Control of some aspects of cis-platinum nephrotoxicity

The elevations of blood urea nitrogen and serum creatinine caused by cis-platinum in rats can be prevented by a combination of procedures centered around the administration of sodium N-methyl-N-dithiocarboxyglucamine (NaG), before and very soon after the cis-platinum is administered in hypertonic (4.5%) saline. Elevations in-blood urea nitrogen and serum creatinine levels subsequent to such treatment are largely eliminated. These same procedures appear to have no effect on the anti-tumor action of the cis-platinum, as measured by tumor size and mass and by survival times, in female Sprague-Dawley rats inoculated with the Walker 256 carcinoma. The degree of myelosuppression, as measured by the white blood cell count is also slightly reduced. White blood cell counts returned to normal values more rapidly in animals treated with NaG than in those treated with cis-platinum alone. An examination of the dose-response curve for the suppression of cis-platinum nephrotoxicity by NaG shows that this can be achieved with mole ratios of NaG: cis-platinum as low as 1:1 given after appropriate pretreatment. A preliminary structure-activity study on the suppression of cis-platinum induced elevations in blood urea nitrogen and serum creatinine by four closely related dithiocarbamates shows that this can also be achieved effectively by several dithiocarbamates in which the nitrogen atom bears polar substituents.