Antifolate resistance mechanisms from bacteria to cancer cells with emphasis on parasites.

Abstract

Reduced folates serve as co-factors in a variety of one-carbon transfer reactions including the biosynthesis of thymidylate, of purine nucleotides, and of the amino acids serine and methionine. Dihydrofolate reductase (DHFR) and thymidylate synthase (TS) catalyze consecutive reactions in the de novo synthesis of dTMR In protozoa and plants, these two enzymes are fused resulting in a DHFR-TS protein (Ferone and Roland, 1980). The enzyme DHFR is the target for the action of antifolates, which are widely used during chemotherapeutic interventions. Commonly used antifolates are shown in Figure 1. The folate antagonist trimethoprim (TMP) is used to treat bacterial infections caused by urinary tract or enteric pathogens (Huovinen et al., 1995). The antifolate pyrimethamine (PYR) is used against the protozoan parasites Plasmodium and Toxoplasma (Borst and Ouellette, 1995) whereas trimetrexate with leucovirin is used in fungal infections caused by Pneumocystis carinii (Hitchings, 1989). The antifolate methotrexate (MTX) is widely used for the treatment of various forms of cancer as well as for the treatment of rheumatoid arthritis, psoriasis and some autoimmune diseases (Gorlick et al., 1996). The primary structures of DHFR from a variety of organisms share very little homology, hence explaining, in part, the specificity and activity of different antifolates against targeted organisms. The basis for this selectivity was studied further by using comparative enzymology and structural analyses. Differences in the kinetic properties of the various DHFRs are likely to contribute to the selectivity of antifolates (Schweitzer et al., 1990).KeywordsDihydrofolate ReductaseFolate ReceptorReduce Folate CarrierMarine Biological LaboratoryDHFR GeneThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.