The effect of benzamide riboside on the VX2 model of liver cancer in rabbits.

摘要

PURPOSE: Benzamide riboside (BR) causes apoptosis in multiple tumor cell lines by its inhibition of guanylate biosynthesis. The purpose of this study was to determine the feasibility of the use of BR as a therapeutic agent for hepatic artery infusional cancer therapy in a rabbit VX2 papilloma tumor model. MATERIALS AND METHODS: VX2 tumor was implanted into the left lobe of the liver of each of 14 New Zealand White rabbits and allowed to grow for 19 days +/- 3. The proper hepatic artery was selected with a 3-F catheter via right femoral cutdown. The animals were treated with one infusion of 0.9% saline solution (n = 2), 1 mg/kg BR (n = 4), 5 mg/kg BR (n = 4), or 10 mg/kg BR (n = 4). One animal treated with 5 mg/kg BR did not develop tumor. Livers were explanted after 24 hours and sectioned through the tumor. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining was performed on the slides and they were imaged at a magnification of 40 to detect apoptotic cells. Four random fields were obtained from each slide and the percentage of apoptotic cells was calculated by dividing the number of TUNEL-positive cells by the total number of cells. Sections of liver not involved with tumor were seen in five animals: two that received 1 mg/kg BR, one that received 5 mg/kg, and two that received 10 mg/kg. RESULTS: The mean tumor apoptosis rates were 1.3% with saline solution treatment, 44.8% with 1 mg/kg BR, 52.7% with 5 mg/kg BR, and 70.7% with 10 mg/kg BR. The mean tumor apoptosis in treated animals was significantly greater than in control animals (P = .003) and mean tumor apoptosis was significantly greater with 10 mg/kg BR than with 1 mg/kg BR (P = .03). There were no apoptotic cells in normal liver treated with 1 mg/kg BR or 10 mg/kg BR. The animal that received 5 mg/kg BR exhibited 10.5% apoptotic cells in the field examined (eight of 76 cells). In the animal treated with 5 mg/kg BR but in which tumor did not grow, only one of 76 cells (0.65%) was apoptotic in the area of the injection scar. CONCLUSION: BR induces apoptosis in VX2 tumor in the rabbit model with minimal apoptosis in normal liver.