Alkylating Agents - Pharmacology of Cancer Chemotherapeutic Drugs

BASIC PHARMACOLOGY OF CANCER CHEMOTHERAPEUTIC DRUGS

ALKYLATING AGENTS

The major clinically useful alkylating agents (Figure 54–3) have a structure containing a bis(chloroethyl)amine, ethyleneimine, or nitrosourea moiety, and they are classified in several different groups. Among the bis(chloroethyl)amines, cyclophosphamide, mechlorethamine, melphalan, and chlorambucil are the most use-ful. Ifosfamide is closely related to cyclophosphamide but has a somewhat different spectrum of activity and toxicity. Thiotepa and busulfan are used to treat breast and ovarian cancer, and chronic myeloid leukemia, respectively. The major nitrosoureas are carmustine (BCNU) and lomustine (CCNU).

Mechanism of Action

As a class, the alkylating agents exert their cytotoxic effects via transfer of their alkyl groups to various cellular constituents. Alkylations of DNA within the nucleus probably represent the major interactions that lead to cell death. However, these drugs react chemically with sulfhydryl, amino, hydroxyl, carboxyl, and phosphate groups of other cellular nucleophiles as well. The general mechanism of action of these drugs involves intramolecular cycliza-tion to form an ethyleneimonium ion that may directly or through formation of a carbonium ion transfer an alkyl group to a cellular constituent (Figure 54–4). In addition to alkylation, a secondary mechanism that occurs with nitrosoureas involves carbamoylation of lysine residues of proteins through formation of isocyanates.

The major site of alkylation within DNA is the N7 position of guanine; however, other bases are also alkylated albeit to lesser degrees, including N1 and N3 of adenine, N3 of cytosine, and O6 of guanine, as well as phosphate atoms and proteins associated with DNA. These interactions can occur on a single strand or on both strands of DNA through cross-linking, as most major alky-lating agents are bifunctional, with two reactive groups. 

Alkylation of guanine can result in miscoding through abnormal base pairing with thymine or in depurination by excision of guanine residues. The latter effect leads to DNA strand breakage through scission of the sugar-phosphate backbone of DNA. Cross-linking of DNA appears to be of major importance to the cytotoxic action of alky-lating agents, and replicating cells are most susceptible to these drugs. Thus, although alkylating agents are not cell cycle specific, cells are most susceptible to alkylation in late G₁ and S phases of the cell cycle.

Resistance

The mechanism of acquired resistance to alkylating agents may involve increased capability to repair DNA lesions, decreased trans-port of the alkylating drug into the cell, and increased expression or activity of glutathione and glutathione-associated proteins, which are needed to conjugate the alkylating agent, or increased glutathione S-transferase activity, which catalyzes the conjugation.

Adverse Effects

The adverse effects usually associated with alkylating agents are generally dose-related and occur primarily in rapidly growing tis-sues such as bone marrow, gastrointestinal tract, and reproductive system. Nausea and vomiting can be a serious issue with a number of these agents. In addition, they are potent vesicants and can damage tissues at the site of administration as well as producesystemic toxicity. As a class, alkylating agents are carcinogenic in nature, and there is an increased risk of secondary malignancies, especially acute myelogenous leukemia.

Cyclophosphamide is one of the most widely used alkylating agents. One of the potential advantages of this compound relates to its high oral bioavailability. As a result, it can be administered via the oral and intravenous routes with equal clinical efficacy. It is inactive in its parent form, and must be activated to cytotoxic forms by liver microsomal enzymes (Figure 54–5). The cyto-chrome P450 mixed-function oxidase system converts cyclophos-phamide to 4-hydroxycyclophosphamide, which is in equilibrium with aldophosphamide. These active metabolites are delivered to both tumor and normal tissue, where nonenzymatic cleavage of aldophosphamide to the cytotoxic forms—phosphoramide mus-tard and acrolein—occurs. The liver appears to be protected through the enzymatic formation of the inactive metabolites 4-ketocyclophosphamide and carboxyphosphamide.

The major toxicities of the individual alkylating agents are outlined in Table 54–2 and discussed below.