The thiazole C-nucleoside 2-Beta-D-ribofuranosylthiazole-4-carboxamide is a new potential antitumor agent which was recently found to be very effective against several murine tumors, including the Lewis lung carcinoma. Preliminary studies indicate the agent to be a specific inhibitor of guanine nucleotide biosynthesis in tumor cells. The objective of this proposed project is to determine the cellular mechanism of action of this compound by evaluating the nature of relative significance of (a) cellular uptake, (b) cellular metabolism, and (c) cellular site of action in determining the biochemical basis for the selective antitumor activity of the compound. These three elements will initially be studied using in vitro cultures of sensitive tumor cells and isolated enzymes from these cells to establish a correlation between specific cellular biochemical effects and the in vitro cellular cytotoxicity of the drug. The significance of these in vitro effects to the in vivo antitumor activity of the compound will then be determined by comparing the uptake, metabolism, and cellular effects of the compound in normal and malignant tissues of tumor-bearing animals. The results of this study should provide important information to direct the therapeutic usage of this agent. If the purine antagonism of the compound is establihsed as the mechanism of antitumor action, it will provide an alternative pathway to the treatment of solid tumors from the established pyrimidine antagonists methotrexate and 5-fluorouracil, as well as opportunities for combination therapy with these agents. The in vitro studies will also provide information for establishing useful screening assays to determine the therapeutic potential of related compounds and to establish structure-activity relationships for the design of improved agents.
