Folate antagonists, mechanisms

Mechanism of Action A folate antagonist that blocks bacterial biosynthesis of nucleic acids and proteins by interfering with the metabolism of folinic acid. Therapeutic Effect Bacteriostatic. 

Mechanism of Action A folate antagonist that inhibits the enzyme dihydrofolate reductase (DHFR). Therapeutic Effect Disrupts purine, DNA, RNA, protein synthesis,... 

Folic Acid Antagonists - Interest in antimetabolites that interfere with the synthesis of nucleic acids continues. Studies on the transport and uptake of methotrgxate ° and 2,4-diamino-5-(3,4-dichlorophenyl)-6-methylpyrimidine indicate that clinical response is related to cellular uptake of drugl and the resistance of certain cells to methotrexate appears to be due to lack of transport into these cells. Work on other resistant cell lines indicates that resistance can also be due to an increase in cellular content of folate reductase, but no correlation was observed between resistance and the level of other enzymes involved in folate metabolism. Despite these results there is evidence that the ability of methotrexate to kill cells cannot be entirely explained by its inhibition of folate reductase. Leucovorin at appropriately timed intervals improved the therapeutic index of methotrexate in the treatment of head and neck cancer, and lymphosarcoma and reticulum cell sarcoma. The use of methotrexate in the treatment of hormone-refractory metastatic breast carcinoma " and the use of intrathecal methotrexate also appear promising. Oxidation of methotrexate to 7-hydroxymethotrexate by liver aldehyde oxidase is probably a detoxification mechanism. Material previously reported to be tetrahydromethotrexate has now been found to be a mixture of di- and tetrahydromethotrexate, both of which are less effective than methotrexate in the inhibition of folate reductase, but more effective in the inhibition of thymidylate synthetase. ... 

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