Clinical resistance to antimetabolites

Abstract

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.