It is hypothesized that changes in cellular phenotypic properties associated with resistance to radiation and certain drugs can occur as a result of the development of pathophysiological microenvironments during tumor progression. As a consequence, significant microregional cellular and environmental heterogeneities, including hypoxia, glucose deprivation, pH, and cellular metabolic and growth states are present. Experiments are proposed to (a) quantitatively refine and evaluate a new technique (cryomicrospectrophotometry) for the direct measurement of regional heterogeneity of oxyhemoglobin in tumor microvessels; (b) investigate the mechanistic basis and consequences of differences of tumor oxygenation measured by cryomicrospectrophotometry as related to heterogeneity of certain cellular growth, metabolic, and molecular properties which may be associated with differences in responsiveness to therapeutic agents; (c) develop a better biological basis for interpreting noninvasive methods and magnetic resonance spectroscopy and imaging of tumors based on these and related experiments; and (d) determine whether the specific tumor pathophysiological factors and cellular properties measured by these and other recently developed techniques can be used to predict and/or monitor therapeutic responsiveness in order to develop improved combined modality strategies in human tumor model systems. The research proposed is a direct extension of studies based on discoveries made in this laboratory using experimental rodent and human multicell spheroid and xenograft tumor models as well as specialized microelectrode, centrifugal elutriation, and flow cytometry techniques. In addition to cryomicrospectrophotometry and magnetic resonance spectroscopy and imaging, several other technologies have been developed recently which permit extension of the research to human tumors in the laboratory and, potentially, in the clinic. These are: bioluminescence to measure regional metabolite distributions, automated optical analyses of growing cultures of human tumor cells, and antibody/flow cytometry methods which measure different cell growth states. The research to be performed should provide a much stronger base of information than previously possible so that we can understand the mechanisms of at least some of the major causes of therapeutic resistance in human cancer, predict and monitor factors related to resistance, and develop better means of therapy.
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