This project has as its prime objective the development of new chemotherapeutic agents for the treatment of colorectal adenocarcinoma. Current estimates indicate that greater than 100,000 new cases of this disease occur in the United States each year and that 58,000 people died in 1983 as a direct result of this tumor. These low growth fraction tumors are characterized by a high propensity for metastasis particularly to liver and existing systemic chemotherapeutic agents offer only questionable advantage over surgical resection as the sole therapeutic modality. A variety of in vitro and in vivo antitumor studies have shown that certain quinazoline analogues of folic acid, such as 5,8-dideazaisofolic acid (IAHQ), have potential in this regard. Of particular significance is the fact that IAHQ was effective in two in vivo solid tumor models against which the folate antagonist methotrexate (MTX) was without effect. The proposed synthetic effort will be directed toward analogues or derivatives of IAHQ which will have improved therapeutic efficacy by virtue of more rapid uptake into cells, enhanced metabolic conversion to polyglutamylforms (the presumed active metabolites), and/or reduced toxicologic and immunosuppressive effects. In addition, new deaza analogues of MTX will be synthesized in an effort to identify structural features necessary for effective inhibition of MTX-insensitive dihydrofolate reductases (DHFRs). The production of these alter enzymes may be a major mechanism of resistance to MTX for certain human tumors. A multidisciplinary collaborative evaluation process has been established in order to expedite the developmental process. Biological parameters to be studied include inhibition of thymidylate synthase, sensitive and insensitive DHFRs, glycinamide ribonucleotide transformylase, substrate activity for mammalian folypolyglutamate synthetase, mode of uptake into tumor cells, and cytotoxicity toward human colon adenocarcinoma cells in culture. Promising candidates will be resynthesized in larger quantity for treatment studies in murine and hamster models. The synthesis of suitably protected polyglutamate derivatives of active compounds will be performed in an effort to deliver these """"""""active metabolites"""""""" into tumor cells. The multistep synthetic sequences to be conducted represent an expansion of existing technology already developed in this laboratory.
