Protective effect of BNP7787 against cisplatin-induced nephrotoxicity in rats

1385 Cisplatin is one of the most active and widely used drugs in the treatment of several types of solid tumors, while nephrotoxicity is a common and serious dose limiting toxicity for platinum chemotherapy. BNP7787 (disodium-2,2’-dithio-bis-ethane sulfonate), a novel water-soluble disulfide, is being developed to prevent the clinical toxicities of platinum chemotherapy. BNP7787 is reported to be rapidly taken up into renal tubular epithelial cells and undergoes conversion into the water-soluble free thiol species, 2-mercapto-ethane sulfonate sodium (mesna), which can locally detoxify active forms of cisplatin. In this study, we demonstrated the protective effect of BNP7787 on cisplatin-induced nephrotoxicity in rats using biochemical and histopathological approaches. Furthermore, we investigated the influence of BNP7787 on the anti-tumor effect of cisplatin in tumor bearing rats and mice. Intravenous injections of BNP7787 (400, 600, 800 and 1000 mg/kg) inhibited cisplatin (6 mg/kg)-induced increases in both BUN and serum creatinine levels in a dose dependent manner. BNP7787 (1000 mg/kg) also reduced proximal tubular degeneration and necrosis. Additionally, BNP7787 (1000 mg/kg) significantly inhibited increases in both BUN and serum creatinine levels following repeated administration of cisplatin (4 mg/kg, once a week, 6 times). When the protective effect of BNP7787 (1000 mg/kg) on BUN and serum creatinine levels was compared with that of a hydration control (40 mL/kg of saline), it was comparable to the protective effects observed with the hydration control, although total volume administered to rats treated with BNP7787 was eight-fold less than that with hydration. Free thiol concentrations in the kidney at 30 min after an intravenous injection of BNP7787 (1000 mg/kg) showed a marked increase compared with the other organs tested including tumors. Furthermore, the pre-treatment of BNP7787 (1000 and 2000 mg/kg) significantly decreased platinum concentrations in the kidney (23.2 and 37.1% reduction compared to control, respectively) at 8 hr after the administration of cisplatin (6 mg/kg) without any influence on platinum concentrations in the tumor. The combination of BNP7787 with cisplatin did not affect the anti-tumor activity of cisplatin in tumor-bearing rats and mice. These results suggest that BNP7787 may protect against cisplatin-induced nephrotoxicity without reducing anti-tumor activity, and improved QOL may be observed when BNP7787 is used in conjunction with cisplatin in the clinic.