This application is for the continued support of the clinical and laboratory program to develop, and optimize the use of chemical modifiers of radiation or chemotherapy. The modifiers, while not necessary of therapeutic value by themselves, will alter the response of tumors or normal tissues to treatment resulting in superior tumor control and reduction in normal tissue injury. At the Joint Center for Radiation Therapy we have assembled a group of investigators who can develop these approaches from the basic concept, through drug development and the initial Phase I and II trails, to large scale efficacy trails. This group includes basic scientists with different areas of expertise, and clinicans from all aspects of cancer care. The major emphasis of the clinical trails will be the continuation of the use of the hypoxic cell radiosensitizers, particularly the drug SR 2508. Recent data suggest that tumors have both acutely and chronically hypoxic cells, that hypoxic cells may well be clinically significant, and that the electron affinic sensitizers have therapeutic efficacy. Therefore, the approach to the hypoxic cell with SR 2508 hypoxic cell cytoxic agents and perfluorocarbons is warranted. Novel methods of delivery of SR 2508, by continuous infusion and by intratumoral injection with a drug-associated collagen matrix will be evaluated. We will investigate the oxygenation and biochemical status of tumors during fractionated radiotherapy in vivo in order to optimize the utility of the various chemical modifiers in the clinic. We have established an in vitro system to study the neuropathy of SR 2508 in an attempt to ameliorate its the dose-limiting toxicity, thereby further increasing the utility of this agent. Based on the positive results of a randomized phase II trail of mephalan - Misonidazole we will continue to pursue the use of nitroimidazoles as chemosenitizers. Thiol modifications can increase the efficacy of hypoxic cell radiosensitizers, and alter chemosensitivity and radiosensitivy of tumors and normal tissues. We will conduct laboratory studies, and clinical trails, if deemed appropriate, with agents that either or augment glutathione and other thiols. The interrelated clinical and laboratory research proposed in this application, provides an important base for other programs of the Joint Center, as well as providing direction and support for national clinical trails with sensitizers.
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