PARA-AMINOBENZOIC ACID SUPPRESSION OF CIS-DIAMMINEDICHLOROPLATINUM(II) NEPHROTOXICITY

Concurrent administration of para-aminobenzoic acid (PABA) reduced the toxicity of cis-diamminedichloroplatinum(II) (DDP) in a dose-related manner in rats. When administered i.p. simultaneously with 7.5 mg/kg D DP, PABA (100 mg/kg) significantly reduced plasma urea nitrogen (PUN) and plasma creatinine levels as well as DDP-induced weight loss. Incre asing doses of PABA (25, 50 and 100 mg/kg) correlated with progressive ly better parameters of renal activity and body wt and with lower leve ls of platinum in plasma and tissues ire rats killed 5 days after drug administration. The formation of cisplatin - DNA adducts, the total p latinum levels in kidney and testes and the DDP-induced tumor response were investigated in the presence and absence of PABA exposure in mic e bearing P388 leukemic cells. Renal and testicular DNA-adducts in mic e treated i.p. with 16 mg/kg DDP in normal saline were higher than tho se observed in mice receiving the same protocol and added PABA. Analys is of tissue platinum content demonstrated significantly lower platinu m levels both in kidneys (P < 0.05) and testes (P < 0.01) of mice rece iving DDP and PABA in normal saline compared to those receiving only D DP in normal saline. PABA did not affect the in vivo and in vitro anti tumor activity of DDP against P388 leukemia, and there was no signific ant PABA-induced modification in the concentration of platinum both in the tumor cells and in DNA samples isolated from P388 leukemic cells of DDP-treated mice. We conclude that PABA may be a promising compound far reducing DDP-toxic side effects, including nephrotoxicity, withou t compromising its antitumor activity.