EFFECT OF THE ANTIARRHYTHMIC DRUG PROCAINAMIDE ON THE TOXICITY AND ANTITUMOR-ACTIVITY OF CIS-DIAMMINEDICHLOROPLATINUM(II)

The class I antiarrhythmic drug procainamide (Pd) was tested on BDF1 m ice for its chemoprotective activity against cis-diamminedichloroplati num(II) (DDP) toxicity. Pd at the dose of 50 mg/kg protected mice agai nst otherwise lethal doses of DDP (survivors at Day 14 after 25 mg/kg DDP or 25 mg/kg DDP-Pd treatment: 0% vs 100%) and greatly reduced the weight loss induced by DDP, Moreover, the increased plasma urea nitrog en levels caused by a single ip administration of DDP in water (8 or 1 6 mg/kg) as well as the tubular degenerative changes detected by light microscopy were prevented by Pd. Pd had no effect on the sensitivity of P388 leukemic cells to DDP in vitro, but the administration of DDP (16 mg/kg) and Pd (50 mg/kg) to BDF1 mice bearing P388 leukemic cells produced a significant increase in survivals compared to mice receivin g ip DDP alone diluted in 0.9% NaCl solution, The increased efficacy o f this combination therapy in P388 leukemic mice compared to a single DDP treatment at the same dose was observed both when the drugs were a dministered ip simultaneously (p = 0.042) and when DDP and Pd were giv en ip and iv, respectively (p = 0.018), Since procaine, which differs from Pd merely in the replacement of the amide by the ester linkage, h as also been reported to significantly enhance DDP efficacy (M. Esposi to et al., 1990, J. Natl. Cancer Inst. 82, 677-684.), a comparison of their effects in tumored mice exposed to DDP has been made, Although b oth drug combinations were superior to that of DDP alone, in terms of both survival time and numbers of cures, Pd treatment seems to offer b etter protection against DDP-induced lethality than did procaine. (C) 1996 Academic Press, Inc.