Miscellaneous Cytotoxic Drugs

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Chapter: Essential pharmacology : Anticancer Drugs

These drugs (except L-asparaginase) have been developed by random synthesis and testing for antitumour activity.


MISCELLANEOUS CYTOTOXIC DRUGS

 

These drugs (except L-asparaginase) have been developed by random synthesis and testing for antitumour activity.

 

Hydroxyurea

 

It blocks the conversion of ribonucleotides to deoxyribonucleotides by inhibiting the enzyme ribonucleoside diphosphate reductase—thus interferes with DNA synthesis; exerts Sphase specific action. Its primary therapeutic value is in chronic myeloid leukaemia, psoriasis, polycythaemia vera and in some solid tumours. Myelosuppression is the major toxicity.

 

Dose: 20–30 mg/kg daily or 80 mg/kg twice weekly; CYTODROX, HYDAB 500 mg cap.

 

Procarbazine

 

After metabolic activation (it is inactive as such), procarbazine depolymerizes DNA and causes chromosomal damage. Inhibition of nucleic acid synthesis also occurs. Because of damage to DNA, mutagenic and carcinogenic action is noted experimentally. Procarbazine is a component of the popular MOPP regimen for Hodgkin’s disease. It is also useful in non-Hodgkin lymphomas and oat cell carcinoma of lung.

 

Procarbazine is a weak MAO inhibitor, produces some CNS effects and interacts with foods and drugs. Alcohol causes hot flushing and a disulfiram like reaction in patients receiving procarbazine. Vomiting, leucopenia, thrombocytopenia and dermatitis are the prominent toxicities.

 

Dose: 100–300 mg oral daily; maintenance dose 1–2 mg/ kg/day.

 

L-Asparaginase

 

It was introduced on the basis of a qualitative difference observed between normal cells and those from childhood lymphoblastic leukemia—the leukaemia cells are deficient in L-asparagine synthase and depend on the supply of L-asparagine from the medium. The enzyme L-asparaginase (from E. coli) degrades L-asparagine to L-aspartic acid, depriving leukaemic cells of an essential metabolite—may cause cell death. However, the clinical response to L-asparaginase has been disappointing. Though, remission is induced in acute leukaemia, it is short lasting. Thus, it is now used when other drugs have failed to induce remission. It is ineffective in solid tumours.

 

Many of the typical adverse effects of anticancer drugs are not seen with L-asparaginase (no leucopenia, alopecia or mucosal damage); but it produces liver damage, pancreatitis and CNS symptoms (due to defective protein synthesis). Being a foreign protein, it produces allergic reactions in a significant percentage of patients— even anaphylaxis can occur.

 

Dose: 50–200 KU/kg i.v. daily for 2–4 weeks.

 

LEUNASE 10,000 KU per vial inj.

 

Cisplatin

 

It is a platinum coordination complex that is hydrolysed intracellularly to produce a highly reactive moiety which causes cross linking of DNA. The favoured site is N7 of guanine residue. It can also react with –SH groups in proteins and has radiomimetic property. It is bound to plasma proteins, enters tissues and is slowly excreted unchanged in urine with a t½ about 72 hrs. Negligible amounts enter brain.

 

Cisplatin is very effective in metastatic testicular and ovarian carcinoma. It has found use in many other solid tumours as well.

 

It is administered by slow i.v. infusion 50–100 mg/m2 BSA every 3–4 weeks; CISPLATIN, CISPLAT, PLATINEX 10 mg/10 ml, 50 mg/50 ml vial.

 

Cisplatin is a highly emetic drug. Antiemetics are routinely administered before infusing it. The most important toxicity is renal impairment which is dependent on total dose administered. Renal toxicity can be reduced by maintaining good hydration. Tinnitus, deafness, neuropathy and hyperuricaemia are other problems. Shock like state sometimes occurs during i.v. infusion.

 

Carboplatin

 

It is a less reactive second generation platinum compound that is better tolerated and has a toxicity profile different from cisplatin. Nephrotoxicity, ototoxicity and neurotoxicity are low. Nausea and vomiting is milder and is delayed: only infrequently limits the dose. The doselimiting toxicity is thrombocytopenia and less often leucopenia. Because of less plasma protein binding, it is rapidly eliminated by the kidney (t½ 4–6 hr). It is primarily indicated in ovarian carcinoma of epithelial origin, and has shown promise in squamous carcinoma of head and neck, small cell lung cancer and seminoma.

 

ONCOCARBIN 150 mg inj, KEMOCARB 150, 450 mg/ vial inj. 400 mg/m2 as an i.v. infusion over 15–60 min, to be repeated only after 4 weeks.

 

Imatinib

 

This novel antineoplastic drug inhibits the tyrosine protein kinases in chronic myeloid leukaemia (CML) cells and the ones that are activated by platelet derived growth factor (PDGF) receptor, stem cell receptor and ckit receptor found in gastrointestinal stromal tumour (GIST), a rare tumour. Stricking success has been obtained in chronic phase of CML as well as in accelerated phase, and in metastatic kitpositive GIST. Adverse effects are fluid retention, edema, vomiting, abdominal pain, myalgia and liver damage.

 

Dose: 400 mg/day with meal; accelerated phase of CML 600–800 mg/day.

 

IMATIBα, SHANTINIB 100 mg cap.

 

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