PT  - JOURNAL ARTICLE
AU  - Peter J. Ferguson
AU  - Catherine Currie
AU  - Mark D. Vincent
TI  - 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
DP  - 1999 Dec 01
TA  - Drug Metabolism and Disposition
PG  - 1399--1405
VI  - 27
IP  - 12
4099  - http://dmd.aspetjournals.org/content/27/12/1399.short
4100  - http://dmd.aspetjournals.org/content/27/12/1399.full
SO  - Drug Metab Dispos1999 Dec 01; 27
AB  - 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 withcis-diamminedichloroplatinum II (cisplatin) orcis-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 μg/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 A2-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. The American Society for Pharmacology and Experimental Therapeutics