Acute systemic toxicity of combined cis-diamminedichloroplatinum and hyperthermia in the rat

To investigate the previously observed increased morbidity and mortality of combined cis-diamminedichloroplatinum (cis-DDP) and hyperthermia, BD IX rats were given 4 mg/kg cis-DDP i.p., waterbath hind leg heating (44 degrees C, 60 min) with resultant whole body hyperthermia, or combined treatment with or without systemic cooling. Cardiac blood and histopathologic sections of kidney, small intestine and liver were examined in rats sacrificed 2, 3 and 5 days after and femur bone marrow 5 days after treatment. In a separate experiment, the effect of systemic hyperthermia on renal function was tested. The most significant finding was a marked increase in cis-DDP induced renal damage by systemic hyperthermia, expressed as elevated creatinine levels and quantitatively enhanced proximal tubular necrosis. As both systemic hyperthermia and cis-DDP can result in primarily altered renal haemodynamics, it is postulated that relative tubular epithelial hypoxia and increased tubular exposure time to cis-DDP due to reduced tubular filtrate flow rate are likely mechanisms for the increased toxicity.