Attempts to improve locoregional chemotherapy for the prevention of colonic cancer liver metastasis in the rat

Abstract

To improve prophylactic local treatment of hepatic metastasis from colonic cancer cells in the rat. The in vitro anticancer activity of 30 mn exposure to different drugs was first evaluated by dimethyl-thiazol-diphenyl-tetrazolium-bromide assay on confluent DHD/K12/PROb rat and HT29 human colonic cancer cells. Hepatic metastasis was induced by portal vein infusion of 12 x 106 PROb colonic cancer cells in syngenic BDIX rats. Hepatic and general tolerance to epirubicin was studied. Rats were treated with epirubicin delivered by either intravenous (IV), intraperitoneal (IP) or intraportal (Ipo) administration to compare their antitumoral effects. Hepatic distribution of epirubicin was assessed by fluorescence microscopy after IV, IP, Ipo, and combined administration. High pressure liquid chromatography was used to measure hepatic concentrations of epirubicin. Only pirarubicin was fully cytotoxic in vitro against the two types of tumor cells. No general or hepatic toxicity was observed. The preventive effect on hepatic metastasis was similar for IV, IP, and Ipo pirarubicin treatments. Hepatic pirarubicin concentrations obtained by Ipo administration were 4.1-fold higher than those obtained after IV administration (P=0.013). Three hours after IP and Ipo administration, hepatic remnants of pirarubicin were similar and significantly higher that those obtained after IV administration (P=0.074). Clamping the hepatic vein doubled hepatic pirarubicin concentrations after Ipo administration (P=0.048). Combined hepatic and intraportal administration was necessary to achieve diffuse, intense and homogeneous fluorescence throughout the entire liver. Homogeneous hepatic diffusion of pirarubicin was successfully achieved with combined hepatic vein and intraportal administration but systemic, intraperitoneal or intraportal administration had no preventive effect on hepatic metastasis. Other drugs could be tested using this approach to evaluate their efficacy and toxicity.