Fiche publication
Date publication
février 2002
Journal
Anti-cancer drugs
Auteurs
Membres identifiés du Cancéropôle Est :
Pr MERLIN Jean-Louis
Tous les auteurs :
Merlin JL, Marchal S, Ramacci C, Berlion M, Poullain MG
Lien Pubmed
Résumé
Fotemustine (Muphoran, S10036), a nitrosourea derivative active in the treatment of malignant melanoma and primary brain tumors, was evaluated in combination with the free radicals cytoprotective agent amifostine (Ethyol, WR-2721) and its alkaline phosphatase (AP)-generated active metabolite WR-1065 in four human melanoma (RPMI-7950, SK-MEL2, SK-MEL5 and WM-115) and lung fibroblast (MRC-5) cell lines. No difference in AP activity was found among the melanoma cell lines, but AP was found to be significantly higher in MRC-5. For combination experiments, cell lines were first exposed to amifostine or WR-1065 for 15 min and then exposed to fotemustine for two cell doubling times. Non-cytotoxic amifostine and WR-1065 concentrations used (0.2 and 0.6 and 0.1 and 0.3 mmol/l, respectively) were deduced from clinically achieved plasma values. Interactions were analyzed from the variations in IC(50) of fotemustine induced by pre-exposure of the cells to amifostine or WR-1065. In all melanoma cell lines, amifostine enhanced the cytotoxic activity of fotemustine as a significant decrease in IC(50) was observed. No significant difference was found between synergistic effects achieved with amifostine and WR-1065 given at half concentrations. No differential effect was found in the MRC-5 cell line as compared with the melanoma cell lines. Expression variation of O(6)-methylguanine methyltransferase was not found to be implicated in the interaction. The present results demonstrating that amifostine or its main active metabolite do not impair the cytotoxicity of fotemustine justify an extensive clinical evaluation of this combination in metastatic melanoma.
Mots clés
Amifostine, pharmacology, Antineoplastic Agents, pharmacology, Cell Survival, drug effects, Drug Synergism, Humans, Inhibitory Concentration 50, Melanoma, enzymology, Mercaptoethylamines, pharmacology, Nitrosourea Compounds, pharmacology, O(6)-Methylguanine-DNA Methyltransferase, metabolism, Organophosphorus Compounds, pharmacology, Radiation-Protective Agents, pharmacology, Tumor Cells, Cultured
Référence
Anticancer Drugs. 2002 Feb;13(2):141-7