Support is requested to continue and further expand an ongoing program of investigation on the effects of selected chemotherapeutic agents at the cellular level. Our studies will define the sensitivity to a given anticancer drug by cells from different tissue-type origins and by cells with a common histological origin but with different degrees of differentiation; determine characteristics and mechanisms of action of certain antitumor agents administered alone or in combination; evaluate antiproliferative effects of a newly developed anticolon cancer monoclonal antibody (MoAb); define drug-induced effects on the cellular synthesis of tumor marker products; determine the efficacy of antitumor agents in an in vivo setting (athymic rats); and, finally, compare the predictive capacity of different preclinical antitumor drug screening approaches. Within the context of this program we intend to refine methods for culturing CFU-GM from athymic rat bone marrow and to develop cytometric techniques for rapid assessments of drug-induced DNA interstrand cross-linking. We also plan to elucidate the metabolic pathways and enzyme inhibitory effects of fluorinated pyrimidines on panels of established human colon carcinoma cells and to analyze the mechanisms responsible for the synergistic activity of cis-DDP in combination with ara-C or natural nucleosides and those responsible for the synergistic interaction of high dose dexamethasone, vincristin and doxorubicin.
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