Alkylating Agents

The alkylating agents are the largest class of anticancer agents, comprising five subgroups: nitrogen mustards, alkyl sulfonates, nitrosoureas, ethyleneimine, and thi-azines (Table 56.1). Several other agents, including procarbazine, hexamethylmelamine, dacarbazine, estra-mustine, and mitomycin C, are thought to act at least in part by alkylation.

By definition, alkylating agents are compounds that are capable of introducing alkyl groups into nucle-ophilic sites on other molecules through the formation of covalent bonds. These nucleophilic targets for alkyla-tion include the sulfhydryl, amino, phosphate, hydroxyl, carboxyl, and imidazole groups that are present in macromolecules and low-molecular-weight compounds within cells.

The macromolecular sites of alkylation damage include DNA, RNA, and various enzymes. The inhibition of DNA synthesis occurs at drug concentrations that are lower than those required to inhibit RNA and protein synthesis, and the degree of DNA alkylation correlates especially well with the cytotoxicity of these drugs. This interaction also accounts for the mutagenic and carcinogenic properties of the alkylating agents. The reactions of various alkylating agents with DNA have been studied in detail, and the 7-nitrogen (N7) and 6-oxygen (O6) of guanine have been shown to be particularly

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