CELL BIOLOGY

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PROGRAM 3-CELL BIOLOGY is part of the project entitled: 'DNA Topoisomerase- I-Targeted Therapy of colonic Cancer'. The program will use 3-4 tissue culture lines of human colon cancer, well defined by their DNA topoisomerase I (topo-I) content, growth pattern and morphology for the testing of new analogs directed against topo-I. The level of topo-I and morphology has been evaluated and compared among 1) the specimens of colonic carcinoma and normal mucosa obtained from patients, 2) xenograft and 3) tissue-culture lines, and representative lines of colonic cancer chose. The research will aid the Project in selecting the most effective and well characterized compounds for in-vivo testing. the aims are the following: 1. The compounds, selected by screens in the cell-free system, will be tested for cytotoxicity by the clonogenic assay, and for the formation of topo-I-DNA cleavable complexes. The studies will be expanded by tests against 'quiescent' or euoxic/hypoxic cells, and by the measurement of drug-uptake and metabolism, comparing effective lipophilic and water- soluble congeners. 2. The efficacy of analogs against lines of colonic cancer with the mdrl phenotype will be determined, and an acquired resistance to initially effective analogs studied. 3. The merits of combination treatments will be evaluated, using (a) clinically effective chemotherapeutic agents, or (b) radiation treatment, either sequentially to or concomitantly with an inhibitor of topo-I. Additive versus synergistic versus antagonistic effects on cell kill will be established.