Future directions for antifolate drug development

We have discussed potential ways by which new antifolates could be designed and utilized to effect both sensitive and resistant cell/tumor inhibition. Targeting of alternative folate-dependent enzymes and increasing net intracellular accumulation (transport) and polyglutamation of antifolates should be useful approaches. In addition, antibodies to and cloned cDNAs of the transport components (e.g., folate transport proteins) will allow better characterization and understanding of de novo and acquired antifolate resistance states and may provide insights into new drug development.