title: Enhancement of platinum-drug cytotoxicity in a human head and neck squamous cell carcinoma line and its platinum-resistant variant by liposomal amphotericin B and phospholipase A2-II.
abstract: Platinum drugs comprise one of the main classes of chemotherapy drugs that can induce remissions in various solid tumors. Although tumors often regress on treatment with cis-diamminedichloroplatinum II (cisplatin) or cis-diammine-1,1-cyclobutane dicarboxylate platinum II (carboplatin), they usually relapse as a drug-resistant tumor. Most mechanisms of platinum resistance could be overcome by increasing the amount of drug that is accumulated by tumor cells. Amphotericin B (Amph B) is efficient at increasing platinum drug uptake, but because of nephrotoxicity associated with extended usage, and the potential for synergistic nephrotoxicity when used with platinum drugs, Amph B has not been used clinically for this purpose. A liposomal preparation of Amph B (LipoAmph B), which is substantially less nephrotoxic, was studied for its ability to enhance platinum-drug toxicity to a human oral squamous cell carcinoma line, HN-5a, and its carboplatin-resistant variant, 5a/carbo-15a, in which cisplatin accumulation was reduced by approximately 40%. Amph B at 10 microg/ml enhanced cisplatin accumulation by approximately 100% in both cell lines, enhancing cytotoxicity of the drugs by 35 to 60%, and completely reversed resistance to both cisplatin and carboplatin. LipoAmph B in the presence of phospholipase A(2)-II (PLA2-II) was able to enhance cisplatin and carboplatin cytotoxicity as effectively as free Amph B in both cell lines. At optimal concentrations, LipoAmph B plus PLA2-II enhanced drug uptake sufficiently to abolish resistance in the platinum-resistant line. Because PLA2-II is elevated in some tumor microenvironments and in plasma of ill patients, LipoAmph B has potential clinical usefulness as a modulator of platinum-drug efficacy.
authors.affiliation: Department of Otolaryngology, University of Western Ontario and London Regional Cancer Centre, London, Canada. pfergus1@julian.uwo.ca
authors.forename: P J
authors.initials: PJ
authors.lastname: Ferguson
authors.forename: C
authors.initials: C
authors.lastname: Currie
authors.forename: M D
authors.initials: MD
authors.lastname: Vincent
mesh_terms: D000666:Amphotericin B / Q000494:pharmacology* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D001692:Biological Transport; D016190:Carboplatin / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell; D002945:Cisplatin / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D054501:Group II Phospholipases A2; D006258:Head and Neck Neoplasms; D006801:Humans; D008081:Liposomes; D010741:Phospholipases A / Q000494:pharmacology*; D054467:Phospholipases A2; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D008081:Liposomes; D000666:Amphotericin B; D016190:Carboplatin; D010741:Phospholipases A; D054501:Group II Phospholipases A2; D054467:Phospholipases A2; D002945:Cisplatin