The objective of this proposal is to develop novel, laboratory-based chemotherapeutic treatment strategies for patients with cancers of the breast, lung, and ovary. This goal will be pursued through the formation of a consortium of molecular pharmacologists and clinical investigators from two NCI-designated Cancer Centers and a large University Hospital who will utilize the extensive patient resources of the City of Hope National Medical Center (COH), the Kenneth Norris, Jr. Comprehensive Cancer Center at the University of Southern California (USC), and the University of California, Davis Cancer Center (UCD) to perform pharmacologically-guided Phase II clinical trials that focus on: a) novel high-dose chemotherapies with peripheral blood progenitor cell reinfusion, the molecular pharmacodynamics of the folate-fluoropyrimidine interaction, and combination anthracycline resistance modulation studies for patients with advanced breast cancer; b) modification of intrinsic platinum resistance, chemotherapy dose intensification, new agent development, and clinical radiation sensitization for individuals suffering from small cell and non- small cell lung cancer; and c) targeted intraperitoneal and high-dose chemotherapy investigations for women with cancer of the ovary. This application formalizes an ongoing series of collaborative interactions among these three institutions that have existed since the mid-1980's. Based on the availability of over 6,250 new cancer patients per year (including 710 with breast cancer, 594 with lung cancer, and 157 with ovarian cancer in 1991), and on the major strengths of the consortium in the areas of bone marrow transplantation, the clinical pharmacodynamics of the fluoropyrimidines and the antifols, as well as pioneering experience in the quantitation of relative gene expression from small amounts of human tumor tissue, the biochemical pharmacology of the anthracyclines and platinum compounds, and clinical research strengths in regional chemotherapy, the development of novel treatment regimens, and biostatistics and data management, the COH-USC-UCD Phase II Consortium is well-positioned to utilize its clinical research expertise to perform complex, laboratory-supported investigations of both new agents and new strategies to enhance therapeutic outcomes for patients with cancers of the breast, lung, and ovary.
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