One of the problems facing clinical radiation therapy is the late tissue changes associated with injury to the vascular system - in particular the capillaries - and late effects associated with severe fibrosis. In vivo measurements of microvascular changes in rabbit ear chamber and in vitro experiments using primary cultures of vascular cells are directed to provide fully quantitative pre-clinical information concerning the response of this tissue in vivo and in vitro. The effects of graded doses of x-rays on the microvasculature in vivo and the modification of these effects by hypoxia, WR 2721 and the V2 rabbit carcinoma will be quantitated. Hypoxia and the radioprotector WR 2721 will be studied singly and in combination to determine the degree of protection from radiation injury which can be conferred to microvascular tissue in vivo and in vitro. We propose to develop a rabbit ear chamber tumor model using the V2 rabbit carcinoma to evaluate acute effects of radiation on the tumor microvascular bed in relation to tumor growth and correlate tumor growth patterns with vascular injury patterns to determine the optimal therapeutic strategy to maximize tumor kill. Acute and late vascular changes following single or combined dose modifying treatment regimens will be scored and correlated by measuring the following parameters in vivo on capillaries, arterioles and venules: microvascular length, surface area, and wall thickness. These parameters will be determined separately for capillaries (10 in dia.) larger vessels and for the total microvasculature. From these measured parameters, microvascular volume, microvascular density/mm2 and a dilatation factor over time will be calculated. In vitro studies done in parallel will use comparable cultures of vascular endothelial and smooth muscle cells irradiated in vivo and in vitro to further elucidate the role of these two most reactive cell populations in early and intermediate effects following treatment. Computerized analysis of our in vivo and in vitro data will provide DO, Dg, Beta/Alpha, N, SLD and in situ repair capability as well as linear quadratic and single hit-multitarget data fitting routines for microvessels separated according the size (10 m to 150 m in 10 m bins) and function (aterioles, venules, capillaries).
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