116
Molecular targets

Etoposide

Etoposide is a semi-synthetic derivative of a plant glyco-

side called podophyllotoxin.117,118 It causes DNA damage
by altering DNA topoisomerase-II function, and posing G2
cell cycle arrest.119 Etoposide creates a ternary complex
with DNA and the topoisomeraseeII complex, preventing
the latter’s binding to the DNA strands, while in doing so,
it causes damage to DNA strands.120 Cancer cells depend
on this enzyme more than healthy cells, as they divide
Table 1 (continued )

more quickly; therefore, it causes defects in DNA syn-

Drugs/Compound

thesis that promotes apoptosis of the cancer cells.121

Etoposide is effective against several aggressive malig-
nancies including Kaposi’s sarcoma, Ewing’s sarcoma,
testicular disease, lung disease, lymphoma, non-
lymphocytic leukemia, and glioblastoma multiforme
(Table 1).122

14
 Table 2 Table listing the adverse effects of various chemotherapy drugs, affected organs, their reported toxicities/side effects and current stage of their clinical progresses.
Drugs/Compound Affected organ Reported toxicity/side effects Current status Reference/Sources
(frequency in >30% cases)
Alkylating agents/drugs
278
Altretamine Blood Nausea and vomiting, Low blood counts, Approved
Peripheral neuropathy
311,312
Bendamustine Blood Low blood counts, Increase in bilirubin Approved, Investigational
levels
313,314
Busulfan Blood Low blood counts, Nausea and vomiting Approved, Investigational
(usually mild with standard doses), Loss
of fertility, Diarrhea (usually mild with
standard doses), Poor appetite, Mouth
sores
315
Carboplatin Cervix, skin, endometrium, Low blood counts, Nausea and vomiting, Approved
esophagus, head and neck, Taste changes, Hair loss, Weakness,
lung, bladder, thymus, Blood test abnormalities, abnormal

Genes & Diseases xxx (xxxx) xxx

mesothelium, testicle magnesium level
280
Carmustine Brain, skin Nausea and vomiting, Facial flushing, Approved, Investigational
Pain and burning at the injection site,
Low blood counts

+
316,317

MODEL
Chlorambucil Blood Low blood counts Approved
318,319
15

Cisplatin Testicle, ovary, head-neck, Nausea and vomiting, Low blood counts, Approved
lung, blood, esophagus, Kidney toxicity, Ototoxicity, Blood test
trophoblast abnormalities (low magnesium, low
calcium, low potassium)
320
Cyclophosphamide Blood, ovarian, breast, lung, Low blood counts, Hair loss, Nausea and Approved, Investigational
brain vomiting, Poor appetite, Discoloration of
the skin or nails
321,322
Dacarbazine Skin, blood Local pain, burning sensation and Approved, Investigational
irritation at the needle site during the
infusion, Low blood counts, Nausea and
vomiting, Poor appetite, Elevation of
blood liver enzymes
323,324
Daunorubicin Blood Pain along the site where the medication Approved
was given, Urine may appear red, red-
brown, orange or pink from the color of
the medication for one to two days after
you receive a dose, Low blood counts,
Nausea or vomiting, Hair loss on the
scalp or elsewhere on the body
325
Decitabine Blood Low blood counts, Fatigue, Fever, Approved, Investigational
Nausea, Cough, Petechiae, Diarrhea,
Constipation, Hyperglycemia
(continued on next page)
 Table 2 (continued )
Drugs/Compound Affected organ Reported toxicity/side effects Current status Reference/Sources
(frequency in >30% cases)
326,327
Doxorubicin Blood, breast, ovarian, Pain along the site where the medication Approved, Investigational
bladder, stomach, bronchus was given, Nausea or vomiting, Low
blood counts, Hair loss on the scalp or
elsewhere on the body
321,328
Epirubicin Breast Low blood counts, Mouth sores, Hair loss Approved
on the scalp or elsewhere on the body,
Nausea and vomiting, Fatigue,
Amenorrhea
122
Etoposide Testicle, lung, blood, brain, Low white blood cell count, Low Approved
ovarian platelet, Hair loss, Menopause, Loss of
fertility, Nausea and vomiting
329

U. Anand, A. Dey, A.K.S. Chandel et al.

Idarubicin Blood Pain along the site where the medication Approved
was given, Low blood counts, Urine may
appear red, red-brown, orange or pink
from the color of the medication for one
to two days after you receive a dose,
Nausea or vomiting, Mouth sores (in the

+
MODEL
first week after therapy), Hair loss on the
16

scalp or elsewhere on the body,

Diarrhea/abdominal cramps
330
Ifosfamide Testicle, blood, bladder, bone, Low white blood cell count, Low platelet Approved
pancreas, cervix, breast, count, Hair loss, Nausea and vomiting,
stomach, breast, Poor appetite, Blood in the urine
endometrium, lung, ovary
331
Irinotecan Colon, lung Diarrhea; two types early and late forms, Approved, Investigational
Early diarrhea accompanied by
symptoms runny nose, increased
salivation, watery eyes, sweating, Fever,
flushing, abdominal cramping, Late
diarrhea, Nausea and vomiting,
Weakness, Low white blood cell count,
Low red blood cell count, Hair loss, Poor
appetite, Weight loss
332
Lomustine Brain, blood Low blood counts (bone marrow Approved, Investigational
suppression), Nausea and vomiting
15
Mechlorethamine Blood, lung, brain Low blood counts, Nausea and vomiting, Approved, Investigational
or Hair loss, Mouth sores, Redness, dryness,
Chlormethine irritation with topical use, Loss of
fertility
333
Melphalan Blood, ovary, breast, skin Low blood counts, Nausea and vomiting Approved
 137
Mitomycin C Stomach, intestine, breast, Low blood counts, Mouth sores, Poor Approved
lung, bladder, pancreas, appetite, Fatigue
crevice
334
Mitoxantrone Prostate, blood, breast Low blood counts, Nausea and vomiting, Approved, Investigational
Fever, increases in blood tests measuring
liver function
335,336
Oxaliplatin Intestine, pancreas, stomach Peripheral neuropathy, Nausea and Approved, Investigational
vomiting, Diarrhea, Mouth sores, Low
blood counts, Fatigue, Loss of appetite
337
Temozolomide Brain, skin Nausea and vomiting, Constipation, Approved, Investigational
Headache, Fatigue
338e340
Topotecan Ovary, lung, cervice Low blood counts, Nausea and vomiting, Approved, Investigational
Hair loss, Diarrhea
341
Thiotepa Breast, ovary, thyroid, bladder Low blood counts, Hair loss Approved, Investigational
342,290
Trabectedin Ovary Anemia, Increased liver enzymes, Low Approved, Investigational
white blood cell count, Nausea, Low

Genes & Diseases xxx (xxxx) xxx

platelets, Vomiting, Fatigue, Low
potassium, Low phosphorous, Decreased
appetite, Constipation, Increased CPK
Purine antimetabolites (purine antagonists)

+
291
Azathioprine Blood Black, tarry stools, Bleeding gums, Blood Approved

MODEL
in the urine or stools, Chest pain, Chills,
17

Cough, Fever, Hoarseness, Lower back or

side pain, Painful or difficult urination,
Pinpoint red spots on the skin, Sore
throat, Sores, ulcers, or white spots on
the lips or in the mouth, Swollen glands,
unusual bleeding or bruising, unusual
tiredness or weakness
343
Cladribine Blood Fever, Fatigue, Low white blood cell Approved, Investigational
count, Low red blood cell count,
Neutropenic fever, Myelosuppression
293,344
Clofarabine Blood Leukopenia, Anemia, Infection, Limb Approved, Investigational
pain, Lymphopenia, Low platelet count,
Elevated liver enzymes, Vomiting,
Nausea, Itching, Neutropenia, Diarrhea,
Neutropenic fever, Creatinine increased,
Bilirubin increased, Chills, Headache,
Fever, Rash, High heart rate, Abdominal
pain, Fatigue, Decreased appetite
294
Fludarabine Blood Low blood counts, Fever, Infection, Approved
Weakness, Cough, Nausea and vomiting,
Poor appetite
295
Gemcitabine Breast, ovary, lung, pancreas, Flu-like symptoms (muscle pain, fever, Approved, Investigational
(continued on next page)
 Table 2 (continued )
Drugs/Compound Affected organ Reported toxicity/side effects Current status Reference/Sources
(frequency in >30% cases)
bladder headache, chills, fatigue), Fever (within
6e12 h of first dose), Fatigue, Nausea
(mild), Vomiting, Poor appetite, Skin
rash, Low blood counts, Temporary
increases in liver enzymes, Blood or
protein in the urine
345
Mercaptopurine Blood, intestine Low blood counts, Liver toxicity, Approved
Increased bilirubin, Increased liver
enzymes, jaundice, abdominal swelling
(ascites)
297
Nelarabine Blood Low blood counts, also known as bone Approved, Investigational

U. Anand, A. Dey, A.K.S. Chandel et al.

marrow suppression (anemia, Fatigue,
neutropenia, thrombocytopenia),
Nausea
346
Pentostatin Blood Cough or hoarseness, Fever or chills, Approved, Investigational
Lower back or side pain, Painful or
difficult urination, Skin rash or itching

+
MODEL
(sudden), Unusual tiredness or weakness
18

347
Thioguanine Blood Low blood counts Approved
Pyrimidine antimetabolites (pyrimidine antagonists)
99
Capecitabine Breast, stomach, intestine Low white blood cell count, Low red Approved, Investigational
blood cell count, Hand-foot syndrome,
Diarrhea, Elevated liver enzymes,
Fatigue, Nausea and vomiting, Rash and
itching, Abdominal pain
97
Cytarabine Blood Headache, Low blood counts, nausea Approved, Investigational
and vomiting, Mouth sores, increases in
blood tests measuring liver function
348,349
Gemcitabine Breast, ovarian, lung, Flu-like, Fever, Fatigue, Nausea, Approved
pancreas, bladder Vomiting, Poor appetite, Skin rash, Low
blood counts, Temporary increases in
liver enzymes, Blood or protein in the
urine
98
Fluorouracil Breast, colon, pancreas, skin, Diarrhea, Nausea and possible occasional Approved
stomach, rectal vomiting, Mouth sores, Poor appetite,
Watery eyes, sensitivity to light, Taste
changes, metallic taste in mouth during
infusion, Low blood counts, white and
red blood cells and platelets may
temporarily decrease, Skin reactions,
 Hair thinning, Hand -foot syndrome
102
Raltitrexed Colon, mesothelium Increased risk of infection, Approved, Investigational
Breathlessness and looking pale,
Tiredness and weakness during and after
treatment, Diarrhoea or constipation,
Feeling or being sick, Skin problems,
Mouth sores and ulcers, Tummy
(abdominal) pain, Liver changes, Loss of
appetite and weight loss, Dehydration
350
Tegafur Stomach Myelosuppression, Central neurotoxicity, Approved, Investigational
Gastrointestinal toxicity
Other antineoplastic agents (belong to one or multiple drug classes)
351,352
Arsenic trioxide Blood Nausea and vomiting, Cough, Fatigue, Approved
(Trisenox) Fever, Headache, Rapid heartbeat, Sore
throat, Abdominal pain, Diarrhea, Blood
test abnormalities (low potassium and

Genes & Diseases xxx (xxxx) xxx

magnesium), Shortness of breath,
Blurred vision and eye irritation,
elevated blood sugar level, swelling of
the face, hands, feet or legs, Difficulty

+
sleeping, Rash, Heart rhythm changes,

MODEL
Joint pain, Itching, Numbness or tingling
19

of hands or feet
301
Hydroxyurea Skin, blood, ovary, breast Low blood counts Approved
353
Paclitaxel Bone, lung, ovary, breast Low blood counts, Hair loss, Arthralgias Approved, Vet Approved
(Taxol) and myalgias, pain in the joints and
muscles, Peripheral neuropathy, Nausea
and vomiting, Diarrhea, Mouth sores,
Hypersensitivity reaction
296
Docetaxel Breast, lung, prostate, stomach Low white blood cell count, Low red Approved, Investigational
(Taxotere) blood cell count, Fluid retention with
weight gain, swelling of the ankles or
abdominal area, Peripheral neuropathy,
Nausea, Diarrhea, Mouth sores, Hair loss,
Fatigue and weakness, Infection, Nail
changes
354
Ixabepilone Breast, skin, lung, blood, Peripheral neuropathy, Weakness, Approved, Investigational
(Ixempra) prostate, kidney Muscle and joint pains, Hair loss, Nausea
and Vomiting, Low white blood cell
count
355
Methotrexate Blood, breast chromium Dizziness, Drowsiness, Headache, Hair Approved
Loss, Swollen, Tender Gums Decreased
Appetite, Reddened Eyes
305
Pemetrexed Pleura, lung Fatigue, Nausea Approved, Investigational
(continued on next page)
 + MODEL
U. Anand, A. Dey, A.K.S. Chandel et al.

Camptothecin and its derivatives

Reference/Sources
Camptothecin is a long-known topoisomerase inhibitory
compound of natural origin. It was initially extracted from
the bark of the tree Camptotheca acuminata.123,124

359,360
Camptothecin is a cytotoxic alkaloid comprised of a pen-
tacyclic ring structure containing a pyrrole (3,4-b) quinoline
356

307

357

358
moiety, an S-configured alpha-hydroxy lactone form, and a
carboxylate form.125 In later years, many more effective
derivatives of this topoisomerase inhibitor have been syn-
thesized and are effectively being applied in cancer
Approved, Investigational

Approved, Investigational

Approved, Investigational

Approved, Investigational
chemotherapy.126 The most recognized drug of this class,
topotecan, is used against the advanced cancers of the
ovary and lung. It targets topoisomerase-I, an enzyme
responsible for easing the torsional strain in DNA by
Current status

inducing single-strand breaks during replication.120 The in-

Approved

hibition of topoisomerase-I by the active compounds may

lead to sudden inhibition of DNA replication and transcrip-
tion, causing growth arrest (Table 1).127 In the physiological
conditions, topotecan remains in equilibrium with its
carboxylate structure.128 Its active lactone can intercalate
between DNA bases in the topoisomerase-I cleavage com-
plex.129 The coupling site of topotecan in the cleavage
complex interferes with the topoisomerase-I while reiter-
Low blood counts, Nausea or vomiting,
Nausea and vomiting, Nephrotoxicity

ating the scratched DNA strand in the wake of releasing the

Hair loss, neurotoxicity, alopecia,

strain. Such intercalation traps the topoisomerase-I in the

reactions, Fatigue and weakness
Low blood counts, Injection site

Myelosuppression, Neurotoxicity

cleavage complex bound to the DNA.130 Another well-

Muscle weakness, Constipation
Reported toxicity/side effects

known drug of this class is irinotecan that has shown effi-

(frequency in >30% cases)

cacy against late-stage colorectal carcinoma, aggressive

growths in cancers of the lung, cervix, ovary, colon,
etc.131,132
myelosuppression

Actinomycin D (dactinomycin)

A transcription inhibitor chromopeptide molecule actino-

mycin D (also called dactinomycin) binds to DNA while
initiating transcription at initiation complex and inhibits
RNA elongation steps.133 It can intercalate, preferably be-
tween guanidine and cytosine, or bind the DNA strand’s
minor grooves to form a highly stable drug-DNA complex,
Breast, blood, testicle, bone

preventing DNA unwinding and thus stalling the progress of

Lung, blood, ovary, breast

the RNA chain.134 Dactinomycin was initially obtained from

Streptomyces sp., identified as an antibiotic agent, but
later its anti-tumor potential was recognized, and thus it
was inducted in the chemotherapy as an anticancer anti-
Affected organ

biotic to treat Ewing’s sarcoma, Wilms’ tumor, rhabdo-

myosarcoma, trophoblastic neoplasm, testicular and
ovarian cancers, etc (Table 1).135
Pancreas

Blood

Blood

Mitomycin C

Mitomycins, a class of natural quinones, are also derived

from Streptomyces caespitosus and are known for their
Table 2 (continued )

Streptozotocin

transformation and competence, enhancing potential in

Drugs/Compound

Streptozocin or

bacterial cells. It is also a known antineoplastic agent as it

(Alimta)

Vindesine or

slows down fibroblast cell growth in glaucoma.136,137

Vinorelbine
Vinblastine

Eldisine
Vincristine

These bioreductive alkylating agents (especially mito-

mycin C derivatives) are also utilized as anti-cancer
therapeutics because their structural modification im-
pedes the cell cycle during G1 and S phase transitions. Its

20
 + MODEL
Genes & Diseases xxx (xxxx) xxx

reduction to form mitosene can lead to the N-alkylation of colorectal, oesophageal, pancreatic, and cervical origins.
DNA bases.138 It can lead to inhibition of replication by Porfiromycin is an N-methyl derivative of mitomycin C that
cross-linking at adenine N6 and guanine O6 and N2.139 It is is found effective against cancer of head and neck regions
effectively used in the palliative treatment of non-small (Table 1).140
cell lung carcinoma and other solid tumors of breast,

Figure 3 Schematic diagram showing targeted cancer therapeutic approaches. (A) Model showing targeted drug delivery
approach of anti-cancer drugs/chemical agents conjugated with receptor substrate specific to the cancer cell receptor. (B) Model
showing the building of a personalized medicine approach based on omics data and drug response study targeting specific muta-
tion/signature in individual patients for precision cancer therapeutics. (C) Model showing immunotherapeutic regime involving
reprogramming of T-cells to target cancer cells by a chimeric antigen receptor for their application in cancer immunotherapy.

21
 + MODEL
U. Anand, A. Dey, A.K.S. Chandel et al.

Daunorubicin (rubidomycin) Lateral damage: Putting multiple organs at risk

Daunorubicin causes a break in DNA strands by actuating Aggressive tumors are primarily marked with uncontrolled
topoisomerase-II and producing quinone-type free radicals. and extensive cell division that may compromise the normal
Daunorubicin, otherwise called daunomycin, is a chemo- physiology of other non-transformed cells in the vicinity of
therapy medicine used to treat cancer growth in acute affected organs/tissues. In many ways, cancer cells achieve
myeloid leukemia (AML), acute lymphocytic leukemia super-specialized metabolic and survival potential with the
(ALL), chronic myelogenous leukemia (CML), and Kaposi’s capacity to tolerate extreme stresses like low oxygen and
sarcoma, etc.141,142 It is applied by infusion into a vein, and nutrient supplies. Cancers might start from mutation of one
following its intercalation with DNA, it hinders macromo- type or the other, but as the disease progresses,149,150
lecular biosynthesis. This predominantly obstructs the multiple mutations and genetic abnormalities accumulate
movement of the enzyme topoisomerase-II, which loosens that lead to increased tumor heterogeneity.87 The hetero-
up the DNA supercoiling.143 Daunorubicin impedes the geneous nature of tumor mass plays a vital role in devel-
topoisomeraseeII complex after it unties the DNA chain for oping resistance against most of the drugs that we have
replication and thereby it represses the DNA double helix described here. This leads to a challenge of its kind, leaving
from resealing and therefore interferes with the replication doctors with the only option of changing the medication
to proceed (Table 1).144,145 after certain intervals as one type of drug stops acting
against tumors. In many cases, the combination therapy
that includes more than one drug at a time could be an
effective strategy against some form/type of cancers, such
Bleomycin as cancers affecting bone marrow (leukemia) and lymph
nodes (lymphoma). Clinical trials help a lot in understand-
Another Streptomyces compound with anti-tumor activity ing the effects of new combinations and thus have rapidly
bleomycin is mostly used against Hodgkin’s lymphoma, improved the cancer chemotherapy paradigm.
ovarian and testicular cancers. It chelates copper or iron, The sustainability of chemotherapy relies upon its
produces superoxide radicals, and intercalates between continuous effect on cell division and tumor growth. As
DNA strands e causes chain scission.146 Emerging evidence discussed above, the majority of the treatments work by
proposes that bleomycin also hinders the consolidation of compromising the stability or integrity of nucleic acids that
thymidine into DNA strands, and the cleavage of DNA relies tend to stall the cell cycle or activate programmed cell
upon oxygen and metal particles in vitro.147 The specific death pathways. Other drugs may act by generating
mechanism of DNA strand scission is uncertain, yet it has extreme proteotoxic stress inside the cells by interfering
been proposed that bleomycin chelates metal particles with the protein folding or degradation machinery,
(principally iron), delivering a pseudoenzyme that responds including chaperone, proteasome, and autophagy.151e154
with oxygen to create superoxide and hydroxide free radi- The idea is to generate cellular stresses so that the can-
cals that divide DNA; however, little myelosuppression is cer cells that are already under compromised physiology
the unique highlight.148 The drug has also been effective may die while other cells can survive. However, it is evident
against squamous cell carcinoma of the skin, and cancers of from the above descriptions that most of these drugs act by
the mouth, head, neck, genitourinary tract, and throat interfering with one or multiple cellular pathways of
(Table 1).

Figure 4 Advantages of antimicrobial peptides as anti-tumor agents.

22
 + MODEL
Genes & Diseases xxx (xxxx) xxx

extreme importance.155 Therefore, chemotherapeutic makeup, other medication, and environmental factors
drugs are mostly referred to as cytotoxic agents, causing a (Table 2).174 Despite enormous toxicities and side effects
plethora of side effects. In most cases, long-term treat- prevalent in the public domain, the chemotherapy medi-
ments may lead to enormous toxicity causing severe dam- cines remained the most immediate and viable therapeutic
age or failure of multiple organs. This may lead to option in most cases, where we can see the cancer cells but
enormous physiological and psychological stress to the pa- cannot remove them through surgery or source of radiation.
tients under chemotherapeutic medication. Table 2 sum- To address various above-described detrimental physical
marizes the adverse effects of various chemotherapeutic and psychological changes, modern-day clinical practices
agents and the current stage of their clinical progress. The involve a comprehensive team of doctors and specialists for
side effects of these drugs may depend on many factors and the patients who are undergoing long-term treatments and
variables, such as type, stage, and location of the tumor, are more prone to develop severe physiological
along with age, health, and other clinical aspects of the complications.
patients. The most common and readily visible side effects
originate from the gut that may lead to nausea, vomiting,
constipation, and diarrhea.156,157 Most of the anticancer Recent advancements and next-generation
drugs can directly interrupt the cell division pathways; therapeutic approaches
therefore, the first line of affected organs may also include
those which are formed with continuously dividing cells, Since the early 19th century, rigorous investigations and
such as skin, hair, and intestinal linings.158,148 Skin rashes, clinical studies were carried out around the world. Several
alopecia, and mucositis are the most visible side effects research groups have made landmark discoveries during
that one can observe in patients undergoing chemo- and after the Second World War. Following the develop-
therapy.157,159 Radiation also contributes significantly to ment of a fundamental description of the disease and
these debilitating changes. A general problem observed in associated pathways, the focus shifted majorly towards
many patients is fatigue that can occur due to multiple advancing the diagnosis and treatment methods of the
factors, including depression, anemia, high doses of radia- disease. Despite enormous progress being made in the
tion therapy, etc.160 second half of the last century, not much could have been
Chemotherapeutic drugs may also directly injure the achieved in successfully curing most of the cancers. One
bone marrow and cause a steep decline in blood cell count, primary reason behind the failures is our inability to di-
exposing patients to several other types of possible in- agnose the oncogenic changes inside the body at the early
fections.161 Thrombocytopenia, a condition of excessive stages of cancer development. In recent years, the concept
bleeding because of lower platelet numbers, is observed of liquid biopsies has emerged that primarily relies on the
more frequently in patients taking alkylating and/or anti- screening of mutated DNAs, proteins, RNAs, and other ge-
metabolites agents.162 Alkylating agents may further trigger netic markers in the patient’s blood samples.175e177 This
conditions, such as hemorrhagic cystitis leading to micro- practice can help diagnose the disease at a much earlier
scopic haematuria, nocturia, dysuria, etc. along with mild stage than we do now, using the traditional tissue biopsies
or intense suprapubic pain.163 Whereas, antimetabolites and imaging methods.178 New technological tools, like
can generate enormous toxicity in vital organs, like the advanced software and robotic platforms, have also
liver and kidneys.164,165 The most devastating of all is their speeded cancer diagnosis and treatment. In this subsequent
direct impact on cardiovascular health. Different classes of section taking chemotherapy into account, we compres-
chemotherapeutic drugs have varying impacts on cardiac sively reviewed the recent progress made in the targeted
cells, leading to multiple types of systemic conditions drug delivery, personalized medication, and immuno-
adversely affecting patients’ survival.166 Loss of libido and therapy (Fig. 3).
sexual dysfunctions are other conditions caused due to
long-term exposure to these drugs, which affects not only
physical well-being but also the patient’s psychological Targeted drug delivery
health (Table 2).167,168
These drugs and radiation therapies may have several The major drawback of most chemotherapeutic treatment
direct or indirect impacts on cognitive functioning leading plans is their non-specificity or inability to ascertain and
to a condition, which is now commonly referred to as target cancerous cells directly. Therefore, this lack of
chemo brain.169,170 This is a condition of the inability of specificity poses a major therapeutic limit reflected in the
someone undergoing chemo-drug therapies to do their failure of delivering drugs locally to the cancer tissue mass.
routine cognitive functions, which may be related to their In the past few decades, many new approaches have been
memory, cognition, and behavior.171 The drugs may constituted and tested, and have given hopes for future
adversely impact communication, reasoning, learning, drug delivery (Fig. 3A). Nanoparticle-based delivery
problem-solving, memory storage, concentration, following methods, targeted antibodies, aptamer functionalization,
commands, etc. Damage of optic and the ocular motor and specific drugs like Herceptin (in breast cancer) offered
nerves is also observed in several patients taking antineo- the promise that can harness great success in the upcoming
plastic drugs that may lead to the weakening of vision as years.179e181 Cancer cell-directed antibodies are at the
well.172,173 The majority of chemotherapeutic agents affect forefront of targeted drug delivery methods and have
these tissues in a dose-dependent manner; though, there accelerated the hunt for more effective or potentially
are differences in their sensitivity to individuals due to improvised approaches.182,183 Different types of nano-
enormous factors such as metabolism efficiency, genetic carriers and formulations of nano-drugs have also improved

23
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U. Anand, A. Dey, A.K.S. Chandel et al.

the delivery of drug compounds to the cancer cells.184e186 Next, aberrant changes in the fibroblast growth factors
The most significant advantage of targeted drug deliveries (FGF) signaling pathway have also been associated with the
is that the enormous drug-mediated toxicities on other initiation and progression of oncogenic events. Different
adjacent tissues and organs can be minimized. We can also types of genetic alterations in FGF receptor amplification,
avoid most of the collateral damage leading to stress and mutations, and gene-fusion have been shown to respond
organ failures. However, the effectiveness of many of these variably to certain drugs, and hence demand molecular
delivery methods in patients is still under clinical evalua- profiling for the selection of effective drugs.46,197 Another
tion. Further details regarding these delivery systems can promising example is of using poly ADP ribose polymerase
be accessed in the previously published reports.187,188 (PARP) inhibitor olaparib for the treatment of breast cancer
susceptibility gene (BRCA)-mutant cancers for better tar-
geting of cancer cells, without much effect on the normal
Personalized medication cells.198,199 On the cytoprotective side, recently a natural
alkylated withanolide viz. 2,3-Dihydro-3beta-methoxy
Given the heterogeneity of tumor cells, the cancer of one withaferin-A was shown to protect normal cells against a
patient is different from that of another in terms of accu- variety of stresses enrolled in cancer therapeutics.200 The
mulated genetic abnormalities, its pace and progression, idea of precision or personalized medicine is new but has
the response to the treatment, and the chances of devel- been beneficial for lots of patients; however, the cost of
oping resistance to the administered drugs.45 The current these new generation approaches for genome profiling is
technologies have made it possible to get insights into this still high, making it unaffordable for a large population of
disease heterogeneity or explore molecular variations at the world.201
the individual level, thereby tailoring the treatment regime
as per the personalized needs of every cancer pa-
tient.149,189 This helps in choosing the most appropriate
Antimicrobial peptides
drugs and their dosages for a better outcome in cancer
management.190 For instance, dabrafenib and vemurafenib Advances in cancer therapy have prompted scientists to
are directed against BRAF gene mutation, while trastuzu- look for natural tumoricidal chemicals, such as antimicro-
mab works well against HER-2 mutated cells.47,191,192 The bial peptides (AMPs), that could be used for cancer
idea here is to dive deep into the omics (genomic, tran- treatment.202e204 In addition to antibacterial action,
scriptomic, proteomic, metabolomic, etc.) data of the pa- several AMPs have been shown to have intrinsic anticancer
tient to identify the major molecular players fostering the potential.205,206 These molecules constitute an intriguing
transformed cells, and design the treatments against these new resource for anticancer drugs, and they provide
clinically actionable targets (Fig. 3B).155,193,194 Different several distinct therapeutic advantages over other anti-
types of mutations have been observed to be frequent in cancer treatments since they do not bind directly to any
specific subtypes of cancer. Therefore, measuring and particular receptor in cancer cells.207 The polycationic and
manipulating these driver mutations based on an individual amphipathic character of AMPs has been postulated as a
patient is expected to yield better results. Following are possible explanation for the preferential interaction of
some examples of drugs that are potentially effective in AMPs with cancer cells, as compared to normal cells.208,209
patients harbouring some specific type of genomic alter- Membrane disruption has been identified as a critical stage
ation. A mutation in anaplastic lymphoma kinase (ALK) was in the microbial killing mechanism of several AMPs. These
reported to drive tumor formation in 5% of the non-small- anticancer effects of AMPs are unaffected by molecular
cell lung cancer population and led to the discovery of heterogeneity inside a tumor or across tumors, nor are they
ALK blockers such as crizotinib and ceritinib.195 An oral counteracted by cancer cells’ flexibility and alternate sur-
BRAF inhibitor, namely vemurafenib has been shown to vival pathways, as is commonly found in cancer resistance
possess a greater affinity for the mutant BRAFV600E than the (Fig. 4).204,209,210
wildtype BRAF, and therefore was recommended to the Cathelicidins are members of the antimicrobial peptide
patients carrying the above mutation in the tumors.196 family found in granules of vertebrate neutrophils.211 The
Several potential targets for novel drugs have been iden- only human cathelicidin is the cationic peptide LL-37.
tified using high-throughput screening technologies, and Cathelicidins are composed of a highly conserved N-termi-
various compounds against them have been recently nal signal peptide including a cathelin domain and a C-
approved or are under investigation. Similarly, alterations terminal cationic antimicrobial peptide. Apart from their
in phosphoinositide 3-kinases (PI3K)/protein kinase B antimicrobial activity, cathelicidin-derived antimicrobial
(AKT)/mTOR pathway have also been frequently found in peptides exhibit a range of biological roles, including
many solid tumors. Among these, activation of phosphati- antiviral, antifungal, anticancer, and immunomodulatory
dylinositol-4,5-bisphosphate 3-kinase catalytic subunit properties.212,213 LL-37 exhibits anticancer activity against
alpha (PIK3CA) and loss of phosphatase and tensin homolog oral cancer cells and has been identified as a molecular
(PTEN) mutations are the most common. Basket trials have target for colon cancer.214 Immunohistochemical staining of
been conducted to evaluate the effectiveness of adding colon cancer tissue showed that LL-37 is abundantly
alpelisib, a specific p110a PIK3CA inhibitor to the hormonal expressed in normal colon mucosa but downregulated in
treatment for PIK3CA mutant luminal breast cancer pa- colon cancer tissues due to DNA methylation in the LL-37
tients. The results emphasize the importance of checking promoter.215
for this molecular alteration in patients and following the In human oral squamous cell carcinoma SAS-H1 cells, the
tested treatment regime for better anti-tumor response.193 active domain of LL-37 induces mitochondrial

24
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Genes & Diseases xxx (xxxx) xxx

depolarization, which results in caspase-independent cancers.231e233 Tisagenlecleucel, an FDA-approved drug,

apoptosis. Furthermore, mice lacking cathelicidin are treats B-cell lymphoblastic leukemia by effectively engi-
more susceptible to azoxymethane-induced colon neering the chimeric T cell receptor (CAR-T) of the patient
carcinogenesis.216 (Fig. 3C).234 Some treatment plans also include interferons
Many important advancements have been achieved using and interleukins to jump-start the fight against cancer cells
antimicrobial peptides against colorectal cancer.217 Using by boosting the patient’s immune system. Moreover, the
LL-37 on the surface of magnetic nanoparticles led to a field of immunotherapy is gradually evolving and is beyond
significant reduction in cell viability of colon cancer cell the scope of our present article.
lines, inducing apoptosis at a much higher rate than in the
case of LL-37 peptide alone.218
Fan et al created a biodegradable and injectable ther- Combination therapy
mosensitive hydrogel containing docetaxel and LL-37 poly-
meric nanoparticles. Intraperitoneal injection of this Combination therapy may offer the advantages of the fast
hydrogel substantially inhibited the development of tumor regression of targeted therapies with the long-lasting
HCT116 carcinomatosis in a mouse model of colorectal responses induced by immunotherapy.235 Immunotherapy
carcinoma.219 may be able to consolidate the dramatic tumor responses
In comparison to existing chemotherapeutic agents, the achieved with targeted therapy into durable, long-lasting
flexible nature of peptide structures, along with non- remissions, in which sustained host responses targeting
receptor activity, might confer strategic benefits on AMPs multiple antigens may reduce the risk of developing
for the treatment of colon cancer in the future.220 New potentially lethal drug-resistant clones.236 Combining can-
treatment approaches for patients with advanced-stage, cer vaccines with immune checkpoint inhibitors (ICIs) such
unresectable melanomas continue to be of significant as those targeting cytotoxic T lymphocyte-associated pro-
clinical interest, as these patients cannot be treated sur- tein 4 (CTLA-4) and programmed cell death protein 1/pro-
gically and have only a modest or temporary response to grammed cell death ligand 1 (PD-1/PD-L1) is one approach
chemotherapy and radiation. In phase 1 clinical trial to avoid T cell anergy.237,238 Moreover, T-cell and NK-cell
NCT02225366, intra-tumoral injections of LL-37 are being invasion may be facilitated by targeted drugs that modify
explored for melanoma patients with cutaneous metastases the tumor endothelium.239 Gemcitabine, for example, is a
to determine the most effective dose of LL-37 that could be deoxycytidine analog that induces tumor cell death, which
administered. Patients will receive weekly intra-tumoral results in antigen cross-presentation and cross-prim-
injections of LL-37 (starting dose, 250 mg/tumor) every 7 ing.240,241 Carboplatin, pemetrexed, and pembrolizumab
days for up to 8 weeks. Researchers are also interested in are now commonly used in the treatment of non-small cell
understanding whether LL37 can activate the immune sys- lung cancer as first-line agents.242 For triple-negative
tem, which could help in the control of the disease.221 breast cancer, nab-paclitaxel and atezolizumab (anti-PD-
Although AMPs have the potential to develop into a more L1) were recently authorized based on an improvement in
effective and safer alternative to conventional cancer progression-free survival (PFS) over chemotherapy.243
therapy, future research and development of anticancer Adenosine receptor antagonists (ARs) are involved in
peptide therapeutics will most likely focus on the poor regulating tumor progression.244 The four ARs discovered so
pharmacokinetics, the control of selectivity, toxicity, and far, A1, A2A, A2B and A3, belong to the class A family of G
routes of administration through the establishment of protein-coupled receptors (GPCRs).245 The A2BR seems
appropriate in vivo models.222 more promising as a target in chemotherapeutic in-
terventions,246 whereas the A2AR is the main target in the
immunotherapeutic approach.247,248 The existence of dual
Immunotherapy compounds, i.e., molecules acting on the A2AR and on the
A2BR, has prompted their use in both immunotherapeutic
Supplementing our immune system by devising immuno- and chemotherapeutic interventions.249,250
therapy strategies is another highly-specific and largely Epigenetic modulators may have a dual function in the
promising approach to address the problem of late-stage tumor microenvironment, boosting both antigen expression
cancer therapeutics.223,224 Several new approaches have and T cell effector activity.251,252 ICI-induced reactivation
been developed in the last decade to modify and train a of exhausted T cells is linked with considerable chromatin
patient’s immune system to search, identify and target the remodeling, indicating that epigenetic modification may
transformed cells inside the body by recognizing multiple relieve certain patients with exhausted T cell
cell surface markers.225 For instance, supplementing the function.253,254
treatment regime with immunotherapy has significantly While many strategies focus on modifying the native
improved the success rate of the chemotherapeutic drugs in tumor microenvironment, an alternative strategy involves
many cancer types, especially the triple-negative breast the direct infusion of engineered immune cells or cellular
cancers.226e228 The immunotherapy drugs are given alone receptors into the patient via adoptive cellular therapy
or in combination with chemotherapy drugs to achieve with the goal of increasing the number of effector cells that
better clinical outcomes.229 Prophylactic and therapeutic recognize tumor-expressed antigens.255 Upon reinfusion,
vaccines have been developed to help patients’ immune lymphocytes grown ex vivo may respond more potently to
systems towards learning to tackle the transformed tumor antigen since they have not been continuously
cells.230 Atezolizumab is an example of an anti-cancer im- exposed to tolerogenic microenvironmental signals.256
mune drug that helps to dissolve hard-to-treat breast Tumor infiltrating lymphocytes (TIL) treatment,257

25
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U. Anand, A. Dey, A.K.S. Chandel et al.

chimeric antigen receptor (CAR) engineered T-cells,258,259 personalized medicine, and immunotherapy. It may not
and TCR-engineered cell therapy260,261 are the three main only improve the efficacy of enrolled treatment but can
forms of adoptive T cell therapy currently being also elicit the responsiveness of certain tumors towards
investigated.257,262,263 their effective therapeutic targeting in the clinic. Among
Injecting oncolytic viruses directly into the tumor these, personalized combination therapies that target in-
microenvironment is an alternate technique for improving dividual tumor types based on their molecular signatures
tumor antigen recognition and strengthening T cell re- may offer a great promise. With acquiring more personal-
sponses.264 Talimogene laherparepvec (T-VEC) is a modified ized insights in the chemotherapeutic treatments, a greater
herpes simplex virus that is injected intra-lesionally into emphasis will be on individual regimes that could meet a
the melanoma tumor in individuals who have failed to get high clinical success.277 Therefore, chemotherapy beyond
their tumor removed. It induces immediate lysis of tumor its conventional clinical efficacy offers to improve the
cells and the production of granulocyte-macrophage col- clinical outcome in combination therapies. Translation of
ony-stimulating factor (GM-CSF), which serves as a cytokine these combined approaches in the clinics is yet to see a
to stimulate the recruitment, maturation, and activity of complete success and thus warrants more clinical
antigen presenting cells (APCs).265 investigations.
Several studies combining immunotherapy with molec- Conclusively, clinical practice of cancer chemotherapy
ularly targeted treatment, either concurrently or sequen- has achieved considerable success, however, it still holds
tially, have shown hepatotoxicity as a major concern.266 scope to improve, particularly in terms of efficacy and
Combinations of dabrafenib, trametinib, and anti-PD-1 safety of enrolled chemotherapeutic regimes. Therefore, it
treatment have been associated with a greater risk of further requires concerted efforts and careful in-
grade 3/4 adverse events in melanoma than would be ex- vestigations assessing the efficacy of combined therapeutic
pected with targeted therapy alone.256 regimes. In summary, more investigative focus on drug
Emerging drugs are beginning to take a more compre- design in individual or combined regimes and rigor on their
hensive perspective of the tumor microenvironment (TME) clinical trials involving careful patient selection and strat-
and are revealing complementary techniques to simulta- ification are warranted to achieve the greater therapeutic
neously restore and enhance immune activity and promote success of chemotherapeutic regimens in the clinic.
therapeutic synergy.267,268 Future research of combined
therapy should continue to concentrate on exploring the
Conflict of interests
intricate interplay between targeted drugs and immuno-
therapy, as well as optimizing parameters such as admin-
The authors declare no conflict of interests.
istration time, dose, and sequencing that may enhance the
therapeutic index.240
Funding
Conclusions and future perspectives
This research was funded by "Agencia Canaria de Inves-
Chemotherapy is a largely investigated and clinically tigación, Innovación y Sociedad de la Información (ACIISI)
assessed approach in cancer therapeutics. In this report, del Gobierno de Canarias” (No. ProID2020010134), and
we summarized the present status of chemotherapy and óCaja Canarias (Project No. 2019SP43).
several drugs/agents presently enrolled in the clinical
practice to provide an overview of how the field has Acknowledgements
evolved over the years and has traced the possibilities and
druggability of diverse cancers in the clinic. New trends are All the authors are highly grateful and acknowledge to the
evolving in the drug discovery paradigm that includes authority of the respective departments and institutions for
designing new derivatives of old drugs with high efficacy their support in carrying out this research. The authors also
and lower toxicities.269,270 Several natural compounds iso- express their sincere gratitude to the unknown referee for
lated from microbial, plants, or natural sources were sug- critically reviewing the manuscript and suggesting useful
gested to hold enormous potential to target stress response changes.
pathways by mounting a hyperactive response instigating
cancer cell death.271e274 Natural compounds/agents as
chemotherapeutic drugs demonstrated several advantages References
over synthetic ones, owing to their less cytotoxicity, cost,
and straightforward production/extraction pro- 1. Janssen LME, Ramsay EE, Logsdon CD, Overwijk WW. The
cess.273,275,276 Therefore, recognition and attenuation of immune system in cancer metastasis: friend or foe? J
treatment toxicity in cancer chemotherapy will be a key Immunother Cancer. 2017;5(1):79.
factor in determining the success of its regimes in the 2. Laplagne C, Domagala M, le Naour A, et al. Latest advances in
targeting the tumor microenvironment for tumor suppression.
future.
Int J Mol Sci. 2019;20(19):4719.
Revised clinical strategies further underlined that com- 3. Emon B, Bauer J, Jain Y, Jung B, Saif T. Biophysics of tumor
bination therapy could emerge as a promising therapeutic microenvironment and cancer metastasis - a mini review.
approach to treat diverse cancers in the future. Combina- Comput Struct Biotechnol J. 2018;16:279e287.
tion strategies comprise an obvious overlap of the chemo- 4. Costa A, Scholer-Dahirel A, Mechta-Grigoriou F. The role of
therapeutic regimes with the targeted drug delivery, reactive oxygen species and metabolism on cancer cells

26
 + MODEL
Genes & Diseases xxx (xxxx) xxx

and their microenvironment. Semin Cancer Biol. 2014;25: 26. Wu WK, Wu YC, Yu L, Li ZJ, Sung JJ, Cho CH. Induction of
23e32. autophagy by proteasome inhibitor is associated with prolif-
5. Gilbert S, Oliphant C, Hassan S, et al. ATP in the tumour erative arrest in colon cancer cells. Biochem Biophys Res
microenvironment drives expression of nfP2X7, a key medi- Commun. 2008;374(2):258e263.
ator of cancer cell survival. Oncogene. 2019;38(2):194e208. 27. Selimovic D, Porzig BBOW, El-Khattouti A, et al. Bortezo-
6. Pfirschke C, Siwicki M, Liao HW, Pittet MJ. Tumor microenvi- mib/proteasome inhibitor triggers both apoptosis and
ronment: no effector T cells without dendritic cells. Cancer autophagy-dependent pathways in melanoma cells. Cell
Cell. 2017;31(5):614e615. Signal. 2013;25(1):308e318.
7. Bedoui S, Herold MJ, Strasser A. Emerging connectivity of 28. Hasima N, Ozpolat B. Regulation of autophagy by polyphenolic
programmed cell death pathways and its physiological impli- compounds as a potential therapeutic strategy for cancer.
cations. Nat Rev Mol Cell Biol. 2020;21(11):678e695. Cell Death Dis. 2014;5:e1509.
8. Rodrigues D, Souza T, Jennen DGJ, Lemmens L, Kleinjans JCS, 29. Sannino S, Guerriero CJ, Sabnis AJ, et al. Compensatory in-
de Kok TM. Drug-induced gene expression profile changes in creases of select proteostasis networks after Hsp70 inhibition
relation to intestinal toxicity: state-of-the-art and new ap- in cancer cells. J Cell Sci. 2018;131(17):jcs217760.
proaches. Cancer Treat Rev. 2019;77:57e66. 30. Zhu K, Dunner Jr K, McConkey DJ. Proteasome inhibitors
9. Delou JMA, Souza ASO, Souza LCM, Borges HL. Highlights in activate autophagy as a cytoprotective response in human
resistance mechanism pathways for combination therapy. prostate cancer cells. Oncogene. 2010;29(3):451e462.
Cells. 2019;8(9):1013. 31. Chen J, Chen X, Xu D, et al. Autophagy induced by protea-
10. Kalra RS, Bapat SA. Enhanced levels of double-strand DNA somal DUB inhibitor NiPT restricts NiPT-mediated cancer cell
break repair proteins protect ovarian cancer cells against death. Front Oncol. 2020;10:348.
genotoxic stress-induced apoptosis. J Ovarian Res. 2013;6(1): 32. Stewart DA, Winnike JH, McRitchie SL, Clark RF,
66. Pathmasiri WW, Sumner SJ. Metabolomics analysis of
11. Caccuri F, Sommariva M, Marsico S, et al. Inhibition of DNA hormone-responsive and triple-negative breast cancer cell
repair mechanisms and induction of apoptosis in triple nega- responses to paclitaxel identify key metabolic differences. J
tive breast cancer cells expressing the human herpesvirus 6 Proteome Res. 2016;15(9):3225e3240.
U94. Cancers. 2019;11(7):1006. 33. Sun H, Zhang AH, Liu SB, et al. Cell metabolomics identify
12. Kalra RS, Bapat SA. Expression proteomics predicts loss of regulatory pathways and targets of magnoline against pros-
RXR-g during progression of epithelial ovarian cancer. PLoS tate cancer. J Chromatogr B Analyt Technol Biomed Life Sci.
One. 2013;8(8):e70398. 2018;1102e1103:143e151.
13. Huang C, Vaishnavi K, Kalra R. 3b-methoxy derivation of 34. Kroemer G, Zitvogel L. Immune checkpoint inhibitors. J Exp
withaferin-a attenuates its anticancer potency: bioinformat- Med. 2021;218(3), e20201979.
ics and molecular evidences. Med Aromatic Plants. 2015; 35. Torino F, Barnabei A, Paragliola R, Baldelli R, Appetecchia M,
4(219): 2167-0412. Corsello SM. Thyroid dysfunction as an unintended side effect
14. Chaudhary A, Kalra RS, Malik V, et al. 2, 3-dihydro-3b- of anticancer drugs. Thyroid. 2013;23(11):1345e1366.
methoxy withaferin-A lacks anti-metastasis potency: bioin- 36. Mahner S, Eulenburg C, Staehle A, et al. Prognostic impact of
formatics and experimental evidences. Sci Rep. 2019;9(1): the time interval between surgery and chemotherapy in
17344. advanced ovarian cancer: analysis of prospective randomised
15. Chen Y, Jia Y, Song W, Zhang L. Therapeutic potential of ni- phase III trials. Eur J Cancer. 2013;49(1):142e149.
trogen mustard based hybrid molecules. Front Pharmacol. 37. di Lonardo A, Nasi S, Pulciani S. Cancer: we should not forget
2018;9:1453. the past. J Cancer. 2015;6(1):29e39.
16. Needham DM, Cohen JA, Barrett AM. The mechanism of 38. Papac RJ. Origins of cancer therapy. Yale J Biol Med. 2001;
damage to the bone marrow in systemic poisoning with 74(6):391e398.
mustard gas. Biochem J. 1947;41(4):631e639. 39. Morrison WB. Cancer chemotherapy: an annotated history. J
17. Ghanei M. Delayed haematological complications of mustard Vet Intern Med. 2010;24(6):1249e1262.
gas. J Appl Toxicol. 2004;24(6):493e495. 40. Riddle JM. Ancient and medieval chemotherapy for cancer.
18. Cairns J. The treatment of diseases and the war against Isis. 1985;76(3):319e330.
cancer. Sci Am. 1985;253(5):51e59. 41. Lee CT, Huang YW, Yang CH, Huang KS. Drug delivery systems
19. Duffy MJ. The war on cancer: are we winning? Tumour Biol. and combination therapy by using Vinca alkaloids. Curr Top
2013;34(3):1275e1284. Med Chem. 2015;15(15):1491e1500.
20. Christakis P. The birth of chemotherapy at Yale. Bicentennial 42. Lau YC, Lip GYH. New advances in the treatment of atrial
lecture series: surgery Grand Round. Yale J Biol Med. 2011; fibrillation: focus on stroke prevention. Expet Opin Phar-
84(2):169e172. macother. 2014;15(15):2193e2204.
21. DeVita Jr VT, Chu E. A history of cancer chemotherapy. Can- 43. DeVita VT, Hellman S, Rosenberg SA. Cancer, Principles &
cer Res. 2008;68(21):8643e8653. Practice of Oncology. 11th ed. Philadelphia, PA: Lippincott
22. Sawyers C. Targeted cancer therapy. Nature. 2004;432(7015): Williams & Wilkins; 2018.
294e297. 44. Hanahan D, Weinberg RA. Hallmarks of cancer: the next
23. Dewanjee S, Vallamkondu J, Kalra RS, et al. The emerging generation. Cell. 2011;144(5):646e674.
role of HDACs: pathology and therapeutic targets in diabetes 45. Caon I, Bartolini B, Parnigoni A, et al. Revisiting the hallmarks
mellitus. Cells. 2021;10(6):1340. of cancer: the role of hyaluronan. Semin Cancer Biol. 2020;
24. Mattheolabakis G, Rigas B, Constantinides PP. Nanodelivery 62:9e19.
strategies in cancer chemotherapy: biological rationale and 46. Dieci MV, Arnedos M, Andre F, Soria JC. Fibroblast growth
pharmaceutical perspectives. Nanomedicine. 2012;7(10): factor receptor inhibitors as a cancer treatment: from a
1577e1590. biologic rationale to medical perspectives. Cancer Discov.
25. Leu JIJ, Pimkina J, Pandey P, Murphy ME, George DL. HSP70 2013;3(3):264e279.
inhibition by the small-molecule 2-phenylethynesulfonamide 47. Holderfield M, Deuker MM, McCormick F, McMahon M. Tar-
impairs protein clearance pathways in tumor cells. Mol Can- geting RAF kinases for cancer therapy: BRAF-mutated mela-
cer Res. 2011;9(7):936e947. noma and beyond. Nat Rev Cancer. 2014;14(7):455e467.

27
 + MODEL
U. Anand, A. Dey, A.K.S. Chandel et al.

48. Kalra RS, Chaudhary A, Yoon AR, et al. CARF enrichment 67. Jaffee EM, van Dang C, Agus DB, et al. Future cancer research
promotes epithelial-mesenchymal transition via Wnt/b-cat- priorities in the USA: a lancet oncology commission. Lancet
enin signaling: its clinical relevance and potential as a ther- Oncol. 2017;18(11):e653ee706.
apeutic target. Oncogenesis. 2018;7(5):39. 68. Zhao J, Dean DC, Hornicek FJ, Yu X, Duan Z. Emerging next-
49. Chua TC, Yan TD, Saxena A, Morris DL. Should the treat- generation sequencing-based discoveries for targeted osteo-
ment of peritoneal carcinomatosis by cytoreductive surgery sarcoma therapy. Cancer Lett. 2020;474:158e167.
and hyperthermic intraperitoneal chemotherapy still be 69. Coccia M. Deep learning technology for improving cancer care
regarded as a highly morbid procedure? : a systematic re- in society: new directions in cancer imaging driven by artifi-
view of morbidity and mortality. Ann Surg. 2009;249(6): cial intelligence. Technol Soc. 2020;60:101198.
900e907. 70. Patel S. Emerging adjuvant therapy for cancer: propolis and
50. Jin JF, Zhu LL, Chen M, et al. The optimal choice of medi- its constituents. J Diet Suppl. 2016;13(3):245e268.
cation administration route regarding intravenous, intramus- 71. Grob JJ, Garbe C, Ascierto P, Larkin J, Dummer R,
cular, and subcutaneous injection. Patient Prefer Adherence. Schadendorf D. Adjuvant melanoma therapy with new drugs:
2015;9:923e942. should physicians continue to focus on metastatic disease or
51. Giger-Pabst U, Bucur P, Roger S, et al. Comparison of tissue use it earlier in primary melanoma? Lancet Oncol. 2018;
and blood concentrations of oxaliplatin administrated by 19(12):e720ee725.
different modalities of intraperitoneal chemotherapy. Ann 72. Benson 3rd AB, Schrag D, Somerfield MR, et al. American So-
Surg Oncol. 2019;26(13):4445e4451. ciety of Clinical Oncology recommendations on adjuvant
52. Lichota A, Gwozdzinski K. Anticancer activity of natural chemotherapy for stage II colon cancer. J Clin Oncol. 2004;
compounds from plant and marine environment. Int J Mol Sci. 22(16):3408e3419.
2018;19(11):3533. 73. Matei D, Filiaci V, Randall ME, et al. Adjuvant chemotherapy
53. Weaver BA. How Taxol/paclitaxel kills cancer cells. Mol Biol plus radiation for locally advanced endometrial cancer. N Engl
Cell. 2014;25(18):2677e2681. J Med. 2019;380(24):2317e2326.
54. Omar A, Kalra RS, Putri J, Elwakeel A, Kaul SC, Wadhwa R. 74. Cao L, Xu C, Cai G, et al. How does the interval between
Soyasapogenol-A targets CARF and results in suppression of completion of adjuvant chemotherapy and initiation of
tumor growth and metastasis in p53 compromised cancer radiotherapy impact clinical outcomes in operable breast
cells. Sci Rep. 2020;10(1):6323. cancer patients? Ann Surg Oncol. 2021;28(4):2155e2168.
55. Sun G, Rong D, Li Z, et al. Role of small molecule targeted 75. Salazar MC, Rosen JE, Wang Z, et al. Association of delayed
compounds in cancer: progress, opportunities, and chal- adjuvant chemotherapy with survival after lung cancer sur-
lenges. Front Cell Dev Biol. 2021;9:694363. gery. JAMA Oncol. 2017;3(5):610e619.
56. Apetoh L, Ladoire S, Coukos G, Ghiringhelli F. Combining 76. Kalyanaraman B. Teaching the basics of cancer metabolism:
immunotherapy and anticancer agents: the right path to developing antitumor strategies by exploiting the differences
achieve cancer cure? Ann Oncol. 2015;26(9):1813e1823. between normal and cancer cell metabolism. Redox Biol.
57. Piktel E, Niemirowicz K, Wa ˛tek M, Wollny T, Deptuła P, 2017;12:833e842.
Bucki R. Recent insights in nanotechnology-based drugs and 77. Moore A. Metabolic cycles in cancer cells? Bioessays. 2020;
formulations designed for effective anti-cancer therapy. J 42(4):e2000048.
Nanobiotechnol. 2016;14(1):39. 78. Anand U, Jacobo-Herrera N, Altemimi A, Lakhssassi N. A
58. Anand U, Carpena M, Kowalska-Góralska M, et al. Safer plant- comprehensive review on medicinal plants as antimicrobial
based nanoparticles for combating antibiotic resistance in therapeutics: potential avenues of biocompatible drug dis-
bacteria: a comprehensive review on its potential applica- covery. Metabolites. 2019;9(11):258.
tions, recent advances, and future perspective. Sci Total 79. Alibek K, Bekmurzayeva A, Mussabekova A, Sultankulov B.
Environ. 2022:153472. Using antimicrobial adjuvant therapy in cancer treatment: a
59. Kaur K, Reddy S, Barathe P, et al. Combating drug-resistant review. Infect Agents Cancer. 2012;7(1):33.
bacteria using photothermally active nanomaterials: a 80. Shoshan-Barmatz V, Anand U, Nahon-Crystal E, di Carlo M,
perspective review. Front Microbiol. 2021;12:747019. Shteinfer-Kuzmine A. Adverse effects of metformin from dia-
60. Mitra AK, Agrahari V, Mandal A, et al. Novel delivery ap- betes to COVID-19, cancer, neurodegenerative diseases, and
proaches for cancer therapeutics. J Contr Release. 2015;219: aging: is VDAC1 a common target? Front Physiol. 2021;12:730048.
248e268. 81. Nicholson LB. The immune system. Essays Biochem. 2016;
61. Large DE, Soucy JR, Hebert J, Auguste DT. Advances in 60(3):275e301.
receptor-mediated, tumor-targeted drug delivery. Adv Ther. 82. Gonzalez H, Hagerling C, Werb Z. Roles of the immune system
2019;2(1):1800091. in cancer: from tumor initiation to metastatic progression.
62. Yarchoan M, Agarwal P, Villanueva A, et al. Recent de- Genes Dev. 2018;32(19e20):1267e1284.
velopments and therapeutic strategies against hepatocellular 83. Whiteside TL. Immune responses to cancer: are they potential
carcinoma. Cancer Res. 2019;79(17):4326e4330. biomarkers of prognosis? Front Oncol. 2013;3:107.
63. Vaidyanathan R, Soon RH, Zhang P, Jiang K, Lim CT. Cancer 84. Kreuzaler P, Panina Y, Segal J, Yuneva M. Adapt and conquer:
diagnosis: from tumor to liquid biopsy and beyond. Lab Chip. metabolic flexibility in cancer growth, invasion and evasion.
2018;19(1):11e34. Mol Metabol. 2020;33:83e101.
64. Bera K, Schalper KA, Rimm DL, Velcheti V, Madabhushi A. 85. Yoshida GJ. Metabolic reprogramming: the emerging concept
Artificial intelligence in digital pathology - new tools for and associated therapeutic strategies. J Exp Clin Cancer Res.
diagnosis and precision oncology. Nat Rev Clin Oncol. 2019; 2015;34:111.
16(11):703e715. 86. Wadhwa R, Kalra RS, Kaul SC. CARF is a multi-module regu-
65. Charmsaz S, Prencipe M, Kiely M, Pidgeon GP, Collins DM. lator of cell proliferation and a molecular bridge between
Innovative technologies changing cancer treatment. Cancers. cellular senescence and carcinogenesis. Mech Ageing Dev.
2018;10(6):208. 2017;166:64e68.
66. Markham MJ, Wachter K, Agarwal N, et al. Clinical cancer 87. Mroz EA, Rocco JW. The challenges of tumor genetic diversity.
advances 2020:annual report on progress against cancer from Cancer. 2017;123(6):917e927.
the American society of clinical oncology. J Clin Oncol. 2020; 88. Gambara G, Gaebler M, Keilholz U, Regenbrecht CRA,
38(10):1081. Silvestri A. From chemotherapy to combined targeted

28
 + MODEL
Genes & Diseases xxx (xxxx) xxx

therapeutics: in vitro and in vivo models to decipher intra- 110. Leung JC, Cassimeris L. Reorganization of paclitaxel-
tumor heterogeneity. Front Pharmacol. 2018;9:77. stabilized microtubule arrays at mitotic entry: roles of
89. Palmer AC, Sorger PK. Combination cancer therapy can confer depolymerizing kinesins and severing proteins. Cancer Biol
benefit via patient-to-patient variability without drug addi- Ther. 2019;20(10):1337e1347.
tivity or synergy. Cell. 2017;171(7):1678e1691. e13. 111. Schwab CL, English DP, Roque DM, Santin AD. Taxanes: their
90. Ke X, Shen L. Molecular targeted therapy of cancer: the impact on gynecologic malignancy. Anti Cancer Drugs. 2014;
progress and future prospect. Front Lab Med. 2017;1(2): 25(5):522e535.
69e75. 112. Abu Samaan TM, Samec M, Liskova A, Kubatka P, Büsselberg D.
91. Kondo N, Takahashi A, Ono K, Ohnishi T. DNA damage induced Paclitaxel’s mechanistic and clinical effects on breast cancer.
by alkylating agents and repair pathways. J Nucleic Acids. Biomolecules. 2019;9(12):789.
2010;2010:543531. 113. Zhu L, Chen L. Progress in research on paclitaxel and tumor
92. Qiu H, Wang Y. Exploring DNA-binding proteins with in vivo immunotherapy. Cell Mol Biol Lett. 2019;24:40.
chemical cross-linking and mass spectrometry. J Proteome 114. Mahalaxmi I, Devi SM, Kaavya J, Arul N, Balachandar V,
Res. 2009;8(4):1983e1991. Santhy KS. New insight into NANOG: a novel therapeutic target
93. Mehrmohamadi M, Jeong SH, Locasale JW. Molecular features for ovarian cancer (OC). Eur J Pharmacol. 2019;852:51e57.
that predict the response to antimetabolite chemotherapies. 115. Postma TJ, Vermorken JB, Liefting AJ, Pinedo HM,
Cancer Metabol. 2017;5:8. Heimans JJ. Paclitaxel-induced neuropathy. Ann Oncol. 1995;
94. Katzung BG. Basic and Clinical Pharmacology. 10th ed. 6(5):489e494.
Singapore: McGraw-Hill; 2008. 116. Das T, Anand U, Pandey SK, et al. Therapeutic strategies to
95. Lambie DG, Johnson RH. Drugs and folate metabolism. Drugs. overcome taxane resistance in cancer. Drug Resist Updates.
1985;30(2):145e155. 2021;55:100754.
96. Raimondi MV, Randazzo O, la Franca M, et al. DHFR inhibitors: 117. Stähelin HF, von Wartburg A. The chemical and biological
reading the past for discovering novel anticancer agents. route from podophyllotoxin glucoside to etoposide: ninth Cain
Molecules. 2019;24(6):1140. memorial Award lecture. Cancer Res. 1991;51(1):5e15.
97. Löwenberg B, Pabst T, Vellenga E, et al. Cytarabine dose for 118. Green JA, Tarpey AW, Warenius HM. Pharmacokinetic study of
acute myeloid leukemia. N Engl J Med. 2011;364(11): high dose etoposide infusion in patients with small cell lung
1027e1036. cancer. Acta Oncol. 1988;27(6b):819e822.
98. Grem JL. 5-Fluorouracil: forty-plus and still ticking. A review 119. Infante Lara L, Fenner S, Ratcliffe S, et al. Coupling the core
of its preclinical and clinical development. Invest N Drugs. of the anticancer drug etoposide to an oligonucleotide in-
2000;18(4):299e313. duces topoisomerase II-mediated cleavage at specific DNA
99. Masuda N, Lee SJ, Ohtani S, et al. Adjuvant capecitabine for sequences. Nucleic Acids Res. 2018;46(5):2218e2233.
breast cancer after preoperative chemotherapy. N Engl J 120. Pommier Y, Leo E, Zhang H, Marchand C. DNA topoisomerases
Med. 2017;376(22):2147e2159. and their poisoning by anticancer and antibacterial drugs.
100. Dyawanapelly S, Kumar A, Chourasia MK. Lessons learned Chem Biol. 2010;17(5):421e433.
from gemcitabine: impact of therapeutic carrier systems and 121. Bruni E, Reichle A, Scimeca M, Bonanno E, Ghibelli L.
gemcitabine’s drug conjugates on cancer therapy. Crit Rev Lowering etoposide doses shifts cell demise from caspase-
Ther Drug Carrier Syst. 2017;34(1):63e96. dependent to differentiation and caspase-3-independent
101. Malik P, Cashen AF. Decitabine in the treatment of acute apoptosis via DNA damage response, inducing AML culture
myeloid leukemia in elderly patients. Cancer Manag Res. extinction. Front Pharmacol. 2018;9:1307.
2014;6:53e61. 122. Hande KR. Etoposide: four decades of development of a topo-
102. Liu Y, Wu W, Hong W, Sun X, Wu J, Huang Q. Raltitrexed-based isomerase II inhibitor. Eur J Cancer. 1998;34(10):1514e1521.
chemotherapy for advanced colorectal cancer. Clin Res 123. Wall ME. Camptothecin and taxol: discovery to clinic. Med Res
Hepatol Gastroenterol. 2014;38(2):219e225. Rev. 1998;18(5):299e314.
103. Hasegawa K, Saiura A, Takayama T, et al. Oral adjuvant 124. Martino E, Della Volpe S, Terribile E, et al. The long story of
chemotherapy using uracil-tegafur (UFT) with leucovorin (LV) camptothecin: from traditional medicine to drugs. Bioorg
after resection of colorectal cancer liver metastases: long- Med Chem Lett. 2017;27(4):701e707.
term survival results of the phase III UFT/LV study. J Clin 125. Yu S, Huang QQ, Luo Y, Lu W. Total synthesis of camptothecin
Oncol. 2017;35:672. and SN-38. J Org Chem. 2012;77(1):713e717.
104. Moudi M, Go R, Yien CY, Nazre M. Vinca alkaloids. Int J Prev 126. Li F, Jiang T, Li Q, Ling X. Camptothecin (CPT) and its de-
Med. 2013;4(11):1231e1235. rivatives are known to target topoisomerase I (Top1) as their
105. Bates D, Eastman A. Microtubule destabilising agents: far mechanism of action: did we miss something in CPT analogue
more than just antimitotic anticancer drugs. Br J Clin Phar- molecular targets for treating human disease such as cancer?
macol. 2017;83(2):255e268. Am J Cancer Res. 2017;7(12):2350e2394.
106. Habli Z, Toumieh G, Fatfat M, Rahal ON, Gali-Muhtasib H. 127. Guo Y, Shi M, Shen X, Yang C, Yang L, Zhang J. Capecitabine
Emerging cytotoxic alkaloids in the battle against cancer: plus irinotecan versus 5-FU/leucovorin plus irinotecan in the
overview of molecular mechanisms. Molecules. 2017;22(2): treatment of colorectal cancer: a meta-analysis. Clin Colo-
250. rectal Cancer. 2014;13(2):110e118.
107. Falzone L, Salomone S, Libra M. Evolution of cancer phar- 128. Herben VM, ten Bokkel Huinink WW, Beijnen JH. Clinical phar-
macological treatments at the turn of the third millennium. macokinetics of topotecan. Clin Pharmacokinet. 1996;31(2):
Front Pharmacol. 2018;9:1300. 85e102.
108. Schneider F, Pan L, Ottenbruch M, List T, Gaich T. The 129. Pommier Y. Topoisomerase I inhibitors: camptothecins and
chemistry of nonclassical taxane diterpene. Acc Chem Res. beyond. Nat Rev Cancer. 2006;6(10):789e802.
2021;54(10):2347e2360. 130. Tomicic MT, Christmann M, Kaina B. Topotecan-triggered
109. Fanale D, Bronte G, Passiglia F, et al. Stabilizing versus degradation of topoisomerase I is p53-dependent and impacts
destabilizing the microtubules: a double-edge sword for an cell survival. Cancer Res. 2005;65(19):8920e8926.
effective cancer treatment option? Anal Cell Pathol. 2015; 131. Bailly C. Irinotecan: 25 years of cancer treatment. Pharmacol
2015:690916. Res. 2019;148:104398.

29
 + MODEL
U. Anand, A. Dey, A.K.S. Chandel et al.

132. Sawada S, Yokokura T, Miyasaka T. Synthesis of CPT-11 (iri- 154. Na Y, Kaul SC, Ryu J, et al. Stress chaperone mortalin con-
notecan hydrochloride trihydrate). Ann N Y Acad Sci. 1996; tributes to epithelial-mesenchymal transition and cancer
803:13e28. metastasis. Cancer Res. 2016;76(9):2754e2765.
133. Sobell HM. Actinomycin and DNA transcription. Proc Natl Acad 155. Bapat SA, Krishnan A, Ghanate AD, Kusumbe AP, Kalra RS.
Sci USA. 1985;82(16):5328e5331. Gene expression: protein interaction systems network
134. Avendaño C, Menéndez JC. Medicinal Chemistry of Anti- modeling identifies transformation-associated molecules and
cancer Drugs. Amsterdam: Elsevier; 2008. pathways in ovarian cancer. Cancer Res. 2010;70(12):
135. Arndt C, Hawkins D, Anderson JR, Breitfeld P, Womer R, 4809e4819.
Meyer W. Age is a risk factor for chemotherapy-induced 156. Stringer AM, Gibson RJ, Logan RM, et al. Irinotecan-induced
hepatopathy with vincristine, dactinomycin, and cyclophos- mucositis is associated with changes in intestinal mucins.
phamide. J Clin Oncol. 2004;22(10):1894e1901. Cancer Chemother Pharmacol. 2009;64(1):123e132.
136. Al-Hazmi A, Zwaan J, Awad A, Al-Mesfer S, Mullaney PB, 157. Thorpe D, Stringer A, Butler R. Chemotherapy-induced
Wheeler DT. Effectiveness and complications of mitomycin C mucositis: the role of mucin secretion and regulation, and
use during pediatric glaucoma surgery. Ophthalmology. 1998; the enteric nervous system. Neurotoxicology. 2013;38:
105(10):1915e1920. 101e105.
137. Crooke ST, Bradner WT. Mitomycin C: a review. Cancer Treat 158. Mitchison TJ. The proliferation rate paradox in antimitotic
Rev. 1976;3(3):121e139. chemotherapy. Mol Biol Cell. 2012;23(1):1e6.
138. Tomasz M. Mitomycin C: small, fast and deadly (but very se- 159. McQuade RM, Stojanovska V, Abalo R, Bornstein JC, Nurgali K.
lective). Chem Biol. 1995;2(9):575e579. Chemotherapy-induced constipation and diarrhea: patho-
139. Noll DM, Mason TM, Miller PS. Formation and repair of inter- physiology, current and emerging treatments. Front Phar-
strand cross-links in DNA. Chem Rev. 2006;106(2):277e301. macol. 2016;7:414.
140. Haffty BG, Wilson LD, Son YH, et al. Concurrent chemo- 160. Bower JE. Cancer-related fatigue: mechanisms, risk factors,
radiotherapy with mitomycin C compared with porfiromycin and treatments. Nat Rev Clin Oncol. 2014;11(10):597e609.
in squamous cell cancer of the head and neck: final results of 161. Wang Y, Probin V, Zhou D. Cancer therapy-induced residual
a randomized clinical trial. Int J Radiat Oncol Biol Phys. 2005; bone marrow injury-Mechanisms of induction and implication
61(1):119e128. for therapy. Curr Cancer Ther Rev. 2006;2(3):271e279.
141. Murphy T, Yee KWL. Cytarabine and daunorubicin for the 162. Kuter DJ. Managing thrombocytopenia associated with cancer
treatment of acute myeloid leukemia. Expet Opin Pharmac- chemotherapy. Oncology. 2015;29(4):282e294.
other. 2017;18(16):1765e1780. 163. Manikandan R, Kumar S, Dorairajan LN. Hemorrhagic cystitis:
142. Tan C, Tasaka H, Yu KP, Murphy ML, Karnofsky DA. Dauno- a challenge to the urologist. Indian J Urol. 2010;26(2):
mycin, an antitumor antibiotic, in the treatment of neoplastic 159e166.
disease. Clinical evaluation with special reference to child- 164. Horie S, Oya M, Nangaku M, et al. Guidelines for treatment of
hood leukemia. Cancer. 1967;20(3):333e353. renal injury during cancer chemotherapy 2016. Clin Exp
143. Fornari FA, Randolph JK, Yalowich JC, Ritke MK, Nephrol. 2018;22(1):210e244.
Gewirtz DA. Interference by doxorubicin with DNA un- 165. Maor Y, Malnick S. Liver injury induced by anticancer
winding in MCF-7 breast tumor cells. Mol Pharmacol. 1994; chemotherapy and radiation therapy. Int J Hepatol. 2013;
45(4):649e656. 2013:815105.
144. Bodley A, Liu LF, Israel M, et al. DNA topoisomerase II- 166. Yeh ET, Tong AT, Lenihan DJ, et al. Cardiovascular compli-
mediated interaction of doxorubicin and daunorubicin con- cations of cancer therapy: diagnosis, pathogenesis, and
geners with DNA. Cancer Res. 1989;49(21):5969e5978. management. Circulation. 2004;109(25):3122e3131.
145. Zhang G, Fang L, Zhu L, et al. Syntheses and biological ac- 167. Schover LR, van der Kaaij M, van Dorst E, Creutzberg C,
tivities of disaccharide daunorubicins. J Med Chem. 2005; Huyghe E, Kiserud CE. Sexual dysfunction and infertility as
48(16):5269e5278. late effects of cancer treatment. EJC Suppl. 2014;12(1):
146. Yu Z, Yan B, Gao L, et al. Targeted delivery of bleomycin: a 41e53.
comprehensive anticancer review. Curr Cancer Drug Targets. 168. Voznesensky M, Annam K, Kreder KJ. Understanding and
2016;16(6):509e521. managing erectile dysfunction in patients treated for cancer.
147. Lown JW, Sim SK. The mechanism of the bleomycin-induced J Oncol Pract. 2016;12(4):297e304.
cleavage of DNA. Biochem Biophys Res Commun. 1977;77(4): 169. Mitchell T, Turton P. ’Chemobrain’: concentration and mem-
1150e1157. ory effects in people receiving chemotherapy - a descriptive
148. Weber GF. DNA damaging drugs. In: Molecular Therapies of phenomenological study. Eur J Cancer Care. 2011;20(4):
Cancer. Cham.: Springer; 2015. 539e548.
149. Meldrum C, Doyle MA, Tothill RW. Next-generation sequencing 170. Moore HC. An overview of chemotherapy-related cognitive
for cancer diagnostics: a practical perspective. Clin Biochem dysfunction, or ‘chemobrain. Oncology. 2014;28(9):797e804.
Rev. 2011;32(4):177e195. 171. Dutta V. Chemotherapy, neurotoxicity, and cognitive changes
150. Kalra RS, Cheung CT, Chaudhary A, Prakash J, Kaul SC, in breast cancer. J Cancer Res Therapeut. 2011;7(3):264e269.
Wadhwa R. CARF (Collaborator of ARF) overexpression in p53- 172. Omoti A, Omoti C. Ocular toxicity of systemic anticancer
deficient cells promotes carcinogenesis. Mol Oncol. 2015; chemotherapy. Pharm Pract. 2006;4:55e59.
9(9):1877e1889. 173. Al-Tweigeri T, Nabholtz JM, MacKey JR. Ocular toxicity and
151. Joshi V, Upadhyay A, Prajapati VK, Mishra A. How autophagy cancer chemotherapy. A review. Cancer. 1996;78(7):
can restore proteostasis defects in multiple diseases? Med Res 1359e1373.
Rev. 2020;40(4):1385e1439. 174. Curigliano G, Cardinale D, Suter T, et al. Cardiovascular
152. Mishra R, Upadhyay A, Prajapati VK, Mishra A. Proteasome- toxicity induced by chemotherapy, targeted agents and
mediated proteostasis: novel medicinal and pharmacological radiotherapy: ESMO Clinical Practice Guidelines. Ann Oncol.
strategies for diseases. Med Res Rev. 2018;38(6):1916e1973. 2012;23(Suppl 7):vii155evii166.
153. Upadhyay A, Amanullah A, Chhangani D, Joshi V, Mishra R, 175. Cohen JD, Li L, Wang Y, et al. Detection and localization of
Mishra A. Ibuprofen induces mitochondrial-mediated surgically resectable cancers with a multi-analyte blood test.
apoptosis through proteasomal dysfunction. Mol Neurobiol. Science. 2018;359(6378):926e930.
2016;53(10):6968e6981.

30
 + MODEL
Genes & Diseases xxx (xxxx) xxx

176. Alix-Panabières C, Pantel K. Clinical applications of circu- BRCA2 mutations and advanced breast cancer: a proof-of-
lating tumor cells and circulating tumor DNA as liquid biopsy. concept trial. Lancet. 2010;376(9737):235e244.
Cancer Discov. 2016;6(5):479e491. 199. Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose)
177. Li L, Gao R, Yu Y, et al. Tumor suppressor activity of miR- polymerase in tumors from BRCA mutation carriers. N Engl J
451:identification of CARF as a new target. Sci Rep. 2018; Med. 2009;361(2):123e134.
8(1):375. 200. Chaudhary A, Kalra RS, Huang C, Prakash J, Kaul SC,
178. Shohdy KS, West HJ. Circulating tumor DNA testing-liquid bi- Wadhwa R. 2, 3-dihydro-3b-methoxy withaferin-A protects
opsy of a cancer. JAMA Oncol. 2020;6(5):792. normal cells against stress: molecular evidence of its potent
179. Vivek R, Thangam R, NipunBabu V, et al. Multifunctional cytoprotective activity. J Nat Prod. 2017;80(10):2756e2760.
HER2-antibody conjugated polymeric nanocarrier-based drug 201. Friedman AA, Letai A, Fisher DE, Flaherty KT. Precision
delivery system for multi-drug-resistant breast cancer ther- medicine for cancer with next-generation functional di-
apy. ACS Appl Mater Interfaces. 2014;6(9):6469e6480. agnostics. Nat Rev Cancer. 2015;15(12):747e756.
180. Alley SC, Okeley NM, Senter PD. Antibody-drug conjugates: 202. de la Fuente-Núñez C, Silva ON, Lu TK, Franco OL. Antimi-
targeted drug delivery for cancer. Curr Opin Chem Biol. 2010; crobial peptides: role in human disease and potential as im-
14(4):529e537. munotherapies. Pharmacol Ther. 2017;178:132e140.
181. Wang X, Wang Y, Chen ZG, Shin DM. Advances of cancer 203. Felı́cio MR, Silva ON, Gonçalves S, Santos NC, Franco OL.
therapy by nanotechnology. Cancer Res Treat. 2009;41(1): Peptides with dual antimicrobial and anticancer activities.
1e11. Front Chem. 2017;5:5.
182. Firer MA, Gellerman G. Targeted drug delivery for cancer 204. Hilchie AL, Hoskin DW, Power Coombs MR. Anticancer activ-
therapy: the other side of antibodies. J Hematol Oncol. 2012; ities of natural and synthetic peptides. Adv Exp Med Biol.
5:70. 2019;1117:131e147.
183. Kutova OM, Guryev EL, Sokolova EA, Alzeibak R, Balalaeva IV. 205. Mwangi J, Hao X, Lai R, Zhang ZY. Antimicrobial peptides:
Targeted delivery to tumors: multidirectional strategies to new hope in the war against multidrug resistance. Zool Res.
improve treatment efficiency. Cancers. 2019;11(1):68. 2019;40(6):488e505.
184. Cho K, Wang X, Nie S, Chen ZG, Shin DM. Therapeutic nano- 206. Qin Y, Qin ZD, Chen J, et al. From antimicrobial to anticancer
particles for drug delivery in cancer. Clin Cancer Res. 2008; peptides: the transformation of peptides. Recent Pat Anti-
14(5):1310e1316. Cancer Drug Discov. 2019;14(1):70e84.
185. Rosenblum D, Joshi N, Tao W, Karp JM, Peer D. Progress and 207. Lei J, Sun L, Huang S, et al. The antimicrobial peptides and
challenges towards targeted delivery of cancer therapeutics. their potential clinical applications. Am J Transl Res. 2019;
Nat Commun. 2018;9(1):1410. 11(7):3919e3931.
186. Sutradhar KB, Amin ML. Nanotechnology in cancer drug de- 208. Roudi R, Syn NL, Roudbary M. Antimicrobial peptides as bio-
livery and selective targeting. ISRN Nanotechnol. 2014;2014: logic and immunotherapeutic agents against cancer: a
939378. comprehensive overview. Front Immunol. 2017;8:1320.
187. Lammers T, Kiessling F, Ashford M, Hennink W, Crommelin D, 209. Tornesello AL, Borrelli A, Buonaguro L, Buonaguro FM,
Storm G. Cancer nanomedicine: is targeting our target? Nat Tornesello ML. Antimicrobial peptides as anticancer agents:
Rev Mater. 2016;1(9):16069. functional properties and biological activities. Molecules.
188. El-Readi MZ, Althubiti MA. Cancer nanomedicine: a new era of 2020;25(12):2850.
successful targeted therapy. J Nanomater. 2019;2019: 210. Khare T, Anand U, Dey A, et al. Exploring phytochemicals for
4927312. combating antibiotic resistance in microbial pathogens. Front
189. Dias-Santagata D, Akhavanfard S, David SS, et al. Rapid tar- Pharmacol. 2021;12:720726.
geted mutational analysis of human tumours: a clinical plat- 211. van Harten RM, van Woudenbergh E, van Dijk A, Haagsman HP.
form to guide personalized cancer medicine. EMBO Mol Med. Cathelicidins: immunomodulatory antimicrobials. Vaccines.
2010;2(5):146e158. 2018;6(3):63.
190. Dong L, Wang W, Li A, et al. Clinical next generation 212. Wang G, Narayana JL, Mishra B, et al. Design of Antimicrobial
sequencing for precision medicine in cancer. Curr Genom. Peptides: Progress Made with Human Cathelicidin LL-37.
2015;16(4):253e263. Advances in Experimental Medicine and Biology. Singapore:
191. Fedorenko IV, Gibney GT, Sondak VK, Smalley KSM. Beyond Springer Singapore; 2019:215e240.
BRAF: where next for melanoma therapy? Br J Cancer. 2015; 213. Fabisiak A, Murawska N, Fichna J. LL-37:cathelicidin-related
112(2):217e226. antimicrobial peptide with pleiotropic activity. Pharmacol
192. Zaman A, Wu W, Bivona TG. Targeting oncogenic BRAF: past, Rep. 2016;68(4):802e808.
present, and future. Cancers. 2019;11(8):1197. 214. Chen X, Ji S, Si J, et al. Human cathelicidin antimicrobial
193. André F, Ciruelos E, Rubovszky G, et al. Alpelisib for PIK3CA- peptide suppresses proliferation, migration and invasion of
mutated, hormone receptor-positive advanced breast cancer. oral carcinoma HSC-3 cells via a novel mechanism involving
N Engl J Med. 2019;380(20):1929e1940. caspase-3 mediated apoptosis. Mol Med Rep. 2020;22(6):
194. Kalra RS, Bapat SA. Proteomics to Predict Loss of RXR-g 5243e5250.
during Progression of Epithelial Ovarian Cancer. Methods in 215. Porter RJ, Murray GI, Alnabulsi A, et al. Colonic epithelial
Molecular Biology. New York, NY. New York: Springer; 2019: cathelicidin (LL-37) expression intensity is associated with
1e14. progression of colorectal cancer and presence of CD8þ T cell
195. Soda M, Choi YL, Enomoto M, et al. Identification of the infiltrate. J Pathol Clin Res. 2021;7(5):495e506.
transforming EML4-ALK fusion gene in non-small-cell lung 216. Wang J, Cheng M, Law IKM, Ortiz C, Sun M, Koon HW. Cath-
cancer. Nature. 2007;448(7153):561e566. elicidin suppresses colon cancer metastasis via a P2RX7-
196. Hyman DM, Puzanov I, Subbiah V, et al. Vemurafenib in mul- dependent mechanism. Mol Ther Oncolytics. 2019;12:
tiple nonmelanoma cancers with BRAF V600 mutations. N Engl 195e203.
J Med. 2015;373(8):726e736. 217. Biswaro LS, da Costa Sousa MG, Rezende TMB, Dias SC,
197. Babina IS, Turner NC. Advances and challenges in targeting Franco OL. Antimicrobial peptides and nanotechnology,
FGFR signalling in cancer. Nat Rev Cancer. 2017;17(5):318e332. recent advances and challenges. Front Microbiol. 2018;9:855.
198. Tutt A, Robson M, Garber JE, et al. Oral poly(ADP-ribose) 218. Niemirowicz K, Prokop I, Wilczewska AZ, et al. Magnetic
polymerase inhibitor olaparib in patients with BRCA1 or nanoparticles enhance the anticancer activity of cathelicidin

31
 + MODEL
U. Anand, A. Dey, A.K.S. Chandel et al.

LL-37 peptide against colon cancer cells. Int J Nanomed. 239. Chiossone L, Dumas PY, Vienne M, Vivier E. Natural killer cells
2015;10:3843e3853. and other innate lymphoid cells in cancer. Nat Rev Immunol.
219. Fan R, Tong A, Li X, et al. Enhanced antitumor effects by 2018;18(11):671e688.
docetaxel/LL37-loaded thermosensitive hydrogel nano- 240. Anyaegbu CC, Lake RA, Heel K, Robinson BW, Fisher SA.
particles in peritoneal carcinomatosis of colorectal cancer. Chemotherapy enhances cross-presentation of nuclear tumor
Int J Nanomed. 2015;10:7291e7305. antigens. PLoS One. 2014;9(9):e107894.
220. Chauhan S, Dhawan DK, Saini A, Preet S. Antimicrobial pep- 241. Konstantinopoulos PA, Cheng SC, Wahner Hendrickson AE,
tides against colorectal cancer-a focused review. Pharmacol et al. Berzosertib plus gemcitabine versus gemcitabine alone
Res. 2021;167:105529. in platinum-resistant high-grade serous ovarian cancer: a
221. Dolkar T, Trinidad CM, Nelson KC, et al. Dermatologic toxicity multicentre, open-label, randomised, phase 2 trial. Lancet
from novel therapy using antimicrobial peptide LL-37 in Oncol. 2020;21(7):957e968.
melanoma: a detailed examination of the clinicopathologic 242. Reck M. Pembrolizumab as first-line therapy for metastatic non-
features. J Cutan Pathol. 2018;45(7):539e544. small-cell lung cancer. Immunotherapy. 2018;10(2):93e105.
222. Divyashree M, Mani MK, Reddy D, et al. Clinical applications of 243. Kang C, Syed YY. Atezolizumab (in combination with nab-
antimicrobial peptides (AMPs):where do we stand now? Pro- paclitaxel):a review in advanced triple-negative breast can-
tein Pept Lett. 2020;27(2):120e134. cer. Drugs. 2020;80(6):601e607.
223. Karlitepe A, Ozalp O, Avci CB. New approaches for cancer 244. Allard B, Allard D, Buisseret L, Stagg J. The adenosine pathway in
immunotherapy. Tumour Biol. 2015;36(6):4075e4078. immuno-oncology. Nat Rev Clin Oncol. 2020;17(10):611e629.
224. Weiner LM, Murray JC, Shuptrine CW. Antibody-based immu- 245. Pasquini S, Contri C, Borea PA, Vincenzi F, Varani K. Adenosine
notherapy of cancer. Cell. 2012;148(6):1081e1084. and inflammation: here, there and everywhere. Int J Mol Sci.
225. Vigneron N. Human tumor antigens and cancer immuno- 2021;22(14):7685.
therapy. BioMed Res Int. 2015;2015:948501. 246. Franco R, Rivas-Santisteban R, Navarro G, Reyes-Resina I.
226. Kim I, Sanchez K, McArthur HL, Page D. Immunotherapy in Adenosine receptor antagonists to combat cancer and to
triple-negative breast cancer: present and future. Curr boost anti-cancer chemotherapy and immunotherapy. Cells.
Breast Cancer Rep. 2019;11(4):259e271. 2021;10(11):2831.
227. Marra A, Viale G, Curigliano G. Recent advances in triple 247. Helms RS, Powell JD. Rethinking the adenosine-A2AR check-
negative breast cancer: the immunotherapy era. BMC Med. point: implications for enhancing anti-tumor immunotherapy.
2019;17(1):90. Curr Opin Pharmacol. 2020;53:77e83.
228. Sambi M, Bagheri L, Szewczuk MR. Current challenges in 248. Yu F, Zhu C, Xie Q, Wang Y. Adenosine A2A receptor antago-
cancer immunotherapy: multimodal approaches to improve nists for cancer immunotherapy. J Med Chem. 2020;63(21):
efficacy and patient response rates. JAMA Oncol. 2019;2019: 12196e12212.
4508794. 249. Yan W, Ling L, Wu Y, et al. Structure-based design of dual-
229. Paz-Ares L, Luft A, Vicente D, et al. Pembrolizumab plus acting compounds targeting adenosine A2A receptor and his-
chemotherapy for squamous non-small-cell lung cancer. N tone deacetylase as novel tumor immunotherapeutic agents.
Engl J Med. 2018;379(21):2040e2051. J Med Chem. 2021;64(22):16573e16597.
230. Finn OJ. Vaccines for cancer prevention: a practical and 250. Churov A, Zhulai G. Targeting adenosine and regulatory T cells in
feasible approach to the cancer epidemic. Cancer Immunol cancer immunotherapy. Hum Immunol. 2021;82(4):270e278.
Res. 2014;2(8):708e713. 251. Marks DL, Olson RL, Fernandez-Zapico ME. Epigenetic control
231. Pérez-Garcı́a J, Soberino J, Racca F, Gion M, Stradella A, of the tumor microenvironment. Epigenomics. 2016;8(12):
Cortés J. Atezolizumab in the treatment of metastatic triple- 1671e1687.
negative breast cancer. Expet Opin Biol Ther. 2020;20(9): 252. Lodewijk I, Nunes SP, Henrique R, Jerónimo C, Dueñas M,
981e989. Paramio JM. Tackling tumor microenvironment through
232. Reddy SM, Carroll E, Nanda R. Atezolizumab for the treatment epigenetic tools to improve cancer immunotherapy. Clin
of breast cancer. Expert Rev Anticancer Ther. 2020;20(3): Epigenet. 2021;13(1):63.
151e158. 253. Pan X, Zheng L. Epigenetics in modulating immune functions
233. Cyprian FS, Akhtar S, Gatalica Z, Vranic S. Targeted immu- of stromal and immune cells in the tumor microenvironment.
notherapy with a checkpoint inhibitor in combination with Cell Mol Immunol. 2020;17(9):940e953.
chemotherapy: a new clinical paradigm in the treatment of 254. Duan Q, Zhang H, Zheng J, Zhang L. Turning cold into hot:
triple-negative breast cancer. Bosn J Basic Med Sci. 2019; firing up the tumor microenvironment. Trends Cancer. 2020;
19(3):227e233. 6(7):605e618.
234. Ledford H. Engineered cell therapy for cancer gets thumbs up 255. Lim WA, June CH. The principles of engineering immune cells
from FDA advisers. Nature. 2017;547(7663):270. to treat cancer. Cell. 2017;168(4):724e740.
235. Schirrmacher V. From chemotherapy to biological therapy: a 256. Murciano-Goroff YR, Warner AB, Wolchok JD. The future of
review of novel concepts to reduce the side effects of sys- cancer immunotherapy: microenvironment-targeting combi-
temic cancer treatment (Review). Int J Oncol. 2019;54(2): nations. Cell Res. 2020;30(6):507e519.
407e419. 257. Hulen TM, Chamberlain CA, Svane IM, Met Ö. ACT up TIL now:
236. Vanneman M, Dranoff G. Combining immunotherapy and tar- the evolution of tumor-infiltrating lymphocytes in adoptive
geted therapies in cancer treatment. Nat Rev Cancer. 2012; cell therapy for the treatment of solid tumors. Immunology.
12(4):237e251. 2021;1(3):194e211.
237. Hughes PE, Caenepeel S, Wu LC. Targeted therapy and 258. Newick K, O’Brien S, Moon E, Albelda SM. CAR T cell therapy
checkpoint immunotherapy combinations for the treatment for solid tumors. Annu Rev Med. 2017;68:139e152.
of cancer. Trends Immunol. 2016;37(7):462e476. 259. Singh AK, McGuirk JP. CAR T cells: continuation in a revolution
238. Grosser R, Cherkassky L, Chintala N, Adusumilli PS. Combi- of immunotherapy. Lancet Oncol. 2020;21(3):e168ee178.
nation immunotherapy with CAR T cells and checkpoint 260. Jazirehi AR. Molecular analysis of elements of melanoma
blockade for the treatment of solid tumors. Cancer Cell. insensitivity to TCR-engineered adoptive cell therapy. Int J
2019;36(5):471e482. Mol Sci. 2021;22(21):11726.

32
 + MODEL
Genes & Diseases xxx (xxxx) xxx

261. Tan E, Gakhar N, Kirtane K. TCR gene-engineered cell therapy 279. Chu E, DeVita VT. Physician’s Cancer Chemotherapy Drug
for solid tumors. Best Pract Res Clin Haematol. 2021;34(3): Manual 2015. 15th ed. Burlington, MA: Jones & Bartlett
101285. Learning; 2015.
262. Ö Met, Jensen KM, Chamberlain CA, Donia M, Svane IM. 280. Yerram P, Reiss SN, Modelevsky L, Gavrilovic IT, Kaley T.
Principles of adoptive T cell therapy in cancer. Semin Immu- Evaluation of toxicity of carmustine with or without bev-
nopathol. 2019;41(1):49e58. acizumab in patients with recurrent or progressive high grade
263. Wolf B, Zimmermann S, Arber C, Irving M, Trueb L, Coukos G. gliomas. J Neuro Oncol. 2019;145(1):57e63.
Safety and tolerability of adoptive cell therapy in cancer. 281. Karahoca M, Momparler RL. Pharmacokinetic and pharmaco-
Drug Saf. 2019;42(2):315e334. dynamic analysis of 5-aza-2’-deoxycytidine (decitabine) in
264. Kaufman HL, Maciorowski D. Advancing oncolytic virus ther- the design of its dose-schedule for cancer therapy. Clin Epi-
apy by understanding the biology. Nat Rev Clin Oncol. 2021; genet. 2013;5(1):3.
18(4):197e198. 282. Vanneste M, Huang Q, Li M, et al. High content screening
265. Ferrucci PF, Pala L, Conforti F, Cocorocchio E. Talimogene identifies monensin as an EMT-selective cytotoxic compound.
laherparepvec (T-VEC):an intralesional cancer immuno- Sci Rep. 2019;9(1):1200.
therapy for advanced melanoma. Cancers. 2021;13(6): 283. Rycenga HB, Long DT. The evolving role of DNA inter-strand
1383. crosslinks in chemotherapy. Curr Opin Pharmacol. 2018;41:
266. Lu L, Jiang J, Zhan M, et al. Targeting tumor-associated an- 20e26.
tigens in hepatocellular carcinoma for immunotherapy: past 284. Samuels BL, Bitran JD. High-dose intravenous melphalan: a
pitfalls and future strategies. Hepatology. 2021;73(2): review. J Clin Oncol. 1995;13(7):1786e1799.
821e832. 285. Ma MT, He M, Wang Y, et al. miR-487a resensitizes mitoxan-
267. Liu Z, Han C, Fu YX. Targeting innate sensing in the tumor trone (MX)-resistant breast cancer cells (MCF-7/MX) to MX by
microenvironment to improve immunotherapy. Cell Mol targeting breast cancer resistance protein (BCRP/ABCG2).
Immunol. 2020;17(1):13e26. Cancer Lett. 2013;339(1):107e115.
268. Bejarano L, Jorda o MJC, Joyce JA. Therapeutic targeting of 286. Graham J, Muhsin M, Kirkpatrick P. Oxaliplatin. Nat Rev Drug
the tumor microenvironment. Cancer Discov. 2021;11(4): Discov. 2004;3(1):11e12.
933e959. 287. Jacinto FV, Esteller M. MGMT hypermethylation: a prognostic
269. Anand U, Tudu CK, Nandy S, et al. Ethnodermatological use of foe, a predictive friend. DNA Repair. 2007;6(8):1155e1160.
medicinal plants in India: from ayurvedic formulations to 288. Arrieta O, Lara-Mejı́a L, Zatarain-Barrón ZL. Carboplatin plus
clinical perspectives - a review. J Ethnopharmacol. 2022;284: etoposide or topotecan for small-cell lung cancer. Lancet
114744. Oncol. 2020;21(9):1132e1134.
270. Paul S, Chakraborty S, Anand U, et al. Withania somnifera (L.) 289. Hwang DY, Kim SJ, Cheong JW, et al. High pre-transplant
Dunal (Ashwagandha):a comprehensive review on ethno- serum ferritin and busulfan-thiotepa conditioning regimen
pharmacology, pharmacotherapeutics, biomedicinal and as risk factors for hepatic sinusoidal obstructive syndrome
toxicological aspects. Biomed Pharmacother. 2021;143: after autologous stem cell transplantation in patients with
112175. malignant lymphoma. Leuk Lymphoma. 2016;57(1):51e57.
271. Lin SR, Chang CH, Hsu CF, et al. Natural compounds as po- 290. D’Incalci M, Badri N, Galmarini CM, Allavena P. Trabectedin, a
tential adjuvants to cancer therapy: preclinical evidence. Br drug acting on both cancer cells and the tumour microenvi-
J Pharmacol. 2020;177(6):1409e1423. ronment. Br J Cancer. 2014;111(4):646e650.
272. Nobili S, Lippi D, Witort E, et al. Natural compounds for 291. Maltzman JS, Koretzky GA. Azathioprine: old drug, new ac-
cancer treatment and prevention. Pharmacol Res. 2009;59(6): tions. J Clin Invest. 2003;111(8):1122e1124.
365e378. 292. Hasanali ZS, Saroya BS, Stuart A, et al. Epigenetic therapy
273. Mitra S, Anand U, Jha NK, et al. Anticancer applications overcomes treatment resistance in T cell prolymphocytic
and pharmacological properties of piperidine and piperine: leukemia. Sci Transl Med. 2015;7(293):293ra102.
a comprehensive review on molecular mechanisms and 293. Bonate PL, Arthaud L, Cantrell WR, Stephenson K, Secrist JA,
therapeutic perspectives. Front Pharmacol. 2021;12: Weitman S. Discovery and development of clofarabine: a
772418. nucleoside analogue for treating cancer. Nat Rev Drug Discov.
274. Mitra S, Anand U, Sanyal R, et al. Neoechinulins: molecular, 2006;5(10):855e863.
cellular, and functional attributes as promising therapeutics 294. Ricci F, Tedeschi A, Morra E, Montillo M. Fludarabine in the
against cancer and other human diseases. Biomed Pharmac- treatment of chronic lymphocytic leukemia: a review. Ther-
other. 2022;145:112378. apeut Clin Risk Manag. 2009;5(1):187e207.
275. Bandopadhyay S, Anand U, Gadekar VS, et al. Dioscin: a re- 295. Mini E, Nobili S, Caciagli B, Landini I, Mazzei T. Cellular
view on pharmacological properties and therapeutic values. pharmacology of gemcitabine. Ann Oncol. 2006;17(Suppl 5):
Biofactors. 2022;48(1):22e55. v7ev12.
276. Datta S, Ramamurthy PC, Anand U, et al. Wonder or evil? : 296. Engels FK, Sparreboom A, Mathot RAA, Verweij J. Potential
multifaceted health hazards and health benefits of Cannabis for improvement of docetaxel-based chemotherapy: a phar-
sativa and its phytochemicals. Saudi J Biol Sci. 2021;28(12): macological review. Br J Cancer. 2005;93(2):173e177.
7290e7313. 297. Cohen MH, Johnson JR, Massie T, et al. Approval summary:
277. Dutta T, Anand U, Saha SC, et al. Advancing urban ethno- nelarabine for the treatment of T-cell lymphoblastic leuke-
pharmacology: a modern concept of sustainability, conser- mia/lymphoma. Clin Cancer Res. 2006;12(18):5329e5335.
vation and cross-cultural adaptations of medicinal plant lore 298. Cannon T, Mobarek D, Wegge J, Tabbara IA. Hairy cell leu-
in the urban environment. Conserv Physiol. 2021;9(1): kemia: current concepts. Cancer Invest. 2008;26(8):860e865.
coab073. 299. Wang H, Wang Y. LC-MS/MS coupled with stable isotope dilution
278. Tournilhac O, Cazin B, Leprètre S, et al. Impact of frontline method for the quantification of 6-thioguanine and S6-
fludarabine and cyclophosphamide combined treatment on methylthioguanine in genomic DNA of human cancer cells
peripheral blood stem cell mobilization in B-cell chronic treated with 6-thioguanine. Anal Chem. 2010;82(13):
lymphocytic leukemia. Blood. 2004;103(1):363e365. 5797e5803.

33
 + MODEL
U. Anand, A. Dey, A.K.S. Chandel et al.

300. Sertel S, Tome M, Briehl MM, et al. Factors determining 320. Casak SJ, Lemery SJ, Shen YL, et al. U.S. Food and drug
sensitivity and resistance of tumor cells to arsenic trioxide. administration approval: rituximab in combination with flu-
PLoS One. 2012;7(5):e35584. darabine and cyclophosphamide for the treatment of patients
301. Madaan K, Kaushik D, Verma T. Hydroxyurea: a key player in with chronic lymphocytic leukemia. Oncol. 2011;16(1):97e104.
cancer chemotherapy. Expert Rev Anticancer Ther. 2012; 321. Jiang G, Li RH, Sun C, Liu YQ, Zheng JN. Dacarbazine com-
12(1):19e29. bined targeted therapy versus dacarbazine alone in patients
302. Scripture CD, Szebeni J, Loos WJ, Figg WD, Sparreboom A. with malignant melanoma: a meta-analysis. PLoS One. 2014;
Comparative in vitro properties and clinical pharmacokinetics 9(12):e111920.
of Paclitaxel following the administration of taxol(r) and 322. Velho TR. Metastatic melanoma - a review of current and
paxene(r). Cancer Biol Ther. 2005;4(5):555e560. future drugs. Drugs Context. 2012;2012:212242.
303. Alken S, Kelly CM. Benefit risk assessment and update on the 323. Krauss AC, Gao X, Li L, et al. FDA approval summary:
use of docetaxel in the management of breast cancer. Cancer (daunorubicin and cytarabine) liposome for injection for the
Manag Res. 2013;5:357e365. treatment of adults with high-risk acute myeloid leukemia.
304. Chan ES, Cronstein BN. Mechanisms of action of metho- Clin Cancer Res. 2019;25(9):2685e2690.
trexate. Bull Hosp Jt Dis. 2013;71(Suppl 1):S5eS8. 324. Blair HA. Daunorubicin/cytarabine liposome: a review in
305. Adjei AA. Pharmacology and mechanism of action of peme- acute myeloid leukaemia. Drugs. 2018;78(18):1903e1910.
trexed. Clin Lung Cancer. 2004;5(Suppl 2):S51eS55. 325. Dhillon S. Decitabine/cedazuridine: first approval. Drugs.
306. Weatherstone K, Meyer T. Streptozocin-based chemotherapy 2020;80(13):1373e1378.
is not history in neuroendocrine tumours. Targeted Oncol. 326. Kanwal U, Irfan Bukhari N, Ovais M, Abass N, Hussain K,
2012;7(3):161e168. Raza A. Advances in nano-delivery systems for doxorubicin: an
307. Haque A, Rahman MA, Faizi MSH, Khan MS. Next generation updated insight. J Drug Target. 2018;26(4):296e310.
antineoplastic agents: a review on structurally modified 327. Cagel M, Grotz E, Bernabeu E, Moretton MA, Chiappetta DA.
vinblastine (VBL) analogues. Curr Med Chem. 2018;25(14): Doxorubicin: nanotechnological overviews from bench to
1650e1662. bedside. Drug Discov Today. 2017;22(2):270e281.
308. Beaver C. Vincristine minibag administration: a quality 328. Buzdar AU, Suman VJ, Meric-Bernstam F, et al. Fluorouracil,
improvement project to minimize medical errors. Clin J Oncol epirubicin, and cyclophosphamide (FEC-75) followed by
Nurs. 2018;22(6):669e672. paclitaxel plus trastuzumab versus paclitaxel plus trastuzu-
309. Mehta-Shah N, Ratner L, Horwitz SM. Adult T-cell leuke- mab followed by FEC-75 plus trastuzumab as neoadjuvant
mia/lymphoma. J Oncol Pract. 2017;13(8):487e492. treatment for patients with HER2-positive breast cancer
310. Altinoz MA, Ozpinar A, Alturfan EE, Elmaci I. Vinorelbine’s (Z1041):a randomised, controlled, phase 3 trial. Lancet
anti-tumor actions may depend on the mitotic apoptosis, Oncol. 2013;14(13):1317e1325.
autophagy and inflammation: hypotheses with implications 329. Hollingshead LM, Faulds D. Idarubicin. A review of its phar-
for chemo-immunotherapy of advanced cancers and pediatric macodynamic and pharmacokinetic properties, and thera-
gliomas. J Chemother. 2018;30(4):203e212. peutic potential in the chemotherapy of cancer. Drugs. 1991;
311. Jäger U, Barcellini W, Broome CM, et al. Diagnosis and 42(4):690e719.
treatment of autoimmune hemolytic Anemia in adults: rec- 330. Matz EL, Hsieh MH. Review of advances in uroprotective
ommendations from the first international consensus agents for cyclophosphamide- and ifosfamide-induced hem-
meeting. Blood Rev. 2020;41:100648. orrhagic cystitis. Urology. 2017;100:16e19.
312. Kreitman RJ, Arons E. Update on hairy cell leukemia. Clin Adv 331. de Man FM, Goey AKL, van Schaik RHN, Mathijssen RHJ, Bins S.
Hematol Oncol. 2018;16(3):205e215. Individualization of irinotecan treatment: a review of phar-
313. Begna K, Abdelatif A, Schwager S, Hanson C, Pardanani A, macokinetics, pharmacodynamics, and pharmacogenetics.
Tefferi A. Busulfan for the treatment of myeloproliferative Clin Pharmacokinet. 2018;57(10):1229e1254.
neoplasms: the Mayo Clinic experience. Blood Cancer J. 2016; 332. KuKanich B, Warner M, Hahn K. Analysis of lomustine drug
6(5):e427. content in FDA-approved and compounded lomustine cap-
314. Palmer J, McCune JS, Perales MA, et al. Personalizing sules. J Am Vet Med Assoc. 2017;250(3):322e326.
busulfan-based conditioning: considerations from the Amer- 333. Sun J, Wei Q, Zhou Y, Wang J, Liu Q, Xu H. A systematic
ican society for blood and marrow transplantation practice analysis of FDA-approved anticancer drugs. BMC Syst Biol.
guidelines committee. Biol Blood Marrow Transplant. 2016; 2017;11(Suppl 5):87.
22(11):1915e1925. 334. Fox EJ. Mechanism of action of mitoxantrone. Neurology.
315. Ho GY, Woodward N, Coward JIG. Cisplatin versus carbopla- 2004;63(12 Suppl 6):S15eS18.
tin: comparative review of therapeutic management in solid 335. Ibrahim A, Hirschfeld S, Cohen MH, Griebel DJ, Williams GA,
malignancies. Crit Rev Oncol Hematol. 2016;102:37e46. Pazdur R. FDA drug approval summaries: oxaliplatin. Oncol.
316. Lee HZ, Miller BW, Kwitkowski VE, et al. U.S. food and drug 2004;9(1):8e12.
administration approval: obinutuzumab in combination with 336. Stein A, Arnold D. Oxaliplatin: a review of approved uses.
chlorambucil for the treatment of previously untreated Expet Opin Pharmacother. 2012;13(1):125e137.
chronic lymphocytic leukemia. Clin Cancer Res. 2014;20(15): 337. Mutter N, Stupp R. Temozolomide: a milestone in neuro-
3902e3907. oncology and beyond? Expert Rev Anticancer Ther. 2006;
317. Hew J, Pham D, Matthews Hew T, Minocha V. A novel treat- 6(8):1187e1204.
ment with obinutuzumab-chlorambucil in a patient with B- 338. Ardizzoni A, Hansen H, Dombernowsky P, et al. Topotecan, a
cell prolymphocytic leukemia: a case report and review of the new active drug in the second-line treatment of small-cell
literature. J Investig Med High Impact Case Rep. 2018;6: lung cancer: a phase II study in patients with refractory and
2324709618788674. sensitive disease. The European organization for research and
318. Makovec T. Cisplatin and beyond: molecular mechanisms of treatment of cancer early clinical studies group and new drug
action and drug resistance development in cancer chemo- development office, and the lung cancer cooperative group. J
therapy. Radiol Oncol. 2019;53(2):148e158. Clin Oncol. 1997;15(5):2090e2096.
319. Raudenska M, Balvan J, Fojtu M, Gumulec J, Masarik M. Un- 339. Garst J. Topotecan: an evolving option in the treatment of
expected therapeutic effects of cisplatin. Metallomics. 2019; relapsed small cell lung cancer. Therapeut Clin Risk Manag.
11(7):1182e1199. 2007;3(6):1087e1095.

34
 + MODEL
Genes & Diseases xxx (xxxx) xxx

340. Eckardt JR, von Pawel J, Pujol JL, et al. Phase III study of (Teysuno) for the treatment of advanced gastric cancer
oral compared with intravenous topotecan as second-line when given in combination with cisplatin: summary of the
therapy in small-cell lung cancer. J Clin Oncol. 2007; Scientific Assessment of the Committee for medicinal prod-
25(15):2086e2092. ucts for human use (CHMP). Oncol. 2011;16(10):1451e1457.
341. Kokolo MB, Fergusson D, O’Neill J, et al. Effectiveness and 351. Alimoghaddam K. A review of arsenic trioxide and acute
safety of thiotepa as conditioning treatment prior to stem cell promyelocytic leukemia. Int J Hematol Oncol Stem Cell Res.
transplant in patients with central nervous system lymphoma. 2014;8(3):44e54.
Leuk Lymphoma. 2014;55(12):2712e2720. 352. Emadi A, Gore SD. Arsenic trioxide - an old drug rediscovered.
342. Barone A, Chi DC, Theoret MR, et al. FDA approval summary: Blood Rev. 2010;24(4e5):191e199.
trabectedin for unresectable or metastatic liposarcoma or 353. Menzin AW, King SA, Aikins JK, Mikuta JJ, Rubin SC. Taxol
leiomyosarcoma following an anthracycline-containing (paclitaxel) was approved by FDA for the treatment of patients
regimen. Clin Cancer Res. 2017;23(24):7448e7453. with recurrent ovarian cancer. Gynecol Oncol. 1994;54(1):103.
343. Rosenberg JD, Burian C, Waalen J, Saven A. Clinical charac- 354. Li J, Ren J, Sun W. Systematic review of ixabepilone for treating
teristics and long-term outcome of young hairy cell leukemia metastatic breast cancer. Breast Cancer. 2017;24(2):171e179.
patients treated with cladribine: a single-institution series. 355. Abolmaali SS, Tamaddon AM, Dinarvand R. A review of ther-
Blood. 2014;123(2):177e183. apeutic challenges and achievements of methotrexate de-
344. Zhenchuk A, Lotfi K, Juliusson G, Albertioni F. Mechanisms of livery systems for treatment of cancer and rheumatoid
anti-cancer action and pharmacology of clofarabine. Biochem arthritis. Cancer Chemother Pharmacol. 2013;71(5):
Pharmacol. 2009;78(11):1351e1359. 1115e1130.
345. Schmiegelow K, Al-Modhwahi I, Andersen MK, et al. Metho- 356. Moore AS, Nelson RW, Henry CJ, et al. Streptozocin for
trexate/6-mercaptopurine maintenance therapy influences treatment of pancreatic islet cell tumors in dogs: 17
the risk of a second malignant neoplasm after childhood acute cases (1989-1999). J Am Vet Med Assoc. 2002;221(6):
lymphoblastic leukemia: results from the NOPHO ALL-92 811e818.
study. Blood. 2009;113(24):6077e6084. 357. Said R, Tsimberidou AM. Pharmacokinetic evaluation of
346. Dillman RO. Pentostatin (Nipent) in the treatment of vincristine for the treatment of lymphoid malignancies. Expet
chronic lymphocyte leukemia and hairy cell leukemia. Expert Opin Drug Metabol Toxicol. 2014;10(3):483e494.
Rev Anticancer Ther. 2004;4(1):27e36. 358. Martino E, Casamassima G, Castiglione S, et al. Vinca alka-
347. Munshi PN, Lubin M, Bertino JR. 6-thioguanine: a drug with loids and analogues as anti-cancer agents: looking back,
unrealized potential for cancer therapy. Oncol. 2014;19(7): peering ahead. Bioorg Med Chem Lett. 2018;28(17):
760e765. 2816e2826.
348. Dent S, Messersmith H, Trudeau M. Gemcitabine in the man- 359. Smith GA. Current status of vinorelbine for breast cancer.
agement of metastatic breast cancer: a systematic review. Oncology. 1995;9(8):767e773; discussion774,776,779.
Breast Cancer Res Treat. 2008;108(3):319e331. 360. Gasparini G, Caffo O, Barni S, et al. Vinorelbine is an active
349. Moysan E, Bastiat G, Benoit JP. Gemcitabine versus Modified antiproliferative agent in pretreated advanced breast cancer
Gemcitabine: a review of several promising chemical modifi- patients: a phase II study. J Clin Oncol. 1994;12(10):
cations. Mol Pharm. 2013;10(2):430e444. 2094e2101.
350. Matt P, van Zwieten-Boot B, Calvo Rojas G, et al. The Euro-
pean Medicines Agency review of Tegafur/Gimeracil/Oteracil

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