ALTERATIONS IN THE TOXICITY OF CIS-DICHLORODIAMMINEPLATINUM-II AND IN TISSUE LOCALIZATION OF PLATINUM AS A FUNCTION OF NACI CONCENTRATION IN THE VEHICLE OF ADMINISTRATION

The lethality to mice of the anticancer drug cis-dichlorodiammineplatinum (11) (cisPt) was greatly reduced when the drug was dissolved in hyperonic (4.5%) NaCl relative to preparation in distilled water (DW). Concomitant administration of 4.5% NaCl and cisPt prepared in DW failed to protect mice against cisPt toxicity. When other chloride salts were used as vehicles, partial protection was observed and when NaI was used as a vehicle, nearly complete protection was obtained. Similarly in rats, toxicity was reduced with the hypertonic vehicle when lethality, clinical chemistry or histopathology criteria were evaluated. In vitro and in vivo binding to plasma proteins was greater with the DW vehicle. Tissue Pt levels were less and decayed more rapidly with the hypertonic NaCl vehicle. Antitumor effectiveness of cisPt was not altered when 4.5% NaCl was utilized as the vehicle. A postulated explanation for these results is a shift in the cisPt aquation reaction due to the high concentration of chloride ions in the the vehicle.