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Glucocorticoid Effect on Melphalan Cytotoxicity, Cell-Cycle Position, Cell Size, and [³H]Uridine Incorporation in One of Three Human Melanoma Cell Lines¹

Division of Experimental Therapy, The Netherlands Cancer Institute (Antoni van Leeuwenhoek Huis), 1066 CX Amsterdam, The Netherlands

Three human melanoma cell lines of known content of specific glucocorticoid-binding sites were studied for colony formation after a µM dose of glucocorticoid combined with melphalan. In one of the three cell lines, M-5A, subcloned from M-5 (formerly designated RPMI 8322), the effect of combined treatment was markedly increased compared to that of melphalan even if the glucocorticoid was applied for 1 h only, 10 h before the melphalan. Semilogarithmic dose-effect plots for a reduction of final plating efficiency by glucocorticoid were curvilinear, according to a receptor-mediated process. The effects of glucocorticoid, melphalan, and their combination were linearized by bilogarithmic median-effect plotting which allowed the quantitation of a synergism which was more marked in case of glucocorticoid pretreatment, for 1 or 24 h, than on simultaneous exposure. According to sequential DNA per cell cytophotometry, melphalan abolished in M-5A a glucocorticoid-induced arrest in the G₁ phase of the cell cycle. The cytotoxic synergism correlated with an apparent stimulation by glucocorticoid of the rate of acid-insoluble incorporation of [³H]uridine and [¹⁴C]leucine and an increase in cell size and protein content in M-5A cells but not in the other two cell lines. The way in which glucocorticoids induce an enhanced susceptibility to melphalan is not clear. Our results appear compatible with a hypothesis that chromatin in a transcriptionally activated state is more vulnerable to cytotoxic attack by an alkylating agent than under average conditions.

¹ Financial support by the Nijbakker-Morra Foundation, Amsterdam, is gratefully acknowledged. Part of this study was performed within the Cultural Agreement between the University of Amsterdam and the University of Cairo.

² To whom requests for reprints should be addressed, at Division of Experimental Therapy, The Netherlands Cancer Institute, 121 Plesmanlaan, 1066 CX Amsterdam, The Netherlands.

³ Visiting scientist on leave from the National Cancer Institute, Cairo University, Cairo.

Received 9/17/86. Revised 4/13/87. Revised 6/10/87. Accepted 6/12/87.