Pharmacological Actions

The most important pharmacological actions of the alkylating agents are those that disturb DNA synthesis and cell division (Figure 51-3). The capacity of these drugs to interfere with DNA integrity and function and to induce cell death in rapidly proliferating tissues provides the basis for their therapeutic and toxic properties. Whereas certain alkylating agents may have damaging effects on tissues with normally low mitotic indices—for example, liver, kidney, and mature lymphocytes—effects in these tissues usually are delayed. Acute effects are manifest primarily against rapidly proliferating tissues. Lethality of DNA alkylation depends on recognition of the adduct, creation of DNA strand breaks by repair enzymes, and an intact apoptotic response.

In normal nondividing cells, DNA damage activates a checkpoint that blocks cell-cycle progression at the G1/S interface allowing cells to either repair DNA alkylation or undergo apoptosis. Malignant cells with mutant or absent p53 fail to suspend cell-cycle progression, do not undergo apoptosis, and are resistant to these drugs.

While DNA is the ultimate target of all alkylating agents, there is a crucial distinction between the bifunctional agents, in which cytotoxic effects predominate, and the monofunctional methylat-

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