Reduction of cisplatin nephrotoxicity by procainamide: Does the formation of a cisplatin-procainamide complex play a role?

Procainamide protects mice bearing P388 leukemic cells against the toxicity of cisplatin without diminishing antitumor activity. The mechanism of acti on of procainamide protection was investigated both in vitro and in vivo. H PLC studies showed that procainamide forms a complex with cisplatin in vitr o that has a UV spectrum similar to that of DPR, a triamine platinum comple x that contains procaine as ligand. We report here the effect of the reacti on product of cisplatin and procainamide on both cisplatin-induced DNA inte rstrand cross-links (ISCLs) and on the total DNA platination of isolated DN A. Total DNA platination in vitro of isolated DNA was increased by 113% (P < .01) and 17% (P < .05) after incubation times of 1.75 and 6 h, respective ly, compared with products from the reaction of cisplatin with water. Furth ermore, the reaction product of cisplatin and procainamide was bound to DNA to a significantly greater extent than was cisplatin itself. ISCLs were de creased by 41% when this drug combination was incubated with DNA for 1.75 h , but no changes were observed after incubation for 6 h. We also examined t he influence of the time interval between administration of cisplatin and p rocainamide on normal kidney injury, the renal distribution and urinary exc retion of platinum, and the formation of cisplatin-DNA adducts in renal tis sue of Sprague-Dawley rats after i.p. administration of 7.5 mg/kg cisplatin either with or without procainamide. The plasma concentrations of urea and creatinine and kidney histology demonstrated that procainamide provided ef fective protection in vivo in the rat when administered either simultaneous ly or at 0.5 and 1 h before or after cisplatin. The protection was accompan ied by both higher renal levels of platinum and cisplatin-DNA adducts and b y an increase in the formation of ISCLs. Moreover, a dose-dependent reducti on of urinary excretion and concentration of platinum was also observed. We propose that procainamide, after accumulation in the kidney, may coordinat e with cisplatin to form a less toxic DPR-like complex that renders rats le ss susceptible to cisplatin-induced toxicity.