Dietary agent indole-3-carbinol protects female rats against the hepatotoxicity of the antitumor drug ET-743 (trabectidin) without compromising efficacy in a rat mammary carcinoma

ET-743, an experimental antitumor drug with promising activity in sarcoma, breast and ovarian carcinoma, is currently under phase 2 clinical evaluation. It is hepatotoxic in animals and patients. We tested the hypothesis that indole-3-carbinol (13C), the hydrolysis product of glucosinolates occurring in cruciferous vegetables, may protect against ET-743-induced hepatotoxicity in the female Wistar rat, the animal species with the highest sensitivity toward the adverse hepatic effect of this drug. Hepatotoxicity was adjudged by measurement of plasma levels of bilirubin, alkaline phosphatase (ALP) and aspartate aminotransferase (AST) and by liver histopathology. The effect of 13C on the kinetics of ET-743 in rat plasma and liver was investigated by highpressure liquid chromatography. The effect of 13C on the antitumor efficacy of ET-743 was explored in rats bearing the 13762 mammary carcinoma. ET-743 (40 mug/kg i.v.) alone caused an elevation of plasma bilirubin, ALP and AST levels and degeneration and patchy focal necrosis of bile duct epithelial cells. Addition of 13C to the diet (0.5%) for 6 days prior to ET-743 administration almost completely abolished manifestations of hepatotoxicity. In contrast, a dietary concentration of 0.1% 13C did not protect, nor did dietary diindolylmethane (0.2%), an acid-catalyzed condensation product of 13C. Ingestion by rats of 13C for 6 days prior to ET-743 (40 mug/kg i.v.) decreased plasma but not hepatic concentrations of ET-743 compared to animals that received ET-743 alone. 13C did not interfere with the antitumor efficacy of ET-743. The results suggest that ingestion of 13C may counteract the unwanted effect of ET-743 in the liver. 13C should be investigated as a hepatoprotectant in patients who receive ET-743 therapy. (C) 2004 Wiley-Liss, Inc.