A continuation of studies are proposed on pharmacologic questions of probable importance to the selective antitumor action of antifolates. The basis for the differential in the interaction of folate compounds at the level of membrane transport in target tumors and normal proliferative cell populations will be further explored. Additional emphasis will also be placed on concomitant intracellular events at metabolic and enzymologic levels which also appear to be determining for cytoxicity and the selective action of these agents. For these studies we will continue to employ tumor and normal proliferative cellular systems, the latter as a model for the site of acute drug-limiting toxicity, developed in our laboratory that have established therapeutic relevance. Specific studies are proposed on the kinetics, multiplicity and specificity of membrane transport of folate compounds and their intracellular metabolic disposition as determined from capacities for polyglutamylation and hydrolysis, by folylpolyglutamyl synthetase and folyhydrolase, respectively. The effects of antifolates and their anabolites on folate-related metabolism will also be examined as a parameter of cytotoxicity. The possible differential in enzymatic conversion of 5-formyltetrahydrofolate in tumor versus normal proliferative tissue will be studied as a factor in response to therapies employing this folate with methotrexate or 5FU. Finally, exploratory studies will be initiated examining various biochemical determinants of antifolate cytoxicity as factors in the variable sensitivity observed among subclones of tumors or their metastatic derivatives.
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