MOLECULAR APPROACHES TO IDENTIFY ANTICANCER LEADS FROM MARINE NATURAL PRODUCTS

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The long term objective of this collaborative research is to discover novel drugs that are useful against the major types of cancer. These are the colon, lung, breast, prostate, and ovarian tumors. Together, these tumors comprise over 70% of human cancers. Cancer is a major cause of death in the USA: over 536,000 Americans die from the disease annually. At present, cancer is treated by surgery, X-ray, radiation, biological therapy and chemotherapy, but these therapies are largely ineffective against the major tumors. There is a critical need to discover effective and selective anti tumor drugs, but this research is severely limited by our lack of understanding of cancer. Our work focusses on the development of antitumor drugs that affect some of the more recently discovered targets and/or processes that are unique or present at different levels in tumors rather than normal tissue. The primary and secondary screens employed by the Oncology Research Program (ORP) at Sandoz are aimed at potentially important oncogene targets. Singly or in various combinations, these oncogenes are found in the majority of common tumors. This approach is different from the more traditional "cytotoxicity-based" cancer drug discovery programs. Compounds found to be active in the primary and secondary screens will be further examined using a battery of human tumor lines that are used for in vitro cytotoxicity assays and as xenografts in nude mice for in vivo antitumor experiments. The diversity of natural products provide a rich opportunity to discover novel antitumor agent classes. These molecules will be produced from extracts of a variety of marine organisms by our University collaborators. Purification of these complex mixtures will be guided by the assays described herein. The assays can efficiently direct the isolation of potentially important lead compounds and structure/activity studIes, thus providing an effective framework for cancer drug discovery and development. To complement the natural product screening program, an active rational drug development program is also in place in the ORP. NMR and X-ray studies on target proteins can provide structural information that can direct the design of candidate drugs. Compounds discovered by screening can also be modified as a result of modeling studies on these structures.