Isolated Liver Perfusion Permits Administration of High Doses of Chemotherapeutic Agents

Abstract

Tumor cells are dependent on glutamine metabolism and acivicin, which is a selective glutamine antagonist, has been shown to effectively retard tumor growth in several malignancies. However, systemic treatment with acivicin is associated with significant side effects. The purpose of the present study was to examine whether use of an in vivo isolated liver perfusion model may allow administration of lethal doses of acivicin and compare it to regional infusion of acivicin in the hepatic artery. Five days after tumor inoculation, acivicin was administered by an isolated liver perfusion model or by regional infusion via the hepatic artery. It was found that regional infusion of acivicin (5 and 10 mg/kg) via the hepatic artery caused systemic illness and diarrhea, and all animals in this group died within 3 days. In contrast, we observed no signs of systemic illness, diarrhea or hepatocellular injury in rats receiving isolated liver perfusion with or without acivicin (10 mg/kg) administration. Noteworthy, we found that isolated perfusion with acivicin reduced the glutamine content in liver tumors by 39% compared to perfusion with control medium. In line with this, it was found that isolated perfusion with acivicin (10 mg/kg) inhibited tumor growth in the liver. Taken together, this study suggests that application of the isolated liver perfusion model avoids the toxic and lethal effects of high doses of chemotherapy, herein acivicin, and may provide a useful approach to treat liver tumors in vivo.

Percutaneous Isolated Hepatic Perfusion for Chemotherapy

“…1,30 But, IHP should use the right drug against the right tumor. To enlarge the panel of tumors targeted by IHP, other drug classes, including cytostatic, 43 virus-mediated gene transfer, 44 mutein of tumor necrosis factor-␣, 45 or metabolic 46 agents, should be studied. In light of the remarkable results obtained with isolated limb perfusion, 14 further work is required to establish potential similar applications for IHP.…”