Antimetabolites are rational agents with specific S-phase and
enzyme targets. Low levels of target
enzymes in
tumors are associated with innate
drug sensitivity, and the general requirement for transport and metabolic activation of
antimetabolites creates several loci of acquired drug resistance. Pharmacodynamic studies of TS inhibition after fluoropyrimidines clearly can predict for
tumor sensitivity and response to fluoropyrimidine-based
therapy or identify factors related to resistance, and ara-
dCTP levels in leukemic cells can be useful for refined dosing of araC. Powerful new DHFR and TS directed agents are in advanced levels of clinical evaluation, and
purine analogues directed against
adenosine deaminase are newly available for treatment of indolent
lymphomas. Progress in analysis of
tumors, such as PCR techniques to study gene expression or immunostaining of target
enzymes, offer increasing promise for individualization of patient selection. Increased experience with biochemical modulators, including
biologic response modifiers, has opened the possibility for selective attack on specific mechanisms of drug resistance. Sophisticated pharmacokinetic modeling and pharmacogenetic testing of metabolic phenotypes can now be done to achieve optimal dosing with less risk of toxicity. Considerations of ultimate genetic mechanisms of
antimetabolite effects, especially by programmed cell death, and relationships to mechanisms of cell cycle regulation offer exciting rationales for future
drug development.