title: Digitonin enhances the efficacy of carboplatin in liver tumour after intra-arterial administration.
abstract: Platinum-containing drugs enter the cell slowly and have a poor tissue penetration. Increasing the permeability of the cell membrane might increase the intracellular drug concentration. Digitonin, a detergent that increases cell permeability by binding to cholesterol molecules in the cell membrane, can increase cisplatin accumulation and reduce tumour growth in vitro. The aim of this study was to determine whether digitonin could increase the efficacy of carboplatin (CBDCA) in vivo. In LH rats, a hepatoma was implanted in the liver. At 7 days after implantation, digitonin (or saline in the control group) was infused via the hepatic artery and, 10 min later, CBDCA was injected. Biopsies from the tumour and liver parenchyma were obtained after 1 h. The concentration of platinum measured in the liver tumours was higher in the digitonin group than in the control groups. In the liver parenchyma the concentrations were of the same magnitude. Measured with the 133Xe-clearance technique, digitonin did not alter the tumour blood flow. Digitonin enhanced the tumour-growth-retarding effect of CBDCA given intra-arterially at 5 mg/kg but not at 25 mg/kg. No increase in toxicity was observed for digitonin given together with CBDCA at 5 mg/kg. Systemic administration of CBDCA was not influenced by digitonin. These findings demonstrate that pretreatment with digitonin increases the tumour uptake of CBDCA and potentiates the cytotoxic effect of CBDCA.
authors.affiliation: Department of Surgery, Sahlgrenska Hospital, University of Göteborg, Sweden.
authors.forename: P G
authors.initials: PG
authors.lastname: Lindnér
authors.forename: D
authors.initials: D
authors.lastname: Heath
authors.forename: S B
authors.initials: SB
authors.lastname: Howell
authors.forename: P L
authors.initials: PL
authors.lastname: Naredi
authors.forename: L R
authors.initials: LR
authors.lastname: Hafström
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D016190:Carboplatin / Q000008:administration & dosage / Q000494:pharmacology*; D003902:Detergents / Q000494:pharmacology*; D004072:Digitonin / Q000494:pharmacology*; D005260:Female; D006499:Hepatic Artery; D007261:Infusions, Intra-Arterial; D008114:Liver Neoplasms, Experimental / Q000098:blood supply / Q000188:drug therapy*; D008297:Male; D009929:Organ Size; D051381:Rats; D011919:Rats, Inbred Strains
chemical_list: D000970:Antineoplastic Agents; D003902:Detergents; D016190:Carboplatin; D004072:Digitonin