Chemotherapy for malignancy

Hormonal drugs {CCSA acting on G1 Phase}

1] L-Asparaginase (L-ASPase):
● Healthy non-malignant cells can synthesize asparagine with the help of the enzyme asparagine
synthetase. However, some tumor cells, such as leukemic cells, lack this enzyme and depend on
exogenous supply of asparagine for their survival.
● The enzyme L-ASPase (from E. coli.) degrades L-asparagine to L-aspartic acid and ammonia,
depriving the leukaemic cells of an essential metabolite, and causes cell death.
● Used in childhood acute lymphoblastic leukaemia
● ADR: may produce hypersensitivity reactions, urticarial skin rashes and severe anaphylactic
reactions, pancreatitis
● PEG-Asparginase is more effective, less antigenic and needs to be given less frequently as
compared to L-ASPase. Causes less allergy.

Several types of hormone-dependent cancer (especially breast, prostate, and endometrial cancer)
respond to treatment with their corresponding hormone antagonists.

Estrogen — intracellular Estrogen receptor (ER) — receptor dimerization — complex translocated to

nucleus — binds to chromatin — activates transcription of genes which lead to increases cell growth and
proliferation.

2] Aromatase inhibitors (letrozole, anastrozole):

● Aromatase enzyme is found in elevated concentrations in breast cancer. It is primarily needed for
the conversion of androstenedione and testosterone to estrone and estradiol, which are
biologically active estrogens that bind to and activate estrogen receptors, thereby promoting cell
proliferation.
● By inhibiting aromatase enzyme, the production of estrogens reduces and hence reduces cell
growth and proliferation rate in cancer cells.

3] Selective estrogen receptor modulators (SERMs) (Tamoxifen):

● In hormone receptor-positive cancer cells, these agents competitively bind to the estrogen
receptor and adopt a different conformation to the one seen with estrogen bound.
● The complex then dimerises and it’s transported from the cytosol into the cell's nucleus where it
binds to DNA to form a new complex that is unable to function in the same way as the one formed
with estrogen.
● The overall result is the inhibition of growth-promoting effects.

4] Selective estrogen receptor down-regulator (Fulvestran):

● Works by binding to estrogen receptor monomers and inhibiting receptor dimerization.
● This in turn leads to accelerated receptor degradation, thus making the receptor unavailable to
estrogen.

5] GnRH agonists (Leuprolide,Triptorelin):

● Work by overstimulating GnRH receptors resulting in receptor desensitisation over time.
● This in turn leads to reduced secretion of luteinizing hormone (LH) and follicle-stimulating
hormone (FSH), and ultimately reduced production of estrogen.
 ● GnRH agonists can be helpful in treatment of women with breast cancer, they are more often
used in treatment of men with prostate cancer. This is because in males luteinizing hormone (LH)
directs the testes to produce testosterone. Free circulating testosterone can enter prostate cells,
where, with the help of 5-alpha reductase enzyme, it can be converted to its more potent
metabolite, dihydrotestosterone (DHT).

DHT — intracellular Androgen receptor (AR) — receptor dimerization — complex translocated to nucleus
— binds to chromatin — activates transcription of genes which lead to increases cell growth and
proliferation

6] Glucocorticoids (Prednisolone):
● They have marked lympholytic action—are primarily used in acute childhood leukaemia and
lymphomas.
● Bind to intracellular steroid hormone receptors and inhibit activation of receptor complex by
steroid hormone.
● Thus, inhibit activation of transcription of genes which promote cell growth and proliferation.

7] Estrogen (fosfestrol pro‐drug):

Estrogens inhibit the effects of endogenous androgens and androgen-dependent metastatic prostatic
carcinoma.

Antimetabolites {CCSA acting on S Phase}

These are analogues related to the normal components of DNA or of coenzymes involved in nucleic acid
synthesis. They competitively inhibit utilization of the normal substrate or get themselves incorporated
forming dysfunctional macromolecules.

1] Folate Antagonists (Methotrexate):

● This folic acid analogue acts by inhibiting dihydrofolate reductase (DHFRase)—blocking the
conversion of dihydro- folic acid (DHFA) to tetrahydrofolic acid (THFA)
● THFA is an essential coenzyme required for one carbon transfer reactions in de novo purine
synthesis and amino acid interconversions. Methotrexate has a higher affinity for dihydrofolate
reductase than DHFA and thus blocks formation of THFA.
● In addition to DHFRase it inhibits thymidylate synthase as well so that DNA synthesis is primarily
affected. However, synthesis of RNA and protein also suffers.
● It exerts major toxicity on bone marrow—low doses given repeatedly cause megaloblastic
anaemia, but high doses produce pancytopenia.
● Utilising the folate carrier it enters into cells and is transformed to more active polyglutamate form
by the enzyme folypolyglutamate synthase (FPGS), which is retained in the cells for weeks.
● The toxicity of Mtx cannot be overcome by folic acid, however, Folinic acid (N5 formyl THFA)
(leucovorin) rapidly reverses the effects.

2] Purine Antagonists (6-Mercaptopurine)

● Mercaptopurine is a pro-drug that upon entry into the cell it’s first converted to thioinosine
monophosphate (TIMP) by an enzyme called hypoxanthine-guanine phosphoribosyltransferase
(HGPRT) that plays a key role in the recycling of the purine bases, hypoxanthine and guanine.
 ● TIMP inhibits several chemical reactions involving inosine monophosphate (IMP), including the
conversion of IMP to adenine and guanine nucleotides that are the building blocks for RNA and
DNA.
● Furthermore, through series of reactions, TIMP can be converted into thioguanosine triphosphate
(TGTP) which then can be incorporated into RNA, as well as thio-deoxy-guanosine triphosphate
which can be incorporated into DNA thus leading to inhibition of both, DNA and RNA synthesis,
resulting in cell death.
● Azathioprine and 6-MP are oxidised by xanthine oxidase; their metabolism is inhibited by
allopurinol;
● The main toxic effect of antipurines is bone marrow depression, which develops slowly.
● Azothioprine is prodrug of 6-MP

3] Pyrimidine Antagonists (Fluorouracil)

● 5-FU is converted in the body to the corresponding nucleotide fluoro-deoxyuridine
monophosphate, which forms a covalent ternary complex with methyl-THFA and thymidylate
synthase (TS) resulting in irreversible inhibition of TS.
● Thus, prevents synthesis of thymidine and DNA synthesis fails.
● Accordingly, thymidine can partially reverse 5-FU toxicity.
● 5-FU is dependent on the presence of THFA, infusion of leucovorin enhances its efficacy.
Cisplatin and oxaliplatin also synergise with 5-FU.
● Major toxicity of 5-FU is exerted on the bone marrow and g.i.t and is used in many solid
malignancies.
(Cytarabine: Cytosine arabinoside)
● This cytidine analogue is phosphorylated in the body to the corresponding nucleotide which
inhibits DNA synthesis. The triphosphate of cytarabine is an inhibitor of DNA polymerase, as well
as blocks production of cytidilic acid.
● Useful only in leukaemias and lymphomas, and is not effective in solid tumours.
● Major toxic effects are due to bone marrow suppression

Alkylating agents {CCNSA}

● These compounds produce highly reactive carbonium ion intermediates which transfer alkyl
groups to DNA by forming covalent bonds.
● The N7 of guanine is main target for alkylation in DNA (alkylation of adenosine or cytosine also
occurs to lesser degree)
● Alkylation results in cross linking/abnormal base pairing/scission of DNA strand. Cross linking of
nucleic acids with proteins can also take place.
● After alkylation, DNA is unable to replicate and therefore can no longer synthesize proteins and
other essential cell metabolites.
● Excision of guanine base or pairing of G with T instead of C occurs
Consequently ⇒ cell reproduction is inhibited and the cell eventually dies

1. Nitrogen Mustards: Cyclophosphamide, Mechlorethamine

Mesna is used to reduce toxicity
2. Nitrosoureas: Lomustine
They are highly lipophilic, cross BBB, can be used for brain tumors
3. Alkyl sulfonates: Busulfan
It is the drug of choice for chronic myeloid leukaemia.
4. Platinum Coordination Complexes: Cisplatin
Typical platinum-based agents generate various reactive platinum species by losing one or more of their
so-called leaving groups, a chloride ligand, which is then replaced by water molecules to form mono and
di- aqua platinum complexes.
They react with DNA bases, leading to formation of intrastrand and interstrand cross-links.
When polymerases transcribe DNA, they stall at the platinum cross-link and recruit the repair enzymes.
If these enzymes are unable to repair the lesion, the cell triggers apoptosis.
Cisplatin is very effective in metastatic testicular and ovarian carcinoma. It is widely used in many other
solid tumours. Cisplatin is a highly emetic drug.

Antibiotics {CCNSA}
1. Doxorubicin & Actinomycin D:
● One of the proposed primary mechanisms involves the interaction of anthracyclines with
DNA molecules through intercalation, which is a process by which a drug inserts itself
between adjacent DNA base pairs. The intercalation leads to significant disturbance of
the DNA conformation and results in inhibition of transcription and replication.
● In addition to that, anthracyclines intercalated into DNA, form a stable complex with
topoisomerase type 2, which results in DNA fragmentation, ultimately prompting the
cancer cell to undergo apoptosis.
● As a secondary mechanism, in the presence of oxidoreductive enzymes and iron, the
quinone portion of anthracycline molecules can undergo redox reactions to generate
highly reactive free oxygen radicals. Excessive amounts of these free radicals damage
cell membranes, proteins, and lipids, and also trigger cell apoptosis.

2. Bleomycins:
● Bleomycin is different from anthracycline antibiotics in that it is generally considered to be
cell cycle specific, having its major effects on cells in the G2 phase of the cycle.
● Bleomycin’s mechanism of action involves entry into the cell, where it forms an active
complex with iron and oxygen, which then binds to DNA and generates highly reactive
free radicals that are responsible for scission of the DNA strand. The end result is
accumulation of G2 phase cells, which are unable to progress to mitosis.

Plant Alkaloids {CCSA}

Microtubule Damaging agents: Act on Metaphase
1. Vinca alkaloids (Vincristine, Vinblastine): Derived from periwinkle plant
● These are mitotic inhibitors, bind to ‘tubulin’, prevent its polymerization and assembly of
microtubules, cause disruption of the mitotic spindle and interfere with cytoskeletal
function.
● The chromosomes fail to move apart during mitosis: metaphase arrest occurs.
● They destabilize microtubule structure by binding to the beta-tubulin subunit of the
alpha/beta-tubulin heterodimer and inhibiting polymerization of tubulin into microtubules.

2. Taxanes (Paclitaxel): from bark of the Western yew tree

● It binds to β-tubulin and enhances its polymerization: a mechanism opposite to that of
vinca alkaloids. The microtubules are stabilized and their depolymerization is prevented.
● This stability results in inhibition of normal dynamic reorganization of the microtubule
network that is essential for interphase and mitotic functions.
● Abnormal arrays or ‘bundles’ of microtubules are produced throughout the cell cycle.
3. Epipodophyllotoxins (etoposide & teniposide): semi‐synthetic derivatives of podophyllotoxin
extracted from mayapple root
● Blocks cell division in late S- and G2-phases of the cell cycle
● Inhibits enz. topoisomerase II, which results in DNA damage through strand breakage
● The resulting inhibition of DNA resealing step, leads to large amounts of fragmented
DNA, which arrests cell cycle progression to mitosis, and ultimately triggers apoptosis.