Action of Cis-dichlorodiammineplatinum(II) (NSC-119875) at ehe cellular level.

Abstract

Asynchronous human lymphoma cells treated for 1 hour with increasing concentrations of cis-dichlorodiammineplatinum(II) revealed a marked decrease in survival as estimated by the colony-forming technique. When the treatmentwas extended for 8 hours at a concentration of 5micrograms/ml, a killing effect (greater than 3 log decades) was observed which was similar to that obtained when 50micrograms/ml is incubated with the cells for 1 hour. This finding suggests that better antitumor effects with fewer toxic effects may be obtained clinically by prolonged infusion of low doses of cis-dichlorodiammineplatinum (II). Synchronized lymphoma cells showed no significant degree of cell-cycle-stage sensitivity to cis-dichlorodiammineplatinum (II). The drug kills cells with similar efficiency in all stages of the cell cycle. No killing effect was elicited after incubation of the cells with spironolactone, a compound said to protect the kidneys from the toxic effects of heavy metals. However, simultaneous incubation of spironolactone and cis-dichlorodiammineplatinum (II) did not prevent the lethal action of the second drug. If spironolactone is proven to be an inhibitor of cis-dichlorodiammineplatinum (II) nephrotoxicity, it will become a valuable addition to the treatment of human neoplasia with this platinum compound. Lymphoma cells given a "priming" dose of 10 micrograms/ml of cis-dichlorodiammineplatinum (II) failed to repair the induced damage. A second exposure to 10 micrograms/ml of the drug at various subsequent intervals elicited greater killing effect than that produced by 20 micrograms/ml given at one time. A clear synergistic effect was noted when cis-dichlorodiammineplatinum (II) was given simultaneously with camptothecin or BCNU. The molecular mechanism by which this effect is accomplished is not presently apparent.