Interactions between chemotherapeutic treatment and radiotherapy will be explored both in experimental tumors and normal tissues of the mouse. The tumor studies will employ in vitro multicell spheroids and xenografts of selected human tumors, with ancillary experiments on the Lewis lung tumor. Tumor growth delay and clonogenic cell survival will be the end-points in each of these systems. Xenografts of testicular teratomas, melanomas, and small-cell bronchial carcinomas will be used and drugs that have an established or potential place in the treatment of these diseases will be investigated: for instance cyclophosphamide, MECCNU, bleomycin, cis-platinum, VP-16. Normal tissue damage will be studied following local irradiation of the lung (including hemi-lung irradiation), pelvis, and skin. In each of these areas we will examine both early and late forms of radiation damage, and their modification by drugs. The lung studies will employ ventilation rate as the principal end-point, allowing us to identify two recently-demonstrated phases of reaction. Using these systems we will study the time-dependence of drug-radiation interactions, seeking to draw conclusions about the therapeutic index of the treatments. The hypothesis that the optimum timing may be related to the shrinkage and regrowth pattern of the tumor will be tested and the relationship to tumor cell regrowth and drug-induced reoxygenation will be studied. The influence of chemotherapy on the incidence of radiation-induced carcinomas of the mouse colon and rectum will be studied after local pelvic irradiation. Drugs will be compared for their carcinogenicity in this combined modality situation and the influence of time interval between drug and radiation treatment will be investigated.
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