In addition to induced gene amplification altering the DNA target, a variety of mechanisms resulting in resistance to the topoisomerase inhibitors have also been described, only some of which involve these mechanisms (cf. Skovsgaard et al., 1994). Alteration of the DNA target by hypermethylation induced by chemotherapeutic agents, resulting in altered responses to such drugs, has also been reported (Nyce et al., 1993).
A number of chemotherapeutic agents require "bioactivation" to produce pharmacologically active, cytotoxic species (cf. Sladek, 1987). Both phase I and phase II enzymes (Chapter 3) have been identified as responsible both for differential sensitivity of individuals to chemotherapeutic agents as well as the response of neoplastic cells themselves to specific agents (cf. Iyer and Ratain, 1998; Graham et al., 1991; Chang et al., 1994). Cyclophosphamide and ifosfamide are alkylating agents that require bioactivation by phase I enzymes, although such bioactivation oc-
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