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DNA Damage Induced by a New 2-Chloroethyl Nitrosourea on Malignant Melanoma Cells¹

Institut de la Santé et de la Recherche Médicale Unit 71, B.P. 184, 63005 Clermont-Ferrand [D. G., M. R., J. C. M., A. V.]; Association de Recherche contre le Cancer [A. T.], Groupe "Radiochimie du DNA" (Institut de la Santé et de la Recherche Médicale Unit 247), Institut Gustave Roussy, 94805 Villejuif Cedex [F. L.]; and Centre Jean Perrin, Place Henri Dunant, 63011 Clermont-Ferrand Cedex [P. C.], France

Different biological aspects of a novel 2-chloroethyl nitrosourea derived from cysteamine, N'-(2-chloroethyl)-N-[2-(methylsulfinyl)ethyl]-N'-nitrosourea (CMSOEN₂), were studied. Drug-induced cytotoxic effects, uptake kinetics, DNA damage, and O⁶-alkylguanine-DNA alkyltransferase activity were determined in 3 melanoma cell lines: the murine B16 and 2 human metastatic-derived cell lines (M4 Beu and M3 Dau). We found that radioactivity uptake and incorporation in acido-precipitable material was inversely proportional to cell drug viability. The highly CMSOEN₂-sensitive B16 line showed the lowest total radioactivity uptake. In fact, among the melanoma cell parameters studied, 3 of them were well correlated: (a) cytotoxicity as reflected by the colony-forming assay; (b) DNA cross-link frequency estimated by the alkaline elution technique; and (c) O⁶-alkylguanine-DNA alkyltransferase activity (Mer phenotype), defined as the ability of cell extracts to remove O⁶-methylguanine from N-methyl-N-nitrosourea-alkylated DNA. The 2 human cell lines (M4 Beu and M3 Dau), the most resistant to the cytostatic drug effects, showed little or no ability to form DNA lethal cross-links. These results correspond to the higher O⁶-alkylguanine-DNA alkyltransferase activity found in human-derived cell lines compared with that present in murine B16 cell lines. This study confirms that the cell content in this repair DNA protein is certainly one of the important factors implicated in the variability of response to 2-chloroethyl nitrosourea treatment observed in a number of established malignant cell lines. It has been shown that pretreatment of derived cell lines with methylating agents (N-methyl-N-nitrosourea, N-methyl-N'-nitro-N-nitrosoguanidine) or O⁶-methylguanine used as a free base, increased cytotoxic effects of this class of anticancer agents, likely by saturating receptor sites (sulfhydryl groups) of this specific DNA repair enzyme. Nevertheless, in preliminary Phase I and II clinical trials, 2 patients who had been treated with multiple chemotherapies including alkylating agents [1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, 5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide, platinum derivatives], presented complete or partial remission after CMSOEN₂ treatment. Our results raise the question of the exact relation between the Mer phenotype determined in derived murine or human cultured cells and that directly observed on surgically excised tumors in cancer patients. The original Mer phenotype could be modified by cell culture conditions since it has been shown that O⁶-alkylguanine-DNA alkyltransferase activity is widely distributed between normal and tumoral tissues without any real difference.

¹ This program was supported by grants from the Comité de la Ligue Départementale de la Lutte contre le Cancer (Puy-de-Dôme, France).

² To whom requests for reprints should be addressed.

Received 4/27/90. Accepted 6/19/90.

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