There is a pressing need to better understand the mechanisms of platinum-based anti-cancer drug toxicity to the kidney and to utilize this basic scientific information for the development of biomarkers to detect early manifestations of renal damage in patients treated with these and other nephrotoxic anti-cancer agents. It is our hypothesis that treatment of renal proximal tubule cells to platinum-based drugs will produce specific oxidative cellular effects that will be intrinsically linked to increased excretion of specific oxidized proteins of renal derivation into the urine via chaperoning by specific stress protein families. In vitro studies which will compare the responses of primary cultures of both human and rat kidney cells to cisplatin using a short term dose-response design. These studies will provide a mechanistic basis for testing the hypothesis that stress proteins play a central role in the excretion of specific oxidized proteins from this target cell population. Data from these studies should will also determine whether this proposed mechanism of platinum-induced toxicity is similar in rat and human proximal tubule cells. This hypothesis will be further tested via studies involving acute in vivo exposure of rats to platinum- based drugs using a dose-response, time course design. Examination of urine samples from these animals will be focused on those proteins found to be preferentially excreted by the proximal tubule cells in culture. Data from these studies will be essential for understanding the extent to which urinary biomakers derived in rats may be used for predicting platinum-induced human nephrotoxicity. The utility of these new biomarkers for earlier detection of platinum-induced nephrotoxicity in humans will hopefully be evaluated under a future R33 grant application that will apply knowledge derived from these studies to other nephrotoxic anti-cancer agents.
