Antifolates antagonist

The folate antagonists, pyrimethamine and sulfadiazine, inhibit the parasite s DHFR/TS synthase enzyme complex and the DHPS, respectively (Fig. 4) (see antimalarial drugs). To avoid deficiency of folic acid in patients treated with antifolate antagonists, folinic acid supplementation is recommended to reduce bone-marrow suppression. 

Folic acid antagonist overdosage In the treatment of accidental overdosages of folic acid antagonists, administer leucovorin as promptly as possible. As the time interval between antifolate administration (eg, methotrexate) and leucovorin rescue increases, leucovorin s effectiveness in counteracting toxicity decreases. 

In many areas, resistance to folate antagonists and sulfonamides is common for P falciparum and less common for P vlvax. Resistance is due primarily to mutations in dihydrofolate reductase and dihydropteroate synthase, with increasing numbers of mutations leading to increasing levels of resistance. At present, resistance seriously limits the efficacy of sulfadoxine-pyrimethamine (Fansidar) for the treatment of malaria in most areas, but in Africa most parasites exhibit only moderate resistance, such that antifolates appear to continue to offer preventive efficacy against malaria. Because different mutations may mediate resistance to different agents, cross-resistance is not uniformly seen. 

Pyrimethamine is a fohc acid antagonist (antifol) with pharmacological actions similar to chlorguanide, methotrexate, and trimethoprim. Pyrimethamine may be used in combination with sulfadoxine for suppression and sulfadiazine for treatment of chloroquine-resistant Plasmodium falciparum. 

The key enzymes involved in the biosynthesis of DHFA and THFA are dihy-dropteroate synthetase, dihydrofolate synthetase and dihydrofolate reductase [1-3]. Drugs that block the synthesis of dihydropteroic acid are known as dihydropteroate synthetase inhibitors (PABA antagonists) and those which control the reduction of DHFA to THFA are called dihydrofolate reductase (DHFR) inhibitors. Collectively these drugs are known as antifolates. 

Thus, a large number of substances have been tested as inhibitors for the steps in purine and pyrimidine metabolism (Cory, in Devlin, 1986, p. 674 0. Inclnded are both synthetic compounds and compounds isolated from plants, bacteria, fungi, etc. The substances may be further classed as glutamine antagonists, antifolates, and antimetabolites. Whereas the first-mentioned substances are toxic in the extrane, the latter two classifications have been of main concern although they are toxic enough in their own right. 

Newer antifolates have been developed that are THF antagonists, which potendy inhibit the enzyme thymidylate synthase (TS). Again, cells exposed to increasing levels of the antifolates resulted in an increased resistance to these antifolates. In this circumstance the increased resistance was related to increased expression of TS and not DHFR. Similarly cells made resistant to classical TS inhibitors such as 5-fluorouracil were cross-resistant with the TS inhibitor antifolates. 

Antimetabolites (SEDA-29, 551) Purine antagonists, pyrimidine antagonists, antifolate drugs, phosphatidylcholine antagonists, adenosine deaminase inhibitors... 

Identification of dihydrofolic reductase as the main site for action of aminopterin and amethopterin (Section II, 2) fits with observations that in many systems these antifolics are more efficiently reversed by CF than by PGA e.g. chick embryos (Naber et al., 1952) weanling rats (Sauberlich, 1953) Lactobacillus arabinosus (Hendlin et al., 1953) tissue cultures (Ja-cob.son, 1954) also, amethopterin-resistant Slreptococcus-re ated PGA derivatives (Broquist et al., 1953). Burchenal (1956), in reviewing folic acid antagonists in cancer therapy, notes that the 4-hydroxy derivatives of PGA are reversed by PGA rather than by CF, while diaminodichlorophenyl P3udmidines (e.g. formula III) seem to compete even more with CF than... 

Streptococcus faecalis or Pediococcus cerevisiae (Foley et oZ., 1955). Only the 4-amino PGA derivatives seem to have a selective effect on leukemia in children other leukemias, such as the myeloid mouse leukemias, are resistant. Resistance to one antifolic, e.g. amethopterin, generally confers resistance to all other folic antagonists, including the diaminodichloro-phenylpyrimidines. 

In some systems, especially microbial ones, purine synthesis is quite sensitive to antifolics. One would expect that to some extent purines wotild noncompetitively reverse inhibitions by antifolics. Guthrie et al. (1956) found that hypoxanthine or adenine blocks inhibition of Bacillus aubtUis by amethopterin. Also, Tomisek et al. (1958) present evidence that formylation by AICAR is the primary site of amethopterin inhibition in E. coU, and Ghosh et al. (1958) found that some compounds that were competitive antagonists for PGA or CF were not at all inhibitory to Streptococcus faecalis when the PGA was bypassed with adenine plus thymine. 

---