Cancer chemotherapy

Introduction
• cancer is an uncontrolled growth of abnormal
cells in the body.
– is one of the leading causes of death in developed
countries, responsible for about 25% of all deaths
– can be attributed to mutations in the signals that
regulate the cell cycle of growth and division
• The cell cycle has 5 phases
– cell reproduction happens over and over, the cell
cycle Is shown as a circle.
Fig.2 Cell division:Normal Vs Cancer cell
• Cancer cells overcome the normal cell signaling process
– cell proliferation becoming uncontrollable
– cells becoming resistant to apoptosis (programmed cell death)
• In regards to mutations in tumor suppressors or
activation of proto-oncogenes to oncogenes, the cell
cycle gets disrupted and the cells divide uncontrollably.
• Normal cells remain in the area where they belong and
do not spread to other parts of the body
• Cancer spread through the body in a process called
metastasis
– direct invasion and destruction of the organ of origin or
– spread through the lymphatic system or bloodstream to
distant organs
– Why our immunity fails to defend ?
 Cancer chemotherapy
Definitions
• Cancer chemotherapy is a modality of cancer therapy
that involves the administration of chemical agents to
destroy cancer cells.
Goal of treatment - depend on the cancer stage and
patient factors, such as comorbidities.
• The goals of cancer treatment is
– To cure the patient and may be labeled as curative
therapy.
– To slow the progression of cancer and prolong
survival by months to years.
– To reducing symptoms, the treatment is often called
palliative therapy.
GENERAL PRINCIPLES IN CHEMOTHERAPY
• Chemotherapy is similar with bacterial treatment; cancer
cell viewed as invader. But, there are two major
differences
1. Bacterial metabolism differs from host, while cancer
cells less minor differences. Therefore, selectivity of
drugs limited . It has some unique tumour antigens &
oncogenes (like CML-tyrosine protein kinase gene)
identified that provide specific targets
2. microorganisms amenable to immune response. This is
absent/minimal against cancer cells
 Cancer chemotherapy
• Treatment Modalities-There are three primary
treatment modalities of cancer
 Local treatment

1. Surgery
2. Radiation therapy
 Systemic treatment (Pharmacotherapy)
1. Chemotherapy
2. Hormonal therapy
3. Targeted therapy
4. Immunotherapy & gene therapy
 Classification of Chemotherapy Drugs
• cytotoxic agents classified in to two based on their
ability to reduce stem cell population of normal bone
marrow & lymphoma cells
– Cell-cycle specific agents work by targeting the
microtubules which form spindle fibers thus
interfering with cell division and resulting in cell
death
– Cell-cycle nonspecific agents damage the DNA by
causing the DNA double-helix to break and/or
interfere with the DNA repair mechanism
 Vincristine
Vinblastin Nitrosoureas
Lomustine
Carmustine
Streptozoin
Bleomycin
Etoposide

Antimetabolites
Methotrexate
Fluorouracil
Floxuridine
Thioguanine
Mercaptopurine
Cytarabine Steroids
Asparaginase
A. CHEMOTHERAPY
1. Antimetabolites
2. Alkylating Agents
3. Topoisomerase Inhibitors
A. Topoisomerase I Inhibitors:Topotecan, Irinotecan
B. Topoisomerase II Inhibitor: Etoposide ,Teniposide
4. Antitubulin Agents
A. Vinca Alkaloids:Vinblastine,Vincristine, Vindesine
B. Taxanes : Paclitaxel, Docetaxel
5. Antibiotics (Intercalating Agents)
C. Anthracyclines:-doxorubicin, daunorubicin, epirubicin
D. Anthracenes :- Mitoxantrone
E. Phenoxazines: Dactinomycin(Actinomycin D )
6. DNA-Cleaving Agents : Bleomycins, Enediynes
7. Miscellaneous: Hydroxyurea, L-Asparaginase, Tretinoin ,Arsenic
B. Hormonal drugs
1. Glucocorticoids : Prednisolone and
others
2. Estrogens :Fosfestrol, Ethinylestradiol
3. Selective estrogen receptor modulator:
Tamoxifen,Toremifene
4. Selective estrogen receptor down
Regulators : Fulvestrant
5. Aromatase
inhibitors:Letrozole,Anastrozole,
Exemestane, Vorozole ,
Aminoglutethimide
6. Antiandrogen :Flutamide, Bicalutamide
7. 5-α reductase inhibitor: Finasteride
C. Molecularly Targeted Agents
A. Protein Kinase Inhibitors
 BCR-ABL Inhibition: Imatinib
 HER2/neu Inhibition: Trastuzumab
 EGFR Inhibition: Gefitinib, Erlotinib & Cetuximab
 VEGFR Inhibition , PDGFR Inhibition
B. Inhibition of Ras Pathway Signaling
C. Inhibitors of Farnesyltransferase;Tipifarnib, Lonafarnib
D. Cell Cycle Inhibitors
E. Proteasome Inhibitors
F. mTOR Inhibitors
1. Tyrosine protein- kinase inhibitors: Nilotinib Imatinib,
3. Angiogenesis inhibitors: Bevacizumab , Sunitinib
4. Proteasome inhibitor: Bortezomib
5. Unarmed monoclonal antibody : Rituximab, Trastuzumab
 Alkylating agents

• Are non cell cycle specific agents

MOA
– directly bind to DNA, thereby inhibiting DNA replication and
initiating cell death.
Indications
• used to treat many different cancers, including leukemia,
lymphoma, Hodgkin disease, multiple myeloma, and
sarcoma, as well as cancers of the lung, breast, and ovary
Adverse effects
– Can cause long-term damage to the bone marrow. this can
lead to acute leukemia is ------------“dose-dependent,”
 Alkylating agents……
Classifications - are divided into different classes
• Nitrogen mustards: such as mechlorethamine (nitrogen
mustard), chlorambucil, cyclophosphamide (Cytoxan®),
ifosfamide, and melphalan
• Nitrosoureas such as streptozocin, carmustine (BCNU),
and lomustine,
• Alkyl sulfonates such as busulfan,
• Triazines such as dacarbazine (DTIC) and temozolomide
(Temodar),
• Ethylenimines such as thiotepa and altretamine
(hexamethylmelamine)
A. Aliphatic Nitrogen Mustard
[Link] (Mustine HCl)
 The first nitrogen mustard; highly reactive & local
vesicant- admin only by i.v. route.
 It produces acute effects like nausea, vomite &
haemodynamic changes
 Extravasation during i.v. injec cause sloughing.
It is a component of MOPP regimen.
pks—it spontaneously converts in the body to reactive
cytotoxic product.
use—best known for use in regimens for Hodgkin’s &
non-Hodgkin’s lymphoma
S.E: Gi distress, lacrimation, myelosuppression, alopecia &
sterility
[Link]
-It acts as cytotoxic & immunosuppressor agent
- bifunctional agent & widely used alkylating agent
1. Pk—Prodrug activated to aldophosphamide &
phosphoramide mustard by CYP450 system
• One of the breakdown products is acrolein
 Chloramphenicol retards metabolism of
cyclophosphamide
. ,
Clinical Uses
 Hodgkin’s & Non-Hodgkin’s lymphoma
 Solid tumor of head, neck, ovary, breast & neuroblastoma
 used with methotrexate, doxorubicin, fluorouracil as adjuvant
therapy post breast cancer surgery
 Organ transplant recipient (due to immunosuppressive action)
Side Effects
 bone marrow depression, sterility
 severe nausea & vomiting
 Hemorrhagic cystitis & alopecia due to formation of acrolein
decreased by hydration & by use of mesna
 hypersensitivity reaction, cardiac dysfunction, pulmonary
toxicity & syndrome of inappropriate ADH secretion.
[Link]
• congener of cyclophosphamide has longer & dose-
dependent t½(15 hours ).
• activated by ring hydroxylation in the liver
• dose limiting toxicity of ifosphamide haemorrhagic
cystitis & CNS toxicity
• To prevent same, mesna routinely given with it. Mesna is
a –SH compound, excreted in urine
• binds & inactivates the vasicotoxic metabolites of
ifosfamide & cyclophosphamide
• Ifosfamide causes less alopecia & emetogenic than
cyclophosphamide
[Link]
 very slow acting, especially on lymphoid tissue:
 drug of choice for long-term maintenance therapy for
chronic lymphatic leukaemia; non-Hodgkin lymphoma
& few solid tumours.
 It has some immunosuppressant property
 increase incidence of acute myelocytic leukemia (AML)
& other tumors noted in large controlled study
[Link]
• incorporation of amino acid (i.e., phenylalanine) may
facilitate selective uptake by tumor cells
• melphalan prepared from D-phenylalanine is less active
than that prepared from the L-form, it may be taken-up
into cells by L-phenylalanine active transport mechanism
• 20% to 50% of the drug recovered in stool & 10% to 15%
in the urine
Indication
• effective in multiple myeloma & solid tumors (e.g.,
breast & ovarian) & lymphomas
 Bone marrow toxicity is common & delayed so the drug
admin at 6-week intervals to allow for this.
• Infection, diarrhoea & pancreatitis are complications
B. Ethylenimine
[Link]-TEPA
 It is does not require to form active intermediate.
 It is toxic, seldom used now in ovarian & bladder cancer

• toxicities of thiotepa are similar to other alkylating

agents, namely myelosuppression & lesser extent
mucositis
C. Alkyl sulfonate
Busulfan
 highly specific for myeloid elements; granulocyte
precursors being most sensitive, followed by platelets &
RBC.
• It produces little effect on lymphoid tissue & g.i.t.
Hyperuricaemia is common; pulmonary fibrosis & skin
pigmentation are specific adverse effects. adrenal
insufficiency & Sterility occurs. Cataracts Hepatitis
• Drug of choice for chronic myeloid leukaemia
 D. Triazine
Dacarbazine
 After activation in liver, it acts by methylating DNA &
interfering with its function.
use:- malignant melanoma, Hodgkin’s disease.
Side effects. Nausea, vomiting, flu-like symptoms,
neuropathy & myelosuppression
Temozolamide
 orally active methylating agent ,drug of choice for
glioma & other malignant brain tumours; also utilized in
melanoma. side effects similar to dacarbazine
[Link]
Procarbazine
 After activation (it is prodrug),it methylates &
depolymerizes DNA causing chromosomal damage.
Inhibit nucleic acid synthesis
 Because of damage to DNA, mutagenic & carcinogenic
potential detected.
Pks: orally active & penetrates into most tissues, including
CSF & eliminated via hepatic metabolism
Use: It is a component of MOPP regimens for Hodgkin’s &
non-Hodgkin’s lymphoma & brain tumors
Adverse effect
 myelosuppression, Gi irritation, CNS dysfunction,
peripheral neuropathy & skin reactions.
 it inhibits enzymes, including MAO & those involved in
hepatic drug metabolism.
 Disulfiram-like reactions occur with ethanol.
 The drug is leukemogenic
 Males may suffer sterility.
 Vomiting, leucopenia, thrombocytopenia are
prominent toxicities
[Link]
(Carmustine , Lomustine )
• bifunctional , active against broad spectrum neoplastic
disease
• highly lipophilic, so easily cross BBB & great for CNS
tumors & meningeal leukaemias.
• highly mutagenic & carcinogenic.
side effect :
– Nausea, vomiting & CNS effects.
– Bone marrow depression & Pulmonary fibrosis
delayed, taking 6 wks to develop.
– Visceral fibrosis & renal damage
Clinical uses
 primary & metastasis tumors of the brain
 Hodgkin’s Disease & Non-Hodgkin’s lymphoma
 Adenocarcinoma of stomach, colon & rectal cancer
 Hepatocarcinoma
C. Platinum Analogs (Cisplatin, Carboplatin, Oxaliplatin)
Cisplatin: forms crosslinks within DNA strands. it is not
really an “alkylating” agent, but since it operates via
the same mechanism as alkylating agents, it is placed
within that group
1. Pks—Cisplatin used iv, distributes to most tissues &
cleared in unchanged form by kidney.
2. Clinical use
commonly used as a component of regimens
first-line against cancers of lung, head-&-neck,
oesophagus, stomach, colon, bladder, testis,
ovaries, cervix, uterus and
 as 2nd -line for cancers of breast, pancreas,
liver, kidney, prostate, glioblastomas,metastatic
melanomas, and peritoneal or pleural
mesotheliomas
 Oxaliplatin is used in advanced colon cancer.
3. Toxicity
- Renal damage (minimized via massive hydration)
- Ototoxicity & peripheral neuropathy
- VERY SEVER vomiting( Ondanosetron…?)
 Carboplatin less nephrotoxic than cisplatin & less likely
to cause tinnitus & hearing loss, but it has greater
myelosuppressant actions.
 Oxaliplatin causes dose-limiting neurotoxicity
 Antimetabolites
• These agents damage cells during the S phase,
MOA
• Interfere with DNA and RNA growth
– are small compounds that act as false substrates
during DNA or RNA synthesis.
Indications
• They are commonly used to treat leukemias, cancers of
the breast, ovary, and the intestinal tract, as well as
other types of cancer
• commonly used agents include 5-fluorouracil (5-FU),
Cytarabine,Floxuridine,6-mercaptopurine(6MP),
Capecitabine,Fludarabine,Gemcitabine,hydroxyurea,Methot
rexate and Pemetrexed
1. Antimetabolites
A. DHFR Inhibitors (Antifolates: Methotrexate
B. Purine Antimetabolites
C. Pyrimidine Antimetabolites
D. Thymidylate Synthase Inhibition
E. Adenosine Deaminase Inhibition
F. Ribonucleotide Reductase Inhibition
[Link] INHIBITORS
A. Methotrexate
• A folic acid analogue, prevent formation of
tetrahydrofolate, essential for purine & pyrimidine
synthesis, by inhibiting dihydrofolate reductase.
• block conversion of dihydrofolic acid to tetrahydrofolic
acid
 inhibit production of DNA, RNA & proteins
(tetrahydrofolate used to synthesize serine &
methionine)
• Methotrexate compete with folic acid for DHFR &
inhibits it
DHFR catalyses conversion of dihydrofolate to active
tetrahydrofolat that is used for de novo synthesis of
deoxynucleoside thymidine phosphate DTMP
V
pks
• absorbed orally, 50% plasma protein bound, most
excreted unchanged in urine
• Utilizing folate carrier to enters into cells & transformed
to more active polyglutamate form by
folypolyglutamate synthase
• Aspirin & sulfonamide enhance toxicity by decreasing
its renal tubular secretion.
• MTX & its metabolites relatively insoluble in acid urine
• hydratation & urine alkalinization increase excretion
Indication
 curative in choriocarcinoma
 acute leukaemias
 in non-Hodgkin lymphoma, breast, bladder, head &
neck cancers, osteogenic sarcoma, etc.
 It is immunosuppresive agent used for rheumatoid
arthritis, psoriasis
Side effects:
• bone marrow
low dose cause megaloblastic anaemia, but high
doses produce pancytopenia
• Mucositis & diarrhoea
─ Folinic acid (N5 formyl THFA) decrease side effect
─ renal toxicity is due to precipitation of MTX or its
metabolites in the renal tubules
• resistance to methotrexate attributed to
 Decreased drug transport
 Decreased polyglutamate formation
 Synthesis of increased dihydrofolate reductase
 Dihydrofolate reductase‘s reduced affinity for
methotrexate
[Link]
 congener of Mtx primarily targets thymidylate synthase. Though,
it also DHFRase inhibitor, the pool of THFA not markedly reduced.
─ Like Mtx it utilizes folate carrier to enter cells

indication: mesoepithelioma & non-small cell lung carcinoma

Adverse effects
 mucositis, diarrhoea, myelosuppression similar to Mtx
 But, painful, itching erythematous rash, mostly in hands & feet,
‘handfoot syndrome’ is common
• Dexamethasone pretreatment reduce its incidence
• Low dose folic acid & vit B12 pretreatment limit pemetrexed
induced myelosuppression.

D/i: NSAIDs decrease pemetrexed clearance & increase toxicity

[Link] ANTIMETABOLITES
A. mercaptopurine
B. fludarabine
C. pentostatin
D. cladribine
E. thioguanine
Mercaptopurine (6-MP) & thioguanine (6-TG)
Moa:
• inhibit conversion of inosine monophosphate to
adenine & guanine
• That inhibit de novo purine synthesis
• They also incorporated into RNA & DNA which are
dysfunctional

Purine

Guanine
Indication
 childhood acute leukaemia, choriocarcinoma & some
solid tumours
 In acute leukaemia, both used in combination to
induce remission & 6-MP for maintaining remission
 6-MP is immunosuppressive used in transplantation
to control rejection reactions
Side effect:
• nausea or vomiting , darkening of skin , loss of
appetite , diarrhea , headache , skin rash and itching,
weakness , mouth sores
Mercaptopurine (6-MP)
• oxidised by xanthine oxidase; their metabolism
inhibited by allopurinol
• dose can be reduced to ¼–½ if allopurinol given
concurrently
Thiopurine methyl transferase
xanthine oxidase
Hypoxanthine-Guanine
Phosphoribosyltransferase
 Thioguanine not substrate for xanthine oxidase; follows
a different (S-methylation) metabolic path & its dose
need not be reduced. if allopurinol given
 Methylation by thiopurine methyl transferase (TPMT)
is additional pathway of 6-MP metabolism
 Genetic deficiency of TPMT makes susceptible to 6-MP
induced myelosuppression, mucositis, while over
expression of TPMT causes 6-MP resistance in acute
leukaemia cells

 Toxicity of azathioprine also enhance in TPMT deficiency

Toxic effect
 bone marrow depression, develops slowly.
 reversible jaundice
 Hyperuricaemia: reduced by allopurinol

• Diarrhea, nausea, vomiting, loss of appetite,

• Allergic reaction like rash, itching, swelling, dizziness,
trouble breathing
• Mercaptopurine cause myelosuppression
Azathioprine
 nonenzymatically cleaved to 6 - MP that acts as a purine
analogue & inhibits DNA synthesis

 has immunosuppressant action, due to selective uptake

into immune cells & intracellular conversion to 6-MP

 primarily suppresses cell mediated immunity & used in

autoimmune diseases (rheumatoid arthritis, ulcerative
colitis) & in organ transplantation
Fludarabine
o Phosphorylated intracellularly by deoxycytidine
kinase to triphosphate
o This metabolite inhibits DNA polymerase &
ribonucleotide reductase, induce apoptosis
o Used to treat low-grade non-Hodgkin's lymphoma &
chronic lymphocytic leukemia
o Toxicity: Myelosuppression, immunosuppression,
fever, myalgias, & arthralgias
3-Pyrimidine analogues
1. 5-flurouracil (5-FU)
2. azacitidine
3. Capecitabine: prodrug of 5-FU
4. cytarabine
5. gemcitabine
5-flurouracil (5-FU)
• a uracil analogue, transformed inside cell into 5-FU that
compete with deoxyuridine monophosphate DUMP for
thymidylate synthase leading to inhibit deoxythymidine
monophosphate (DTMP) synthesis inhibition of DNA
synthesis (Not RNA or protien).
• it is also incorporated into DNA non functioning DNA .
finally inducing cell cycle arrest.
• It is an S-phase specific drug
indication
 in combination with other agents treat cancers of
breast, stomach, colon, bowel rectum,
pancreas ,gastric, oesophageal, head & neck, anal &
ovarian cancers
Side effect
-GIT epithelial damage, diarrhea & mouth ulcers
- bone marrow suppression
5-flurouracil (5-FU)
 Capecitabine
Metabolized in to fluorouracil in the tumor and have
the same action as 5-FU
 Clinical uses:
o Metastatic breast cancer (single or combined with
taxane docetaxel)
o Metastatic colorectal cancer (single or combied with
irinotecan or oxaliplatin)
 Toxicities
o Myelosuppression, nausea,vomiting & mucositis
o The incidence is less than IV fluorouracil
 Anticancer Antibiotics
• Cell cycle specific drugs i.e. are derived from
microorganisms
MOA-interact directly with DNA resulting in linkage of
double strands of DNA and prevent replication
– The manner in which antibiotics interact with DNA differs
considerably between agents
Agents
• Anthracyclines w/ch includes Daunorubicin Doxorubicin,
Doxorubicin Liposomal, Epirubicin, Idarubicin
– are non cell cycle specific
– Can permanently damage the heart if given in high doses.
(lifetime dose limits are often placed )
• Other agents -Actinomycin–D ,Bleomycin
Mitomycin ,Mitoxantrone (also acts as a topoisomerase II
Actinomycin D
 blocking RNA transcription ( interference with template
function of DNA), causes single strand breaks in DNA.
use
 Wilms’ tumour & childhood rhabdomyosarcoma.
 Mtx resistant choriocarcinoma,
 Ewing’s sarcoma & metastatic testicular carcinoma
adverse effects
 vomiting, stomatitis, diarrhoea, erythema,
desquamation of skin, alopecia & bone marrow
depression
Anthracyclines
 characterized by tetracyclic chromophore that contains
anthraquinone motif.
 Anthracyclines have antibacterial, antiparasitic,
immunosuppressant & antitumour
 doxorubicin & daunorubicin used clinically & among
the most efficient antitumour drugs.
Doxorubicin
• Doxorubicin is effective in breast, thyroid, ovary,
bladder & lung cancers, sarcomas & neuroblastoma
MOA:
• intercalate between DNA strands & block DNA & RNA
synthesis. breaks in DNA strands by activating
topoisomerase-2 & generating free radicals.
• they have mutagenic & carcinogenic potential.
Maximum action exerted at S phase, but toxicity
exhibited in G2 phase.
Side effect:
• Cardiotoxicity (unique) acutely within 2–3 days,
causing ECG changes, arrhythmias (reversible) or
delayed—CHF
• Marrow depression
• alopecia
• stomatitis
• vomiting
• local tissue damage (on extravasation)
• Urine may be coloured red
Epirubicin
• recently introduced anthracycline with MOA &
properties similar to doxorubicin.
• Therapeutic use
─ adjuvant therapy of breast carcinoma.
─ gastroesophageal, pancreatic, hepatic & bladder
carcinoma
Side effect
– Alopecia
– hyperpigmentation of skin & oral mucosa,
– painful oral ulcers, fever & g.i. symptoms
– Urine may turn red.
– Cardiotoxicity is dose related.
Daunorubicin
• spectrum of activity is narrower than doxorubicin. The
main indications are acute myeloid leukaemia & acute
lymphocytic leukaemia & used to treat neuroblastoma
& chronicmyelogenous leukaemia.
side effects
─ similar to doxorubicin, with severe haematological
toxicity.
• liposomal formulation: show more efficacy than free
daunorubicin against multidrug resistance, lower
toxicity & overcome BBB.
• mainly used to treat AIDS-related Kaposi’s sarcoma,
leukaemia & non-Hodgkin’s lymphoma
Epirubicin: differs from doxorubicin in stereochemistry at
 Topoisomerase inhibitors

MOA
• interfere with enzymes called topoisomerases, which
prevents DNA supercoiling
Indications
• are used to treat certain leukemias, as well as lung,
ovarian, gastrointestinal, and other cancers.
Categories
• Topoisomerase I inhibitors include: Topotecan and
Irinotecan (CPT-11)
• Topoisomerase II inhibitors include: Etoposide (VP-16),
Teniposide and Mitoxantrone
– increase the risk of a second cancer – acute myelogenous
leukemia (AML) – as early as 2 to 3 years after the drug is given
TOPOISOMERASE-2 INHIBITOR
Etoposide
 a derivative of podophyllotoxin, a plant glycoside with
Oral bioavailability is 50%
MOA:
• arrests cells in G2 phase & breaks DNA by inhibiting
topoisomerase-2. cleaving of double stranded DNA not
interfered, subsequent resealing of strand prevented.
Indication
• testicular tumours, lung cancer, Hodgkin’s & other
lymphomas, carcinoma bladder & stomach.
Side effect:
• Alopecia, leucopenia & g.i.t. disturbances
TOPOISOMERASE-1 INHIBITORS
Camptothecin analogues (Topotecan, Irinotecan)
Moa: bind to topoisomerase-1, allows single strand breaks
in DNA, but not its resealing after strand has untwisted.
 They damage DNA during replication; act in S phase &
arrest cell cycle at G2 phase.
Topotecan:
 used in metastatic carcinoma of ovary & small cell lung cancer
after treatment failer.
 Combined with cisplatin, used in cervical cancer.
side effect
• bone marrow depression(major), neutropenia,
• pain abdomen
• vomiting & anorexia
• diarrhoea
Irinotecan
• a prodrug decarboxylated to active metabolite SN-38.
it has Cholinergic effects & suppressed by prior
atropinization
use
– metastatic/advanced colorectal carcinoma
– in cancer lung/cervix/ ovary and stomach.
– combined with 5-FU and leucovorin.
Side effect
– Diarrhoea (Dose limiting)
– Neutropenia, thrombocytopenia
– haemorrhage
– Bodyache & weakness
 Mitotic inhibitors
• are often plant alkaloids and other compounds derived from
natural products.
MOA- stopping mitosis in the M phase of the cell cycle but can
damage cells in all phases )
Classes of agents
• Estramustine
• Taxanes such as paclitaxel and docetaxel
• Epothilones such as ixabepilone
• Vinca alkaloids such as vinblastine, vincristine, and
vinorelbine
Indications - to treat different types of cancer including breast,
lung, myelomas, lymphomas, and leukemias.
Adverse effects -may cause nerve damag-can limit the dose
Vinca alkaloids
• mitotic inhibitors, bind to tubulin, prevent its
polymerization & assembly of microtubules, cause
disruption of mitotic spindle & interfere with
cytoskeletal function.
• chromosomes fail to move apart during mitosis:
metaphase arrest occurs. They are cell cycle specific &
act in mitotic phase.
• Vincristine & vinblastine: though closely related
chemically, have different spectrum of antitumour
activity and toxicity.
Vincristine
• rapid acting, useful for inducing remission in childhood
acute lymphoblastic leukaemia, but is not good for
maintenance therapy.
• Other: acute myeloid leukaemia, Hodgkin’s disease,
Wilms’ tumour, Ewing’s sarcoma, neuroblastoma &
carcinoma lung.
adverse effects
– peripheral neuropathy & alopecia(prominent )
– ataxia, autonomic dysfunction(postural hypotension,
urinary retention) & seizures
– Bone marrow depression(minimal)
– syndrome of inappropriate secretion of ADH (SIADH)
Vinblastine
 primarily used with other drugs in Hodgkin’s disease, Kaposi
sarcoma, neuroblastoma, non-Hodgkin’s lymphoma, breast &
testicular carcinoma

 Bone marrow depression more prominent, while neurotoxicity

& alopecia less marked than with vincristine
 SIADH, local tissue necrosis if extravasation occurs during i.v.
infusion
Vinorelbine
 a semisynthetic vinblastine analogue with similar mechanism
inhibiting microtubule assembly.
 its primary indication is non-small cell lung cancer.
 2nd line in advanced breast & ovarian carcinoma
 Neutropenia is dose limiting toxicity. Thrombocytopenia &
neurotoxicity less marked.
Taxanes
Paclitaxel
– binds to β-tubulin & enhance polymerization: a opposite to
vinca alkaloids.
– microtubules stabilized & depolymerization prevented. This
stability inhibit normal dynamic reorganization of
microtubule that is essential for interphase & mitotic function
Uses
─ metastatic ovarian & breast carcinoma after failure of first
line & relapse
─ advanced cases of head & neck cancer, small cell lung cancer,
esophageal adenocarcinoma, urinary & hormone refractory
prostate cancer.
─ AIDS related Kaposi’s sarcoma
Side efect
─ Acute anaphylactoid reaction due to cremophor
solvent
• Pretreatment with dexamethasone suppress
reaction.
─ myelosuppression (granulocytopenia) & ‘stocking and
glove’ neuropathy.
─ Nausea, chest pain, arthralgia, myalgia, mucositis &
edema
Docetaxel
• a potent congener of paclitaxel with the same
mechanism of action.
Estramustine
 complex of estradiol with nitrogen mustard normustine,
which has weak estrogenic but no alkylating property.
but, it binds to β-tubulin & exert antimitotic action
 it concentrated in prostate & the only indication is
metastatic prostate cancer that is nonresponsive to
hormonetherapy.
 orally active, undergoes first pass metabolism in liver
into active & inactive metabolites, which mainly
eliminated in faeces
 small amount hydrolysed into estradiol & normustine
producing myelosuppression & estrogenic side effects
Plant derived anticancer drugs
 Corticosteroid and other agents

Corticosteroid
• are useful in the treatment of many types of cancer, as
well as other illnesses
• also commonly used to prevent nausea and vomiting
caused by chemotherapy
• are used before chemotherapy to prevent severe allergic
reactions
Examples
• Prednisone, Methylprednisolone and Dexamethasone
Other chemotherapy drugs
• act in slightly different ways and do not fit well into any
of the other categories. Examples - L-asparaginase and
bortezomib
MISCELLANEOUS CYTOTOXIC DRUGS
Hydroxyurea
• blocks conversion of ribonucleotides to
deoxyribonucleotides by inhibiting ribonucleoside
diphosphate reductase—thus interferes with DNA
synthesis; exerts S-phase specific action.
Uses
 chronic myeloid leukaemia
 psoriasis
 polycythaemia vera
 in some solid tumours
• radiosensitizer before radiotherapy & first-line for sickle
cell disease in adults. Hydroxyurea well absorbed orally &
eliminated in urine with t½ of~ 4 hrs
Side effect : Myelosuppression ,GI disturbances & cutaneous
L-Asparaginase (L-ASPase)
childhood lymphoblastic leukaemia viz. leukaemia cells were found
to be deficient in L-asparagine synthase enzyme & depended on
the supply of L-asparagine from the medium
The enzyme L-ASPase (from E. coli.) degrades L-asparagine to L-
aspartic acid, depriving leukaemic cells of essential metabolite &
causes cell death
• L-asparaginase a component of regimen for inducing remission in
acute lymphoblastic leukaemia along with Mtx., prednisolone,
vincristine, etc. However, resistance develops to L-ASPase mostly
by induction of L-asparagine synthase in the leukaemic cells.
• Moreover, L-ASPase is antigenic, produces neutralizing antibodies
which inactivate & clear enzyme rapidly, so that clinical response
is lost. A polyethylene glycol conjugated L-ASPase (Peg-
asparaginase) produced which has very slow clearance from the
84
 Combination of anticancer agents
• The underlying principles of using combination
therapy are
– to use agents with different pharmacologic actions
– agents with different organ toxicities
– agents that are active against the tumor and
ideally synergistic when used together
– agents that do not result in significant drug
interactions
• When two or more agents are used together, the risk
of development of resistance may be lessened, but
toxicity may be increased.
 Combination chemotherapy

.
Combination of anticancer agents…..
GENERAL TOXICITY OF CYTOTOXIC DRUGS
• Most drugs have more profound effect on rapidly
multiplying cells.

• Many cancers (solid tumours) have lower growth

fraction than normal bone marrow, epithelial lining,
reticuloendothelial system & gonads

• These tissues affected in dose-dependent manner by

most anticancer drugs
Bone marrow Depression
─ Results granulocytopenia, agranulocytosis,
thrombocytopenia, aplastic anaemia.
─ limits the dose
─ Cause Infections & bleeding
Lymphocytopenia
─ inhibit lymphocyte function resulting suppression of
cell mediated & humoral immunity
─ Cause opportunistic infections
Mucositis (Stomatitis), Xerostomia
─ oral mucosa susceptible due to high epithelial cell
turnover.
• Diarrhoea & git haemorrhages
─ due to decrease rate of renewal of GI mucous lining
• Drugs that cause mucositis: bleomycin,
fluorouracil, actinomycin D, daunorubicin,
doxorubicin, & methotrexate.
• Nausea & vomiting
─ due to direct stimulation of CTZ
• Alopecia: due to damage to cells in hair follicles
• Oligozoospermia & impotence
─ Inhibition of gonadal cells in males
• ovulation & amenorrhoea
─ Inhibition of gonadal cells in females
Hyperuricaemia
─ due to massive cell destruction (purine metabolism)
likely in leukaemia & lymphoma.
─ renal failure, gout & urate stones may develop.
─ Allopurinol protect by decrease uric acid synthesis
Carcinogenicity
─ Secondary cancer, especially leukaemia, lymphoma &
histocytic tumour may appear after use of drugs.
─ Occur due to depression of cell mediated & humoral
blocking factors against neoplasia
Damage to germinal cells may result mutagenesis
all cytotoxic drugs are teratogenic
LIMITING TOXICITY OF CHEMOTHERAPEUTIC AGENTS
 except cumulative toxicities associated with
Adriamycin(cardiac), bleomycin (pulmonary),& cisplatin
(renal) —common side effects like bone marrow
suppression, GIT lesion, nausea & vomiting usually
reversible within 2 to 3 weeks
 e.g mucositis reversible within 5 to 10 days,
reflecting rapid recovery of normal tissues.
 Several approaches developed to limit toxicity. These
include
1. Coadministration of adjuvants
2. Dose scheduling & coordination of drug types with
cell cycle
3. Design of novel prodrugs & dosage forms
4. use of physical devices like cold cap
5. Selective toxicity

The efficacy & toxicity of some agents influenced by

their time of admin during a 24-hour cycle
[Link] OF ADJUVANTS
 Coadmin of other agents minimize toxicity
Folinic acid
– permitted admin of >100 X dose of Mtx. normal cells
rescued more than cancer cells
mesna & acetylcysteine
– Cystitis due to cyclophosphamide & ifosphamide
blocked by mesna & acetylcysteine
 Both are – SH containing drugs that detoxify toxic
metabolites in bladder.
– fluid intake & frequent bladder voiding also helps
 C. vomiting
• ondansetron, a 5-HT3 antagonist,
dexamethasone or lorazepam enhances
protection against vomiting
Emetogenic potential of cytotoxic drugs
High Moderate Mild
Cisplatin Carboplatin Bleomycin
Mustine Cytarabine Chlorambucil
Cyclophosphami Procarbazine Busulfan
de Vinblastine 6-Thioguanine
Actinomycin D Doxorubicin Hydroxyurea
Dacarbazine Daunorubicin Etoposide
Lomustine Ifosfamide Fluorouracil
6-Mercapto- Vincristine
purine Methotrexate
Paclitaxel l-Asparaginase
D. Cardiotoxicity (doxorubicin )
• cause ECG changes, arrhythmias and hypotension, all of
which are reversible; or be delayed—congestive heart
failure (related to total dose administered).
• CHF is due to cardiomyopathy and may be fatal
• Dexrazoxane: Iron chelating agent infused i.v.
before doxorubicin to reduce toxicity
• It used to ameliorate anthracycline infusion site
reaction due to extravasation.

• mechanism of cardiotoxicity of doxorubicin are (i)

iron-related free radicals & formation of
doxorubicinol metabolite (ii) mitochondrial
disruption
e. neuro/nephrotoxicity (cisplatin )

• Amifostine: an organic thiophosphate acts as a

cytoprotective by free-radical scavenging, DNA
protection & repair acceleration against chemotherapy
& radiotherapy.

• particularly used for prophylaxis of cisplatin induced

neuro/nephrotoxicity & radiotherapy related xerostomia
• hydration during cisplatin infusion also reduces
nephrotoxicity.
f. Hyperuricaemia
– Occur due to destruction of tumour masses
(purines) reduced by
─ allopurinol
─ alkalinization of urine
─ Intake of plenty of fluids
─ Corticosteroids also reduce hyperuricemia.
g. Hypercalcaemia
• complication of malignancies like myeloma, cancer
breast / prostate & aggravated by chemotherapy.
 treated by hydration & bisphosphonate
Long term and Short term toxicities
Thank You