There is strong rationale for specifically studying how hypoxia develops in tumor tissue because oxygen is a strong modifier of radiosensitivity. Fractionated radiotherapy induces reoxygenation, but the process may be incomplete in patients who have local failure after treatment. Hyperthermia may influence hypoxic cells by: 1) Direct cell kill or radiosensitization, 2) causing microcirculatory collapse and ischemia (high temperature effect) or 3) inducing reoxygenation through increased perfusion (lower temperature effect). As detailed in the progress report, there is considerable variation between individual tumors in terms of their microcirculatory response to single doses of radiotherapy or hyperthermia. In addition, tumors tend to respond differently than healing normal tissues. Thus, the environmental impact of various therapeutic manipulations may be expected to differ between tumors and normal tissues as well as within a population of tumors. The hypothesis of this study is that abnormal microvascular morphology and flow patterns in tumors are responsible for spatial variations in oxygen tension and the variability observed in the response of individual tumors to therapeutic manipulation. We will test the stated hypothesis by: 1) Performing detailed morphologic and flow measurements to describe vascular networks 2) Using 02 microelectrodes and radiolabelled hypoxic cell sensitizers to measure local 02 metabolic rates, determine the distribution of oxygen tensions and define regions of tumor that are likely to be hypoxic. 3) Developing theoretical models which can incorporate data on morphology, flow and local metabolism to predict local oxygen tension distributions. The validity of the models will be verified by comparison between measured and predicted p02 distributions, especially utilizing experimental data wherein flow patterns are deliberately altered. 4) Microcirculatory responses of these tissues to single radiation doses (2-5 Gy) and hyperthermia exposures (low temperature = 41.5 degrees C, 30 min, high temperatures = 42.5-3 degrees C, 30 min) will be evaluated. These studies will provide unique insight into the role of microvascular structure and function on the development of tissue hypoxia. As such, the results will provide rationale, based on knowledge of basic physiologic mechanisms, to decrease the numbers of hypoxic cells in tumors, thus resulting in improved probability for cure.
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