Chemotherapy has played a significant role in the improved survival rates observed in several human malignancies. Doxorubicin (DOX), bleomycin (BLM) and cisplatin (DDP) cause irreversible dose limiting damage to the heart, lung and kidney, respectively. The overall goal of this grant proposal is to decrease or, hopefully, eliminate these toxicities using specific experimental approaches designed for each drug (or drug class) listed above. 1) We have developed in vitro model of DOX induced cardiomyopathy using fetal mouse heart organ cultures that us to screen large numbers of compounds as well as to investigate direct drug effects on biochemical and pharmacological indices of cardiac function and damage. Better understanding of the biochemical mechanisms of DOX toxicity will enable us to develop pharmacological means of intervention-- either through analog development or use of of cardiac protective agents. 2) The mechanism of DDP induced nephrotoxicity is not understood. It has shown by us and others that it is possible to develop second and third generation platinum analogs with diminished nephrotoxic potential. We will investigate specific biochemical properties of a series of new platinum complexes apparently free of renal toxicity. This knowledge will aid in the clinical development of this highly promising series of new platinum complexes as well as aid in our understanding of heavy metal induced nephrotoxicity. 3) BLM induced pulmonary fibrosis appears to be an end result of drug induced acute lung inflammation. Using pharmacological and immunological approaches we will study the cellular and molecular changes that occur during this disease process. Such knowledge will allow us to design specific means of attenuating the extent of acute lung damage and thus diminish the severity of end stage fibrosis.
