Within the past ten years significant advances have been made in knowledge of the mechanisms of action as well as resistance to antitumor agents. This knowledge has in turn facilitated the design of new approaches in the minimization of limiting drug toxicities. Unfortunately, the discovery of large numbers of new drugs useful at the clinical level has been far less successful than was originally hoped. Therefore, developing newer ways of using older but effective chemotherapeutic agents will for the near future continue to be an important basic and clinical research goal. Since its inception in 1977, our lab has had as its long-term objective the improvement of the efficacy of anticancer chemotherapy by seeking both to understand the mechanisms of the toxicity to new, as well as established, antitumor drugs and to explore the rational pharmacologic intervention of these limiting toxicities. Efforts aimed at understanding the basic pathogenesis of pulmonary fibrosis as well as the prediction and prevention of pulmonary disease due to bleomycin analogs comprise the first project in the resubmission of a RESEARCH CAREER DEVELOPMENT AWARD application. Acute pulmonary changes due to administration to rats of bleomycin and related analogs will be assessed by determination of tissue, serum and bronchoalveolar lavage enzyme activities (angiotensin-converting and prolyl hydroxylase activities). These will be compared to dose and time-dependent changes in lung histopathology and collagen metabolism. The utility and efficacy of L-dehydroproline as an antifibrotic agent will be determined. Finally, the in vitro coculture of macrophages obtained by lung lavage together with lung fibroblasts will be studied to understand the interaction of these two cell types in the early pathogenesis of drug-mediated fibrosis. The second project involves development of the fetal mouse heart organ culture system as a useful tool in examining anthracycline-mediated cardiomyopathy. Drug-induced leakage of lactic dehydrogenase (LDH) and creatine phosphokinase (CPK) activities will be compared to histopathologic changes in an attempt to 1) produce a model of cardiomyopathy that will quickly and accurately permit determination of cardiac drug toxicities and 2) also permit a model for evaluation of the merit of 'cardioprotectant' agents (ICRF - 190, Vit. E. carnitine, adenosine, etc.) in blocking adverse anthracycline cardiac effects.
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