Procarbazine toxicity

Nitrogen mustard is clinically used for the treatment of lymphomas and some forms of lung cancer. The major indication for mechlorethamine is Hodgkin s disease as a part of the MOPP regimen (mechlorethamine + vincristine (oncovin) + procarbazine + prednisone). The usual dose consists of 6 mg/m2 on days 1 and 8. This drug has pronounced hematological toxicity (myelo-suppression). 

There is an increased risk for bone marrow suppression when levamisole or hydroxyurea are administered witii other antineoplastic dni. Use of levamisole witii phenytoin increases die risk of phenytoin toxicity. Pegaspargase may alter drug response of the anticoagulants. When procarbazine is administered with other central nervous system (CNS) depressants, such as alcohol, antidepressants, antihistamines, opiates, or the sedatives, an additive CNS effect may be seen. Procarbazine may potentiate hypoglycemia when administered witii insulin or oral antidiabetic dru . ... 

Procarbazine -alkylating agent cell cycle independent -bone marrow suppression—prolonged -nausea and vomiting—severe tolerance often develops with repeated dosing -mucocutaneous effects (mucositis, stomatitis, diarrhea) -rash, hives, photosensitivity -interstitial pneumonitis -CNS toxicity—seizures, lethargy, headache, ataxia -flu-like syndrome -azoospermia and amenorrhea almost universal... 

Procarbazine (Matulane) may autooxidize spontaneously, and during this reaction hydrogen peroxide and hydroxyl free radicals are generated. These highly reactive products may degrade DNA and serve as one mechanism of procarbazine-induced cytotoxicity. Cell toxicity also may be the result of a transmethylation reaction that can occur between the A-methyl group of procarbazine and the N7 position of guanine. 

Several other compounds have mechanisms of action that involve DNA alkylation as their cytotoxic mechanism of action. These agents include procarbazine, dacarbazine, and bendamustine. Their clinical activity and associated toxicities are listed in Table 54-2. 

A combined in vivolin vitro system for chemical metabolites has been developed that demonstrates the role of metabolism in activating compounds. In this system, rats are treated with a chemical and serum is removed 1 h later and cultured with explanted embryos. This system has been used to demonstrate that metabolites of procarbazine are toxic to explanted embryos, but that procarbazine and a microsomal preparation are not toxic to explanted embryos grown in culture medium (Schmid et al., 1982). 

Procarbazine Matulane Hodgkin disease Blood disorders [leukopenia, thrombocytopenia] Gl distress [nausea, vomiting] CNS toxicity [mood changes, incoordination, motor problems]... 

SSRIs PROCARBAZINE T risk of serotonin syndrome and CNS toxicity Additive toxicity Monitor BP closely and also CNS side-effects. Because of the long half-life of fluoxetine and its active metabolites, at least 5 weeks should elapse between discontinuation of fluoxetine and initiation of therapy with an MAOI... 

CLOZAPINE PROCARBAZINE, PENICILLAMINE t risk of bone marrow toxicity Additive effect Avoid co-administration... 

METHOTREXATE PROCARBAZINE t risk of renal impairment if methotrexate infusion is given within 48 hours of procarbazine administration. Also t risk of methotrexate toxicity, particularly to the kidneys Procarbazine has a transient effect on the kidneys, and this will delay the renal elimination of methotrexate Do not start methotrexate infusion less than 72 hours after the last dose of procarbazine. Hydrate patients aggressively (plenty of oral fluids or intravenous fluids), alkalinize the urine to pH>7 and closely monitor renal function, e.g. blood urea and creatinine, before and after methotrexate infusion until methotrexate blood levels are <0.05 xmol/L... 

OPIOIDS ANTICANCER AND IMMUNOMODULATING DRUGS - CYTOTOXICS 1. Imatinib may cause t plasma concentrations, with a risk of toxic effects of codeine, dextromethorphan, hydroxycodone, methadone, morphine, oxycodone, pethidine and tramadol 2. Unpredictable reactions may occur associated with hypotension and respiratory depression when procarbazine is co-administered with alfentanil, fentanyl, sufentanil or morphine... 

Mahmood T, Mudad R. Pulmonary toxicity secondary to procarbazine. Am J Clin Oncol 2002 25(2) 187-8. 

Rarely, azathioprine and its major metabohte 6-mercaptopurine have been reported to produce an acute restrictive lung disease. Procarbazine, a methylhydrazine associated more commonly with Loef-fler s syndrome, rarely has been associated with pulmonary fibrosis. The vinca alkaloids vinblastine and vindesine have been reported to produce severe respiratory toxicity in association with mitomycin. The incidence with the combination is 39% and may represent a true synergistic effect between these agents. ... 

Answer A. It can help to know which anticancer drugs are cell-cycle specific and which have characteristic toxicities. Bleomycin fits both categories acting mainly in G2, it is cell cycle specific and is distinctive for causing mucocutaneous reactions and pulmonary dysfunction. Busulfan and procarbazine may also cause pulmonary toxicity, but neither drug is cell-cycle specific. 

Procarbazine Alkylating agent Hodgkin s (MOPP) BMS, pulmonary toxicity, hemolysis, neurotoxicity, leukemogenic... 

Toxicity Procarbazine is myelosuppressant and causes gastrointestinal irritation, CNS dysfunction, peripheral neuropathy, and skin reactions. Procarbazine inhibits many enzymes, including MAO and those involved in hepatic drug metaboUsm. Disulfiram-like reactions have occurred with ethanol. The drug is leukemogenic. 

The anticancer drug most commonly associated with pulmonary toxicity is bleomycin. If pulmonary dysfunction with infiltration developed, the drug would be discontinued. High-dose steroids and empiric antibiotic therapy would also be indicated. Note that procarbazine (not listed), used in the MOPP regimen for Hodgkin s lymphoma, may also cause cough and pleural effusions. The answer is (A). 

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