This grant application is based on the premise that characterization and understanding of an antineoplastic agent's pharmacology should allow better clinical utilization of that agent. Impeccable characterization of the clinical toxicities and maximum tolerated dose (MTD) of an agent is no longer sufficient. Ideally, an agent's pharmacologic characteristics--including its pharmacokinetics, metabolism, and pharmacodynamic manifestations on the molecular, cellular, and clinical levels--would be defined during early clinical trials. This pharmacologically-based approach will promote the performance of scientifically directed, phase I trials that integrate information regarding the mechanisms of action and pharmacodynamic consequences of NCl anti-cancer agents into their design. There will be continued characterization of novel tubulin-interactive agents, and the studies involving texaphyrin-based photodynamic and radiation-sensitizing agents will be extended. In addition to cytotoxic agents, other agents with novel mechanisms, including antiangiogenesis agents, differentiating agents, apoptosis-inducing agents, anti-sense oligonucleotides, and related gene-specific therapies will be evaluated. Agents whose pharmacology has been well characterized by the UPCl investigators, under the umbrella of the NCl-sponsored contract """"""""Preclinical Studies of Antitumor and Anti-HIV Agents,"""""""" will be further explored in phase I studies. The UPCl will continue to assume a leadership role in the study of antineoplastic agents for specific groups of patients (i.e., those with hepatic or renal dysfunction). Additional evaluation of mechanistic aspects and correlative science studies will be incorporated into phase I studies of novel agents. This application reflects the areas of interest and documented expertise of the investigators in conducting phase I trials. The commitment of the UPCl and the facilities described convincingly demonstrates that these studies can be successfully completed. It is hoped that these approaches will allow for better understanding of how these agents can be optimally utilized in clinical practice. ? ? ?
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