One of the primary physiologic determinants of tumor radiocurability is the presence of hypoxic but clonogenic tumor cells, which are 2.5 to 3 times more resistant to radiation than aerobic cells. These cells exist in tumors as a result of abnormal microcirculatory structure and function. Fractionated radiotherapy reduces the importance of these cells by inducing reoxygenation. Hyperthermia can influence the importance of these cells in three ways: 1) By reducing their radioresistance, 2) By destroying some of the tumor microcirculatory bed, resulting in infarction, and 3) By direct cytotoxicity. The ability of hyperthermia and radiation combinations to cure tumors will depend on the relative strengths of these effects in tumor and normal tissue. These effects can only be measured sequentially, before and after treatment. Secondly, the primary mechanism by which tissue dissipates heat is by blood flow. Optimal use of hyperthermia may therefore be dependent on techniques which can maximize the differential in blood flow between tumor and adjacent normal tissue, thereby leading to preferential heating in the tumor bed. These effects can only be measured on-line, during a hyperthermic treatment. A transparent access window Algire chamber developed at the University of Arizona with implanted tumor or normal tissue will permit direct visualization of normal and tumor microvasculature. Videotechniques make it possible to quantitate or describe before, during, and after treatment, single vessel responses, branching patterns, morphology, and tissue perfusion. Radiolabeled 14C misonidozole will be used to spatially identify potentially hypoxic regions. Confirmation will be made by locally measuring pH and p02 with microelectrodes. These measurements will be performed for different time-temperature combinations and rates of heating. Fractionated hyperthermia will also be investigated. Radiation alone and combination of heat and radiation will be studied following heat alone experiments. The goal of this work is to develop rationale of how best to combine heat and radiation based on detailed knowledge of how these modalities effect tumor and normal tissue microcirculatory physiology. Ultimately, one must be able to have the maximum deterious effect on all portions of the tumor, while minimizing effects in normal tissue.
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