PHASE I MOLECULAR AND CLINICAL PHARMACODYNAMIC TRIALS

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The University of Southern California (USC) and the City of Hope National Medical Center (COH) have made a significant commitment to Phase I trials of new anticancer drugs. Preclinical and clinical investigators have exchanged views and shared resources on a wide range of activities relevant to such trials; biochemical modulation of halopyrimidines, folate biochemistry and drug development, locoregional therapy, dose- intensification of chemotherapy, reversal of multidrug resistance, modulation of platinum action, bioreductive activation of antitumor quinones, topoisomerase-interacting drugs, and emerging targets related to the biology of differentiation, tumor angiogenesis and metastases. We now have the opportunity to establish a formal collaborative relationship supported by a joint pharmacokinetic core facility, and to work more closely with the National Cancer Institute's drug development programs. These collaborations will enhance our capability to perform Phase I molecular pharmacodynamic trials focused by the pharmacologic expertise available at both institutions. Areas of known strength available to support Phase I studies include our long-standing experience in the pharmacokinetics and pharmacodynamics of fluoropyrimidines and other nucleoside antimetabolites, expertise in the mechanism of action of the anticancer quinones and platinum analogs, and in modeling pharmacokinetic/pharmacodynamic relationships, pioneering experience in the quantitation of relative gene expression from small amounts of tissue, and the availability of reliable data management and biostatistical facilities.