Determinants of resistance to antifolates: biochemical phenotypes, their frequency of occurrence and circumvention.
Biochemical alterations associated with acquired resistance of tumor cells to antifolates are diverse and multiple in number. These most often have included both quantitative and qualitative alterations at the level of membrane transport and of the primary intracellular target, dihydrofolate reductase (DHFR). More recent studies suggest determining biochemical alterations at the level of thymidylate synthase activity and 4-aminofolate polyglutamylation. Approaches to the circumvention of acquired antifolate resistance at the level of new drug design are described which incorporate a kinetic analysis of the various biochemical phenotypes and a systematic analysis of their structure-activity relationships. A consideration of the relative frequency of occurrence of individual phenotypes during therapy is also included. This introduces the notion of population genetics in an evaluation of resistance phenomenon and of clinically significant approaches for its circumvention.
D001692:Biological Transport; D004351:Drug Resistance; D005493:Folic Acid Antagonists; D006801:Humans; D010641:Phenotype; D011099:Polyglutamic Acid / Q000378:metabolism; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism
D005493:Folic Acid Antagonists; D011099:Polyglutamic Acid; D013762:Tetrahydrofolate Dehydrogenase