Medical Pharmacology Chapter 33-34:  Anticancer Drugs

• Alkylating Agents (Continued)

  • Classification⁸

    • Non-Classical Agents (Nitrogen Mustard Compound):

      • Procarbazine (Matulane)

        • Procarbazine (Matulane)

        • Procarbazine is used both for Hodgkin's and non-Hodgkin's lymphoma and in treating brain tumors.²

          • Usually, procarbazine administration is part of a multidrug protocol that may involve a nitrogen mustard such as mechlorethamine, a mitosis inhibitor such as vincristine and a steroid such as prednisone.²

          • Procarbazine, a methylhydrazine  derivative, exhibits both antineoplastic and mutagenic characteristics.⁷

            •  Cytotoxicity may result from the drug's ability, following metabolic activation, to inhibit trans-methylation of methionine into tRNA.

              • As a result of this effect, protein synthesis, as well as DNA and RNA synthesis are inhibited.⁷

              • The prodrug procarbazine is converted to highly reactive alkylating agents capable of methylating DNA.¹  This mechanism represents another possible mechanism of action.

                • The activation step depends on the cytochrome P450 microsomal metabolizing system.¹  

                • Once activated, procarbazine induces chromosomal damage that includes both chromosomal translocation and chromatid breaks.¹  

                  • When used as monotherapy, procarbazine resistance develops rapidly.

                    • A proposed mechanism of resistance involves increased expression of the DNA repair protein O-6-methylguanine DNA methyltransferase (MGMT) which repairs guanine methylation.^1,8 

        • Absorption, Distribution, Metabolism, Excretion:

          • Procarbazine undergoes both rapid and nearly total absorption from the G.I. tract following the oral route of administration. ⁷

            • The plasma peak concentrations appear within one hour. Furthermore, oral administration results in plasma concentrations comparable to that observed following IV drug administration.⁷

          • Procarbazine undergoes metabolism by cytochrome P450 isoforms to azo-, methylazoxy and benzylazoxy intermediates which are alkylating metabolites.¹  

            • When procarbazine is used in the treatment of brain cancer, concurrent anti-seizure drugs which are also likely employed and which do induce liver microsomal metabolizing enzymes do not substantially change procarbazine pharmacokinetics.¹  

          • About 45%-70% of the procarbazine dose is excreted in the urine, as metabolites, during the first day. Less than 5% of excreted drug is found as the parent, unchanged compound.⁷

        • Some Clinical Uses:

          • Procarbazine is used in combination protocols such as MOPP (Mechlorethamine, Vincristine (Oncovin), Prednisone, Procarbazine) for Hodgkin lymphoma, approved for this indication in 1969.^1,6,9

            • Subsequently, procarbazine has been demonstrated to exhibit clinical activity in non-Hodgkin lymphoma as well as cutaneous T-cell lymphoma.

          • Procarbazine is also used in treating gliomas as it is a component of the PCV regimen, Procarbazine, Lomustine, Vincristine; PVC (Procarbazine, Vincristine, bis-2-chloroethyl-3-cyclohexyl-1-nitrosourea (CCNU).

        • Adverse Effects:

          • Several important drug-drug and drug-food interactions are associated with procarbazine.

            • Patients receiving procarbazine should avoid tyramine-containing foods including cheese, yogurt, bananas and smoked foods.

            • Procarbazine induces a "disulfiram-like" reaction upon ingestion of alcohol.

            • Use of procarbazine along with tricyclic antidepressants and sympathomimetic drugs may result in acute hypertensive reactions.

            • Procarbazine in combination with antihistamines as well as other CNS depressants can result in CNS and/or respiratory depression.⁶

          • Dose-limiting toxicities:

            • The principal dose-limiting toxicity is myelosuppression, usually manifest as thrombocytopenia.

              • Lowest levels in platelet count is observed in about one month after drug initiation.

              • A subset of patients who have glucose-6-phosphate dehydrogenasespace deficiency are at risk of hemolytic anemia during procarbazine treatment.

              • Procarbazine, rarely, may cause interstitial pneumonitis which in turn requires therapy discontinuation.

              • Infertility or azoospermia following MOPP (Mechlorethamine, Vincristine (Oncovin), Prednisone, Procarbazine) therapy is probably attributed to procarbazine, at least in part.

              • Procarbazine administration carries the risk of second malignancy development, particularly acute leukemia.⁶