DNA TOPOISOMERASE I-TARGETED THERAPY OF COLONIC CANCER

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A class of novel chemotherapeutic agents, with an unprecedented effectiveness against human colon cancer xenografts, has been identified in our pilot study. The proposal presents a plan to synthesize camptothecin analogs, to test them in preclinical screens for eventual use in chemotherapy of colonic cancer. As such, the project represents a focused effort in drug development molecular, cell and tumor biology. The rational of the program is based on pilot studies conducted by participating laboratories over the past several years. The principal objectives of the project include: 1. Accelerated effort in preclinical evaluation of 9-amino-20(RS),10,11- methylenedioxy-20(RS) camptothecins and their water-soluble congeners. 2. Preparation and development of totally synthetic 20(s) isomers of camptothecin analogs, and analogs with novel properties, such as increased stability of the topo-I-DNA cleavable complex or the E (lactone) ring of the drug molecule, as well as improved overall effectiveness. 3. Screening of new analogs using topo-I-directed assay systems, designed for human colonic cancer. Studies of the mechanism of de-novo and acquired resistance to camptothecin analogs. 4. Side-by-side testing of selected highly effective lipophilic and water- soluble congeners, using a panel of established and well characterized lines of human colon carcinoma, propagated in tissue culture and as xenografts in nude mice. Studies of drug pharmacokinetics and toxicity. 5. Bringing one or two target analogs to clinical trials.