title: Isolated liver perfusion permits administration of high doses of chemotherapeutic agents. Comparison with hepatic artery infusion.
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.
authors.affiliation: Department of Surgery, Malmö University Hospital, Malmö, Sweden.
authors.forename: H
authors.initials: H
authors.lastname: Thorlacius
authors.forename: M
authors.initials: M
authors.lastname: Larmark
authors.forename: M
authors.initials: M
authors.lastname: Randell
authors.forename: B
authors.initials: B
authors.lastname: Hultberg
authors.forename: B
authors.initials: B
authors.lastname: Jeppsson
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D010478:Chemotherapy, Cancer, Regional Perfusion; D005973:Glutamine / Q000378:metabolism; D006499:Hepatic Artery; D007261:Infusions, Intra-Arterial; D007555:Isoxazoles / Q000008:administration & dosage* / Q000627:therapeutic use; D008102:Liver Circulation; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051381:Rats; D011920:Rats, Inbred WF; D016896:Treatment Outcome; D005723:gamma-Glutamyltransferase / Q000037:antagonists & inhibitors
chemical_list: D000970:Antineoplastic Agents; D007555:Isoxazoles; D005973:Glutamine; D005723:gamma-Glutamyltransferase; C006303:acivicin