I. ALKYLATING AGENTS AND PLATINUM COORDINATION COMPLEXES
In 1942, Louis Goodman and Alfred Gilman, the originators of this text, began clinical studies of intravenous nitrogen mustards in patients with lymphoma, launching the modern era of cancer chemotherapy. 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 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 general mechanisms actions of alkylating agents on DNA are illustrated in Figure 61-1 with mechlorethamine (nitrogen mustard). The extreme cytotoxicity of bifunctional alkylators correlates very closely with interstrand cross-linkage of DNA.
Mechanism of action of alkylating agents. A. Activation reaction. B. Alkylation of N7 of guanine.
The ultimate cause of cell death related to DNA damage is not known. Specific cellular responses include cell-cycle arrest and attempts to repair DNA. The specific repair enzyme complex utilized will depend on 2 factors: the chemistry of the adduct formed and the repair capacity of the cell involved. The process of recognizing and repairing DNA generally requires an intact nucleotide excision repair (NER) complex, but may differ with each drug and with each tumor. Alternatively, recognition of extensively damaged DNA by p53 can trigger apoptosis. Mutations of p53 lead to alkylating agent resistance.
Structure-Activity Relationships. Although these alkylating agents share the capacity to alkylate biologically important molecules, modification of the basic chloroethylamino structure changes reactivity, lipophilicity, active transport across biological membranes, sites of macromolecular attack, and mechanisms of DNA repair, all of which determine drug activity in vivo. With several of the most valuable agents (e.g., cyclophosphamide, ifosfamide), the active alkylating moieties are generated in vivo through hepatic metabolism (Figure 61-2). Consult Chapter 61 of the 12th edition of the parent text for details on metabolic activation and structure-activity relationships among these compounds.
Metabolic activation of cyclophosphamide. Cyclophosphamide is activated (hydroxylated) by CYP2B, with subsequent transport of the activated intermediate to sites of action. The selectivity of cyclophosphamide against certain malignant tissues may result in part from the capacity of normal tissues to degrade the activated intermediates via aldehyde dehydrogenase, glutathione transferase, and other pathways. Ifosfamide is structurally similar to cyclophosphamide: whereas cyclophosphamide has 2 chloroethyl groups on the exocyclic nitrogen atom, 1 of the ...