I. ALKYLATING AGENTS AND PLATINUM COORDINATION COMPLEXES
The pervasive toxic effects of sulfur mustard gas were noted as the result of its use in World War I. A potent vesicant, the gas caused a topical burn to skin, eyes, lungs, and mucosa and, after massive exposure, aplasia of the bone marrow and lymphoid tissue and ulceration of the GI tract. Early clinical experiments with topically applied sulfur mustard led to regression of penile tumors. Thereafter, Goodman, Gilman, the originators of this text, working with colleagues at Yale in a consortium organized by the U.S. Department of Defense, confirmed the antineoplastic action of the nitrogen mustards against a murine lymphoma. In 1942, they began clinical studies of intravenous nitrogen mustards in patients with lymphoma, launching the modern era of cancer chemotherapy (Gilman and Philips, 1946).
At present, six major types of alkylating agents are used in the chemotherapy of neoplastic diseases:
In addition, because of similarities in their mechanisms of action and resistance, platinum complexes are discussed with classical alkylating agents, even though they do not alkylate DNA but instead form covalent metal adducts with DNA. The mechanism of action of alkylating agents is shown in Figure 61–1.
Mechanism of action of alkylating agents. A. Activation reaction. B. Alkylation of N7 of guanine.
Chemistry. The chemotherapeutic alkylating agents have in common the property of forming highly reactive carbonium ion intermediates. These reactive intermediates covalently link to sites of high electron density, such as phosphates, amines, sulfhydryl, and hydroxyl groups. Their chemotherapeutic and cytotoxic effects are directly related to the alkylation of reactive amines, oxygens, or phosphates on DNA. The N7 atom of guanine is particularly susceptible to the formation of a covalent bond with bifunctional alkylating agents and may represent the key target that determines their biological effects. Other atoms in the purine and pyrimidine bases of DNA, including N1 and N3 of the adenine ring, N3 of cytosine, and O6 of guanine, react with these agents, as do the amino and sulfhydryl groups of proteins and the sulfhydryls of glutathione.
The possible actions of alkylating agents on DNA are illustrated in Figure 61–1 with mechlorethamine (nitrogen mustard). First, one 2-chloroethyl side chain undergoes a first-order (SN1) intramolecular cyclization, with release of Cl− and formation of a highly reactive ethyleneimine intermediate (Figure 61–1). The unstable quaternary amine then reacts with a variety of electron-dense sites. This latter reaction proceeds as a second-order (SN2) nucleophilic substitution. Alkylation of the N7 of guanine in DNA, a highly favored reaction, exerts several biologically important effects. Guanine residues in DNA exist predominantly as the keto tautomer and readily make Watson-Crick base pairs by hydrogen ...