At Stanford there is an ongoing program involving chemical modifiers of radiation and chemotherapy. These are drugs, which, while not having antitumor activity per se, are able to either enhance tumor cell killing by radiation or chemotherapy, or to protect normal tissues. We have an extensive drug development program and a strong commitment to collaborative cooperative group clinical trials which will ultimately provide the vehicle for the testing of these agents. This application is requesting support for the developmental clinical trials, which is the major step required for a drug to go from the basic science laboratory to general clinical use, and for the interfacing science necessary to optimally link the clinic and the laboratory. The developmental clinical trials (Phase I and II trials) include drug administration, pharmacokinetic analysis, toxicity assessment, treatment of drug related toxicity, and, if possible, alteration of drug administration to lessen or prevent toxicity. The close clinical and laboratory interaction at Stanford greatly facilitates our ability to design an optimal clinical trial, to assess its results, to study mechanisms of drug toxicity in the laboratory, and to design new drugs or modify existing ones to reduce toxicity, thereby increasing drug efficacy and utility. There are four closely related areas to be investigated: radiosensitizers, chemosensitizers, augmentation of intracellular thiol content as a means of normal tissue protection, and intracellular thiol depletion as a means of increasing tumor sensitivity to irradiation, to drugs, and to hypoxic cell radiosensitizers. These investigations exploit the fact that a dose-response relationship exists when both tumors and normal tissues are treated with radiation or chemotherapy. By sensitizing tumors and protecting dose-limiting normal tissues the therapeutic index will be increased which could lead to an improvement in the local control rate and curability of certain tumors. In addition studies are planned for the use of chemical modifiers in conjunction with the particle radiotherapy program at University of California Berkeley.
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