The overall objective is more rapid application and acceptance of new lung cancer treatment strategies.
The specific aim of this program is to develop a canine spontaneous tumor model for isolated lung perfusion to manipulate such factors as temperature, time and radiation dose delivery to modify response of tumor and normal tissue, to develop methods to obtain better temperature differentials in tumor and normal tissue, and to improve targeting of various agents including radiolabeled antibodies and intraoperative radiotherapy. Various physiologic parameters will be evaluated for acute and late response of lungs including pulmonary venous admixture, pulmonary shunt fraction, physiologic dead space, pulmonary arterial pressure, pulmonary vascular resistance, dynamic lung compliance and pulmonary resistance. Indices of pulmonary vascular leak and pulmonary endothelial injury will be evaluated by multiple indicators dilution techniques. Pulmonary lavage will be done for biochemical and cellular studies. Late tissue injury will be evaluated by morphometric analysis of components of the lung, including epithelial cells, microvasculature and connective tissue. Selection of the most appropriate functional tests will be done in collaboration with investigators of program 3, the lung physiology component. Initially normal beagles will be given hemibody irradiation and whole body hyperthermia to determine the influence of heat on the radiation response of the lung. This will provide radiation and hyperthermia dose estimates for the later studies of use of radiolabeled antibodies and hyperthermia using isolated lung perfusion. The initial studies also will provide background for future studies of hemibody irradiation combined with hyperthermia and/or chemotherapeutic agents. Based on the preliminary information of normal tissue response and information obtained from program 1 of response of human tumors in nude mice and rats, protocols will be designed to evaluate the use of isolated lung perfusion techniques. These studies will be done in dogs with naturally occurring primary adenocarcinomas of the lung and adenocarcinomas which have metastasized to lungs. Radiolabeled antibodies selected from preliminary studies in program 2 will be used to provide low dose rate continuous irradiation. In addition, studies will be done of heated perfusates to determine thermal enhancement of tumor and normal tissue response.
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