Hepatic Artery Infusion of Obatoclax Increases Survival and Decreases Tumor Size in a Rat Model of Cholangiocarcinoma
Rory Smoot*1, Alphonse E. Sirica2, Gregory J. Gores3
1Department of Surgery, Mayo Clinic, College of Medicine, Rochester, MN; 2Department of Pathology, Virginia Commonwealth University School of Medicine, Richmond, VA; 3Division of Gastroenterology and Hepatology, Mayo Clinic, College of Medicine, Rochester, MN
Background: Obatoclax is a BH3-only protein mimetic currently in phase II trials for hematologic malignancies and lung cancer. We have previously demonstrated a Bax-mediated mechanism for obatoclax cytoxicity in in vitro studies employing several cholangiocarcinoma cell lines. Herein we report our in vivo studies utilizing a previously validated rat model of cholangiocarcinoma (Hepatology. 2008 Apr;47(4):1178-90.)Methods: Male Fisher 344 rats were anesthetized and the hilum of the liver exposed. Ligation of the bile duct to the left lateral lobe was completed and BDEneu cells, a rat cholangiocarcinoma cell line, were injected into the liver parenchyma. The gastroduodenal artery was cannulated in a retrograde fashion with a tunneled catheter connected to a sub-cutaneous port which was implanted on the lower back of the rats. Results: Given uncertainty regarding the pharmacokinetics for obatoclax in rodents, we chose a locoregional route of drug delivery via hepatic artery infusion. Following a 10-day recovery period, the rats were treated by injection through the subcutaneous port with vehicle or obatoclax (1.5mg/kg) for five days. Tumor burden was evaluated by removing the livers five days after completion of treatment (n=8). An additional group of rats were followed after treatment to determine effect on survival (n=12). Following hepatic artery infusion of obatoclax the tumor weight was decreased 10-fold from a mean (+/- SD) of 0.04 g (+/- 0.03) versus control animals, 0.38 g (+/-0.10), p<0.001. When comparing the ratio of tumor weight to liver weight similar results were noted with a 12-fold decrease for obatoclax treated rats, mean of 0.003 (+/- 0.002) versus 0.036 (+/- 0.010) for controls, p<0.001. This effect on tumor size correlated with an increased survival in obatoclax treated rats as compared to vehicle treated animals with a median survival of 23 days in the vehicle treated rats versus 44 days in the obatoclax treated group, p=0.005 by log-rank analysis. No toxicity was observed in the hepatic parenchyma as assessed by histopathology. Discussion: Obatoclax, a novel BH3-only protein mimetic, has significant in vivo activity in a rat model of cholangiocarcinoma when delivered via a hepatic artery catheter. This preclinical work supports the evaluation of obatoclax for the treatment of human cholangiocarcinoma.
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