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Chapter: Essential pharmacology : Anticancer Drugs

These are analogues related to 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.



These are analogues related to 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.





Methotrexate (Mtx)


It is one of the oldest and highly efficacious antineoplastic drugs; inhibits dihydrofolate reductase (DHFRase)—blocking the conversion of dihydrofolic acid (DHFA) to tetrahydrofolic acid (THFA) which is an essential coenzyme required for one carbon transfer reactions in de novo purine synthesis and amino acid interconversions. The inhibition is pseudoirreversible because Mtx has 50,000 times higher affinity for the enzyme than the normal substrate.


Methotrexate has cell cycle specific action— kills cells in S phase; primarily inhibits DNA synthesis, but also affects RNA and protein synthesis. It exerts major toxicity on bone marrow—low doses given repeatedly cause megaloblastic anaemia, but high doses produce pancytopenia. Desquamation and bleeding may occur in g.i.t.


Methotrexate is absorbed orally, 50% plasma protein bound, little metabolized and largely excreted unchanged in urine. Salicylates, sulfonamides, dicumerol displace it from protein binding sites. Aspirin and sulfonamides enhance toxicity of Mtx by decreasing its renal tubular secretion.


The toxicity of Mtx cannot be overcome by folic acid, because it will not be converted to the active coenzyme form. However, Folinic acid (N5 formyl THFA, cirtrovorum factor) rapidly reverses the effects. Thymidine also counteracts Mtx toxicity.


Methotrexate is apparently curative in choriocarcinoma: 15–30 mg/day for 5 days orally or 20–40 mg/m2 BSA i.m. or i.v. twice weekly. It is highly effective in maintaining remission in children with acute leukaemias, but not good for inducing remission: 2.5–15 mg/day. It is also useful in other malignancies, rheumatoid arthritis, psoriasis and as immunosuppressant.


NEOTREXATE 2.5 mg tab, 50 mg/2 ml inj; BIOTREXATE 2.5 mg tab, 5, 15, 50 mg/vial inj.


The use of folinic acid rescue has permitted much higher doses of Mtx and has enlarged its scope to many difficult to treat neoplasms. A nearly 100 times higher dose (250–1000 mg/m2 BSA) of Mtx is infused i.v. over 6 hours, followed by 3–15 mg i.v. calcium leucovorin within 3 hours, repeated as required. This procedure can be repeated weekly.





Mercaptopurine (6-MP) and Thioguanine (6-TG)


These are highly effective anti-neoplastic drugs. They are converted in the body to the corresponding mono-ribonucleotides which inhibit the conversion of inosine monophosphate to adenine and guanine nucleotides. There is also feedback inhibition of de novo purine synthesis.


They are especially useful in childhood acute leukaemia, choriocarcinoma and have been employed in some solid tumours as well. In acute leukaemia, both have been used in combination regimens to induce remission and 6MP to maintain it as well.




It has marked effect on T-lymphocytes; suppresses cell mediated immunity (CMI) and is used primarily as immuno-suppressant in organ transplantation, rheumatoid arthritis, etc.


All antipurines are absorbed orally (though incompletely). Azathioprine and 6MP are metabolized by xanthine oxidase; their metabolism is inhibited by allopurinol; dose has to be reduced to ¼–½ if allopurinol is given concurrently. Thioguanine is not a substrate for xanthine oxidase; follows a different (S-methylation) metabolic path and its dose need not be reduced if allopurinol is given.


Methylation by thiopurine methyl transferase (TPMT) is an additional pathway of 6MP metabolism. Genetic deficiency of TPMT makes the individual more susceptible to 6MP toxicity, while over expression of TPMT is an important mechanism of 6MP resistance by acute leukaemia cells. Toxicity of azathioprine is also enhanced in TPMT deficiency.


The main toxic effect of antipurines is bone marrow depression, which develops slowly. Mercaptopurine causes more nausea and vomiting than 6TG. It also produces a high incidence of reversible jaundice. Hyperuricaemia occurs with both; can be reduced by allopurinol.


6-Mercaptopurine: 2.5 mg/kg/day, half dose for maintenance; PURINETHOL, EMPURINE 50 mg tab.


6Thioguanine:   100–200 mg/m2/day for 5–20 days; 6TG 40 mg tab.


Azathioprine: 3–5 mg/kg/day, maintenance 1–2 mg/kg/ day; IMURAN, TRANSIMUNE, AZOPRINE 50 mg tab.




This newer purine anti-metabolite is phosphorylated intracellularly to the active triphosphate form which then inhibits DNA polymerase as well as gets incorporated to form dysfunctional DNA. Tumour cell apoptosis is promoted by multiple mechanisms confering activity even in slow growing neoplasm. It is indicated in chronic lymphatic leukaemia and non-Hodgkin’s lymphoma that have recurred after treatment. Prominent adverse effects are chills, fever and vomiting after injection, myelosuppression and opportunistic infections.


Dose: 25 mg/m2 BSA daily for 5 days every 28 days by i.v. infusion


FLUDARA 50 mg/vial inj.




Pyrimidine analogues have varied applications as antineo-plastic, antifungal and antipsoriatic agents.


Fluorouracil (5-FU) is converted in the body to the corresponding nucleotide 5fluoro2deoxyuridine monophosphate, which inhibits thymidylate synthase and blocks the conversion of deoxyuridilic acid to deoxythymidylic acid. Selective failure of DNA synthesis occurs due to nonavailability of thymidylate: thymidine can partially reverse its toxicity. Fluorouracil itself gets incorporated into nucleic acids and this may contribute to its toxicity. Even resting cells are affected, though rapidly multiplying ones are more susceptible.


Dose: 1 g orally on alternate days (6 doses) then 1 g weekly or 12 mg/kg/day i.v. for 4 days—6 mg/kg i.v. on alternate days; FLURACIL, FIVE FLURO 250 mg cap, 250 mg/5 ml for i.v. inj, also 1% topical solution.


It has been particularly used for many solid tumours—breast, colon, urinary bladder, liver, etc. Topical application in cutaneous basal cell carcinoma has yielded gratifying results.




It is phosphorylated in the body to the corresponding nucleotide which inhibits DNA synthesis. The triphosphate of cytarabine is an inhibitor of DNA polymerase and blocks generation of cytidilic acid. However, it is now believed that its incorporation into DNA is more important for the expression of cellular toxicity. It also interferes with DNA repair. Cytarabine is cell cycle specific and acts primarily during S phase. Its main use is to induce remission in acute leukaemia in children, also in adults. Other uses are—Hodgkin’s disease and non-Hodgkin lymphoma.


Dose: 1.5–3 mg/kg i.v. BD for 5–10 days (also by continuous i.v. infusion): CYTARABIN, CYTROSAR, CYTABIN, 100, 500, 1000 mg inj.


Both 5FU and cytarabine exert primary toxicity on bone marrow and g.i.t. Genetic deficiency of dihydropyrimidine dehydrogenase (DPD) predisposes to severe 5FU toxicity.


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