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 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.
Footnotes
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Send reprint requests to: Dr. P. J. Ferguson, Cancer Research Laboratories, London Regional Cancer Center, 790 Commissioners Road East, London, Canada N6A 4L6. E-mail:pfergus1{at}julian.uwo.ca.
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This work was supported by the Department of Otolaryngology, University of Western Ontario; the Office of the Vice-President Research, University of Western Ontario; the Lawson Research Institute, St. Joseph's Health Center; the Ministry of Health, Province of Ontario; the Medical Oncology Research Fund, London Regional Cancer Center; and NeXstar, Inc., Boulder, CO.
- Abbreviations used are::
- cisplatin
- cis-diamminedichloroplatinum II
- carboplatin
- cis-diammine-1,1-cyclobutane dicarboxylate platinum II
- Amph B
- amphotericin B
- LipoAmph B
- liposomal amphotericin B
- HNSCC
- head and neck squamous cell carcinoma
- PLA2-II
- phospholipase A2-II
- FAAS
- flameless (graphite furnace) atomic absorption spectroscopy
- DC
- desoxycholate
- Received December 14, 1998.
- Accepted August 19, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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