PROGRAM 4 - TUMOR BIOLOGY is part of the Project entitled: 'DNA Topoisomerase I-Targeted Therapy of Colon Cancer'. Highly active topoisomerase I inhibitors, identified in Program 2 and 3 and synthesized in adequate quantities by Program 1, will be tested using the xenograft system. The highest priority has been given to advanced studies of camptothecin analogs with unprecedented efficacy against colon cancer xenografts (See Overall Research Plan, Preliminary Studies). Every effort will be made to bring these analogs to early clinical trials. Our approach follows several steps: 1. Each compound received for evaluation will be tested for acute and chronic toxicity in nude mice. 2. Initial testing of a new analog, active in in-vitro screens, will be done on two xenograft tumor lines, and the advanced drug studies on two additional lines. The overall toxicity, as well as intestinal, bone marrow and urinary bladder toxicities will be monitored. The endpoints include tumor growth prevention, delay in growth, tumor regression/regrowth. 3. The treatment of artificial liver, lung, or brain metastases and cecal implants will be part of the advanced drug testing. The data will be evaluated and their statistical significance established. 4. Attempts will be made to identify tumors with de-novo resistance and develop one or several human colonic tumor lines with acquired resistance to camptothecin analogs. Studies of drug resistance will be done in close collaboration with Program 3. 5. Drug distribution studies in tumor-bearing mice will test, following subcutaneous, intravenous or femoral drug administration, drug plasma levels, disposition via urinary and hepatobiliary tract, as well as tissue distribution.
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