DIHYDROFOLATE REDUCTASE INHIBITORS have as a target the enzyme dihydrofolate reductase, and are known as folate antagonists. These include anticancer agents (‘antimetabolites’) such as methotrexate, antibacterial AGENTS such as trimethoprim, and the ANTIPROTOZOALS pyrimethamine and proguanil (which are used to treat malaria). Folate is required for synthesis of purine nucleotides, which in turn are essential for DNA synthesis and cell division. In mammals it is necessary to convert body folates, through two separate enzyme-catalysed reduction stages, to tetrahydrofolate (FH4). The first stage involves the enzyme dihydropteroate reductase, which catalyses the conversion of beta-aminobenzoic acid to folate (and this stage can be inhibited by sulphonamides). The second stage is conversion of folate to tetrahydrofolate by the enzyme dihydrofolate reductase. Methotrexate, trimethoprim, pyrimethamine and proguanil inhibit this latter conversion and lead to depletion of folic acid.

Methotrexate is used as an oral anticancer agent, but resistance may develop in tumour cells, and there are a number of unwanted side-effects. It has a high affinity for the mammalian form of dihydrofolate reductase and cannot be used as an antibacterial or antimalarial drug. After use at high doses in humans, the extent of depletion of folic acid may be such, that ‘rescue’ with administration of folinic acid (a form of tetrahydrofolate) is necessary.

Pyrimethamine and proguanil are used as oral antimalarials.and inhibit the utilization of folate by the malarial parasite, so are valuable in chemoprophylaxis and in preventing the transmission of malaria. (See ANTIMALARIALS.) Trimethoprim is a useful antibacterial, and as an antiprotozoal in antimalarial therapy. The selectivity of these agents derives, in part, from the fact that whereas mammals can obtain folic acid from the diet, bacteria and the asexual forms of the malarial parasite must synthesize it. Also, the dihydrofolate reductase enzyme in humans is less sensitive to these drugs than that of the parasites.