procarbazine Several methylhydrazine derivatives have anticancer activity, but only procarbazine (N-isopropyl-a-(2-methylhydrazino)-p-toluamide) is used clinically. The antineoplastic activity of procarbazine results from its conversion by hepatic CYPs to highly reactive alkylating species that methylate DNA. The first step in activation involves oxidation of the hydrazine function, yielding an azo metabolite that exists in equilibrium with its hydrazone tautomer. N-oxidation of azoprocarbazine generates the isomeric benzylazoxy and methylazoxy metabolites, the latter of which liberates an entity resembling diazomethane, a potent methylating reagent. Free-radical intermediates also may be involved. Activated procarbazine can produce chromosomal damage, including chromatid breaks and translocations, consistent with its mutagenic and carcinogenic actions. Exposure to procarbazine leads to inhibition of DNA, RNA, and protein synthesis in vivo. Resistance to procarbazine develops rapidly when it is used as a single agent. One mechanism results from the increased ability to repair methylation of guanine via AGT.

Procarbazine is efficiently absorbed from the GI tract and rapidly distributes into the CNS. The drug and its metabolites are predominantly eliminated in the urine, with N-isopropyl-terephthala-mic acid being the major metabolite, accounting for ~25% of doses given either orally or intravenously. Multiple metabolites of the drug (e.g., azo, methylazoxy, and benzylazoxy derivatives) have been identified in the plasma after oral procarbazine. A marked decrease in the apparent clearance of the drug upon repeated daily oral administration has been observed. Although CYPs have well-defined roles in the activation of procarbazine, the concurrent use of antiseizure drugs that induce hepatic CYPs did not significantly alter the pharmacokinetics of the parent drug in brain cancer patients.

The recommended dose of procarbazine (matulane) for adults is 100 mg/m2 daily for 10—14 days in combination regimens. The drug rarely is used alone. Procarbazine is used in combination with mechlorethamine, vincristine, and prednisone (the MOPP regimen) for the treatment of Hodgkin's disease. Alternative regimens with less leukemogenic potential have largely replaced MOPP. Of primary importance, procarbazine lacks cross-resistance with other mustard-type alkylating agents. Procarbazine has been used in combination with lomustine and vincristine (the PCV regimen) for treating patients with newly diagnosed or recurrent primary brain tumors.

The most common toxic effects include leukopenia and thrombocytopenia, which begin during the second week of therapy and reverse within 2 weeks following treatment. GI symptoms such as mild nausea and vomiting occur in most patients; neurological and dermatological manifestations have been noted in 5—10% of cases. Behavioral disturbances also have been reported. Because of augmentation of sedative effects, the concomitant use of CNS depressants should be avoided. Since procarbazine is a weak monoamine oxidase inhibitor, hypertensive reactions may result from its use concurrently with sympathomimetic agents, tricyclic antidepressants, or ingestion of foods with high tyramine content. Procarbazine has disulfiram-like actions and the ingestion of alcohol should be avoided. Procarbazine is highly carcinogenic, mutagenic, and teratogenic, and its use in MOPP therapy is associated with a 5—10% risk of acute leukemia; the greatest risk is for patients who also receive radiation therapy. Procarbazine also is a potent immunosuppressive agent, and it causes infertility, particularly in males.

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