Medical Pharmacology Chapter 33-34: Anticancer Drugs
Alkylating Agents (Continued):
Non-Classical Agents (Nitrogen Mustard Compound):
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).
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
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
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