Hypoxia is the underlying theme of these studies. The proposed experiments may be divided conveniently into those which attempt to eliminate hypoxia in tumors and those which seek to exploit it. A strong emphasis will be placed on gaining an understanding of the mechanism of the effects using radiobiological, histological, biochemical and isotope techniques. The application of any successful strategy to conventional fractionated radiotherapy will also be given high priority along with studies in normal tissue systems. 1) Reduction of Tumor Hypoxia These studies will aim to reduce the radiobiologically hypoxic fractions of tumors by alterations in the oxygen transport characteristics of the blood. Several strategies will be used: a. The modification of hemoglobin/oxygen affinity. b. The alteration of tumor blood flow characteristics c. The modification of hemoglobin concentrations. These methods will not, in general, be use in isolation as single procedures. The concept of preconditioning tumors to adverse conditions of oxygen delivery followed by restored oxygenation before irradiation will be applied in many experiments. 2) Enhancement and Exploitation of Tumor Hypoxia Several compounds have recently been shown to be preferentially cytotoxic to hypoxic cells. These include some nitroimidazoles and the benzotriazine SR-4233 and some of its analogues. They have the ability to kill hypoxic tumor cells in vivo. A major aim of this project is to develop methods of preferentially increasing the proportion of hypoxic cells in tumors compared with normal tissues. Initially, three phenomena based on our own studies and those of others will be exploited: a. Acute anemia increases the hypoxic fraction of many tumors substantially. b. Procedures which increase hemoglobin/oxygen affinity cause increased hypoxic fractions and necrosis in tumors. c. Hypotensive drugs preferentially reduce tumor blood flow.
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