Leukemia antifolics

Rothem, L., Aronheim, A., and Assaraf, Y.G. (2003) Alterations in the expression of transcription factors and the reduced folate carrier as a novel mechanism of antifolate resistance in human leukemia cells. Journal of Biological Chemistry. 278, 8935-8941. 

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 The N10-methyl homolog, now designated as MTX (Table 4-5), superseded aminopterin the same year.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. 

Antifolate chemotherapy occupies a Special place in the history of cancer treatment, as this class of drugs produced the first striking, although temporary, remissions in leukemia, and the first cure of a solid tumor, choriocarcinoma. These advances provided great impetus to the development of chemotherapy for cancer. Interest in folate... 

Antifolate chemotherapy produced the first cure of a solid tumor, choriocarcinoma. Introduction of high-dose regimens with rescue of host toxicity by the reduced folate, leucovorin (folinic acid, citrovorum factor, 5-formyl tetrahydrofolate, N -formyl FH ), further extended the effectiveness of these drugs to both systemic and CNS lymphomas, osteogenic sarcoma, and leukemias. Most recently, analogs that differ from methotrexate in their transport properties and sites of action have proven useful in treating other cancers. 

Sydney Farber uses antifolates successfully to induce remissions in children with acute lymphoblastic leukemia... 

More knowledge of pterinoids means renewed hope of solving such old clinical problems as the pathogenesis of sprue. Increased interest, too, attaches to the unconjugated pterins in the body Are they increased or diminished in some diseases The effectiveness of antifolics in the palliative treatment of leukemia is halted by toxic symptoms and, eventually, by drug fastness this emphasizes the need to explore pteridine metabolism to find new opportunities for chemotherapy aimed at pterinoid targets. 

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. 

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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