The synthesis and in vitro and in vivo evaluation of a series of folate antagonists are proposed, with the primary goal being to develop therapeutically useful anticancer agents. The compounds to be investigated are analogs of folic acid and the well-known anticancer drug methotrexate. Major emphasis will be placed on development of further analogs of 8,10-dideazafolates and 5,10-dideazafolates, effective agents developed in our laboratories. The analogs are to be evaluated in vitro for their effects against human Manca leukemia nd L1210 leukemia cells and their associated folate enzymes. Other in vitro work will involve mouse intestine epithelial cells, a site of drug-limiting toxicity of these agents. The results will serve as guidelines for potency, bioavailability, and host-tumor toxicity relationships. The analogs will be assayed in vivo against a variety of transplantable tumors in mice as experimental models. In addition, a detailed study of transport and folyl polyglutamylation phenomena in normal and tumor cells will be conducted. Both factors appear to be important determinants of selective antitumor action for this general class of agents. An optimal analog will be presented for clinical trial consideration.
