) The primary focus of the Developmental Therapeutics Program at Case Western Reserve University (CWRU)/University Hospitals Ireland Cancer Center (UHICC) has been to incorporate both pharmacokinetic and pharmacodynamic clinically assessable endpoints on which to base therapeutic intervention in all phase I clinical trials. It is anticipated that with more rational administration of cytotoxic chemotherapy that is mechanistically based the therapeutic ratio will be enhanced. For the p a s t several years, an interactive and multi-disciplinary team of investigators at our institution has effectively and creatively designed a variety of phase I clinical studies. Which are mechanistically-based. Recent efforts have explored the biochemical modulation of enzymes involved in DNA damage and repair metabolism, including principally, O-alkylguanine DNA alkyltransferase (AGT) and topoisomerase I. It is the intent of this application to continue to build on this strong clinical translational research theme and, more importantly, to provide a resource for the cooperative evaluation of scientifically directed phase I trials of anti-cancer agents in collaboration with the CTEP. Four areas of active interest have been identified by our program for phase I drug development as part of this cooperative agreement: 1) develop therapeutic regimens based on the biochemical modulation of the DNA repair enzyme (AGT) using a variety of agents including O benzylguanine (OBG), BCNU, temozolomide, and SarCNU; 2) i n i t i ate the first clinical trials of the photosensitizer silicon phthalocyanine Pc 4 - photodynamic therapy (PDT), a compound discovered at our institution; 3) translate promising strategies based in laboratory programs involving poly (ADP-ribose) polymerase (PARP) and NAD depletion, modulation of alkylating agent sensitivity by glucose-regulated protein GRP78, and topisomerase I into clinical trials; and finally 4) continue to employ the strategy of pharmacokinetic and pharmacodynamic-guided correlative studies in the evaluation of new agents that become available for study during the course of this cooperative agreement. A unique and important component of these studies is to continue to obtain sequential visceral CT-guided tumor biopsies for translational laboratory correlative studies. The identification, design, and prioritization of phase I studies for new agents will be based on laboratory evaluation in preclinical models conducted at the CWRU/UHICC and developed in collaboration with CTEP.
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