Intracellular Transformations of Antimetabolites

Many antimetabolites must undergo modification within the cell before they are active agents, and so in essence are prodrugs. MTX and pemetrexed exert much of their pharmacological effects as polyglutamates. Classical antifolate drugs usually require polyglutamation within the cell to achieve maximum efficacy.19 This transformation is carried out by the enzyme folylpolyglutamate synthetase (FPGS). Formation of the polyglutamate of antifolate drugs can cause a dramatic increase in the activity of the agent toward its intended target. Further, polyglutamates (above diglutamate) are less susceptible to cellular efflux, thus providing a long-lived pool of drug within the cell.20 Most natural folate cofactors exist as polyglutamates, and so the beneficial action of FPGS on antifolate drugs is not surprising. It also follows that any cellular change leading to decreased FPGS activity could lead to antifolate resistance. Nonclassical or lipophilic antifolates do not require or are incapable of polyglutamation through the action of FPGS, and are thus not susceptible to resistance related to decreased FPGS activity.

Most nucleoside derived antimetabolite analogs also undergo intracellular transformations to become active agents (Figure 4). The earliest of these agents, 5-fluorouracil (5-FU, 3) is converted into three major metabolites that are responsible for its activity. 5-FU is changed into 5-fluoro-2'-deoxyuridine monophosphate (FdUMP, 4) which acts as a mimic

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