title: High mitomycin C concentration in tumour tissue can be achieved by isolated liver perfusion in rats.
abstract: To enable the treatment of hepatic metastasis with higher, theoretically more effective, doses of systemically toxic anticancer drugs, an isolated liver perfusion (ILP) technique was developed in WAG/Ola rats. First, in a toxicity study the maximally tolerated dose (MTD) of mitomycin C (MMC) was determined for a 25-min ILP and for hepatic artery infusion (HAI) after the administration of a bolus dose. The MTD in the ILP setting (4.8 mg/kg) was 4 times that using HAI (1.2 mg/kg). Subsequently, in a rat colorectal hepatic-metastasis model, concentrations of MMC in tumour, liver, plasma and perfusate were measured during a 25-min ILP to investigate the expected pharmacokinetic advantage of ILP. The mean plasma level determined after ILP (1.2 as well as 4.8 mg/kg MMC) was significantly lower (P less than 0.001) than that obtained following HAI. This may explain both the absence of severe systemic toxicity and the higher MTD in ILP-treated groups. No significant difference in mean tumour and liver tissue concentrations of MMC were found when the groups treated with 1.2 mg/kg drug via HAI vs ILP were compared. The mean MMC concentration in tumour tissue was significantly higher (almost 5 times; P less than 0.05) in rats treated by ILP with the MTD (4.8 mg/kg) than in those treated via HAI with the MTD (1.2 mg/kg). ILP of MMC can be safely performed using a dose 4 times higher than the MTD in the HAI setting, leading to an almost 5-fold concentration of MMC in hepatic metastasis. ILP of MMC may therefore represent a promising therapy for metastasis confined to the liver.
authors.affiliation: Department of Surgery, University Hospital, Leiden, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Marinelli
authors.forename: D H
authors.initials: DH
authors.lastname: Pons
authors.forename: J A
authors.initials: JA
authors.lastname: Vreeken
authors.forename: S K
authors.initials: SK
authors.lastname: Nagesser
authors.forename: P J
authors.initials: PJ
authors.lastname: Kuppen
authors.forename: U R
authors.initials: UR
authors.lastname: Tjaden
authors.forename: C J
authors.initials: CJ
authors.lastname: van de Velde
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity; D010478:Chemotherapy, Cancer, Regional Perfusion; D002851:Chromatography, High Pressure Liquid; D006499:Hepatic Artery; D007261:Infusions, Intra-Arterial; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism; D016685:Mitomycin; D008937:Mitomycins / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents; D008937:Mitomycins; D016685:Mitomycin