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Chapter: Basic & Clinical Pharmacology : Cancer Chemotherapy

Nonclassic Alkylating Agents

Several other compounds have mechanisms of action that involve DNA alkylation as their cytotoxic mechanism of action.

NONCLASSIC ALKYLATING AGENTS

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



Procarbazine

Procarbazine is an orally active methylhydrazine derivative, and in the clinical setting, it is used in combination regimens for Hodgkin’s and non-Hodgkin’s lymphoma as well as brain tumors.

The precise mechanism of action of procarbazine is uncertain; however, it inhibits DNA, RNA, and protein biosynthesis; pro-longs interphase; and produces chromosome breaks. Oxidative metabolism of this drug by microsomal enzymes generates azopro-carbazine and H2O2, which may be responsible for DNA strand scission. A variety of other drug metabolites are formed that may be cytotoxic. One metabolite is a weak monoamine oxidase (MAO) inhibitor, and adverse events can occur when procarbazine is given with other MAO inhibitors as well as with sympathomimetic agents, tricyclic antidepressants, antihistamines, central nervous system depressants, antidiabetic agents, alcohol, and tyramine-containing foods.

There is an increased risk of secondary cancers in the form of acute leukemia, and its carcinogenic potential is thought to be higher than that of most other alkylating agents.

Dacarbazine

Dacarbazine is a synthetic compound that functions as an alkylat-ing agent following metabolic activation in the liver by oxidative N-demethylation to the monomethyl derivative. This metabolitespontaneously decomposes to diazomethane, which generates a methyl carbonium ion that is believed to be the key cytotoxic spe-cies. Dacarbazine is administered parenterally and is used in the treatment of malignant melanoma, Hodgkin’s lymphoma, soft tis-sue sarcomas, and neuroblastoma. In terms of safety profile, the main dose-limiting toxicity is myelosuppression, but nausea and vomiting can be severe in some cases. This agent is a potent vesi-cant, and care must be taken to avoid extravasation during drug administration.

Bendamustine

Bendamustine is a bifunctional alkylating agent consisting of a purine benzimidazole ring and a nitrogen mustard moiety. As with other alkylating agents, it forms cross-links with DNA resulting in single- and double-stranded breaks, leading to inhibition of DNA synthesis and function. This molecule also inhibits mitotic check-points and induces mitotic catastrophe, which leads to cell death. Of note, the cross-resistance between bendamustine and other alkylating agents is only partial, thereby providing a rationale for its clinical activity despite the development of resistance to other alkylating agents. This agent is approved for use in chronic lym-phocytic leukemia, with activity also observed in Hodgkin’s and non-Hodgkin’s lymphoma, multiple myeloma, and breast cancer. The main dose-limiting toxicities include myelosuppression and mild nausea and vomiting. Hypersensitivity infusion reactions, skin rash, and other skin reactions occur rarely.


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