Isolated liver perfusion for regional chemotherapy in rats

BACKGROUND: In the isolated liver perfusion (ILP) technique, the liver is temporarily isolated from the systemic circulation in order to infuse large doses of chemotherapeutic agents through the hepatic inflow. The hepatic tissue can show a drug concentration higher than that after systemic chemotherapy, and a general toxic reaction from chemotherapeutic agent is avoided. In a modified ILP model in rats, we explored the distribution of the chemotherapeutic agent, fluorouracil (5-FU) in the systemic circulation and in the hepatic tissue, and assessed the pathological changes in the liver. METHODS: 306 Sprague-Dawley rats were randomly divided into 4 groups: control, ILP without 5-FU, ILP with 5-FU at different doses, and infusion of 5-FU through the portal vein. All animals were subjected to modified ILP, and 5-FU concentrations in the hepatic tissue and the systemic blood were determined at different time points. Levels of thromboxane B-2 (TXB2) and 6-keto-prostaglandin F-1 alpha (6-keto-PGF(1 alpha)), and changes in hepatic function, pathology and liver enzymes were assessed. RESULTS: ILP through the portal vein at three dosages (25, 50 and 100 mg/kg) resulted in significantly higher 5-FU concentrations in the liver tissue for 50 and 100 mg/kg and there was only a small leakage of 5-FU from the perfusion system into the systemic circulation. The pathological findings revealed that the liver tissue tolerated ILP below the maximum tolerance dose (MTD) of 5-FU. If the 5-FU dose exceeded the MTD the ultrastructure and the enzymatic activity of hepatocytes were clearly affected The change of TXB2 and PGF(1 alpha) balance were closely related to the injury of hepatic tissue caused by ILP with 5-FU doses greater than the MTD. CONCLUSIONS: Hepatic tissue sustains a higher drug concentration using ILP than that from systemic chemotherapy, and avoids a general toxic reaction to the drug entering into the systemic circulation. Evident injury may not occur in hepatocytes, and the changes of liver function are slight and transient by using ILP with no more than the MTD of 5-FU.