The long rang goal of this project is to use animal model systems to evaluate the potential value of perfluorochemical emulsions (PFC-E) as adjuncts to radiotherapy and to provide the background information needed to design and implement clinical rials testing these agents. The studies proposed in this five year renewal application will focus on studies of second generation PFC-E, having characteristics more appropriate for use as adjuncts to cancer therapy than the lead compound (Fluosol) used in our initial laboratory studies and in all past and ongoing clinical trials. Studies with transplanted tumors in rats and mice will be extended to assess fractionated treatment regimens which more closely model those used in clinical radiotherapy and to determine the optimal parameters for administering PFC-E during such regimens. The potential value of multi-agent regimens combining PFC-E with hypoxic cell sensitizers or drugs toxic to hypoxic cells will be examined, to assess whether the use of multiple agents directed against hypoxic cells, which may target different hypoxic cell populations, offer the potential for greater therapeutic benefit. The biological bases of observed changes in tumor response will be examined, to assess whether factors other than changes O2 delivery to tumor cells are important to the effects of the PFC-E. Effects of second generation perfluorochemical emulsions on the radiation responses of normal tissues (bone marrow, skin, lung and bone) will be examined so that the potential for obtaining therapeutic gain with these agents can be assessed. The effects of these PFC-E on tumor growth and progression will also be examined, to ensure that these agents have no unexpected effects on the malignancies. Data from these studies will be used to help design clinical trials testing second generation PFC-E as adjuncts to radiotherapy.
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