Antimetabolites antifolates

Methotrexate -antifolate antimetabolite cell cycle dependent -bone marrow suppression -nausea and vomiting—mild to moderate -mucocutaneous effects (mucositis, stomatitis, diarrhea) -hepatotoxicity—more common in high-dose therapy -CNS toxicity—dizziness, malaise, blurred vision, encephalopathy -nephrotoxicity—including acute renal failure, particularly at high doses... 

Trimetrexate -antifolate antimetabolite -bone marrow suppression -mucocutaneous effects (mucositis, stomatitis) -nausea and vomiting -fever -maculopapular rash—usually self-limited -anorexia, malaise -above toxicities increased in patient with hypoalbuminemia (<3.5)... 

Antimetabolites that are used to prevent the formation of DNA may be classified as antifolates, purine antimetabolites and pyrimidine antimetabolites (Table 7.5). Antifolates are believed to inhibit dihydrofolate reductase (DHFR). This enzyme is responsible for catalysing the conversion of dihydro-folic acid (DHF or FH2) to tetrahydrofolic acid (THF or FH4), which occurs in... 

At present, there are two different types of antimetabolites, having large structural changes and acting as reversible enzyme inhibitors, which need to be discussed here. They are represented by two major classes of important chemotherapeutic drugs the sulfonamides and the 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. 

The isolation in the 1940s of the antianemic factor now known as folic acid and its subsequent synthesis resulted, after many false leads, in the first successful antivitamin antimetabolite aminopterin (Table 4-5). This compound produced sustained remissions in leukemia. The N10-methyl homolog, now designated as MTX (Table 4-5), superseded aminopterin the same year. It is still the only clinically significant antifolate carcinolytic drug. 

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

Nutritional dependence on pterinoid antimetabolites is a fascinating phenomenon and part of the problem of resistance to the antifolics in cancer therapy. Law (1958) noted that some strains of mouse leukemia have become dependent on antifolics. Is the explanation like that for Neurospora If one had antifolio-dependent strains of protozoa and bacteria, analysis of their growth requirements might uncover new metabolites, as happened for streptomycin-dependent bacteria. 

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