Differential sensitivities of murine melanocytes and melanoma cells to buthionine sulfoximine and anticancer drugs.
High levels of intracellular glutathione (GSH) may result in resistance of tumor cells to cytotoxic drugs. Because of the innate refractory nature of melanoma cells to chemotherapy, we have used a syngeneic murine system consisting of nontumorigenic Mel-ab melanocytes, tumorigenic H-ras-transformed melanocytes (C9.1), and the highly metastatic BL6 melanoma cells to examine the GSH content, glutathione S-transferase (GST) activity, and sensitivity to buthionine sulfoximine (BSO) and other cytotoxic drugs. Compared to the nontumorigenic melanocytes, both C9.1 and BL6 melanoma cells have nearly fivefold higher GSH content, and BL6 cells have increased GST activity. C9.1 and BL6 cells are more resistant to the cytotoxic effects of BCNU and adriamycin; however, the degrees of resistance do not reflect the increased GSH content in these cells. Pretreatment of BL6 melanoma cells with 50 microM BSO depleted over 90% of their GSH content and enhanced the growth-inhibitory effects of L-dopa methylester, BCNU, bleomycin, and dacarbazine. Exposure to BSO alone was not toxic to the tumor cells for up to 24 hr, but was significantly cytotoxic in the melanocytes after 9 hr. The sensitivity of these cells to BSO appears to depend on a critical level of GSH depletion which is not related to the initial GSH content. These studies suggest that the resistance of melanoma cells to cytotoxic drugs is only partially attributed to changes in the GSH system caused during cellular transformation.
Thrall
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College of Pharmacy and Pharmacology/Toxicology Graduate Program, Washington State University, Pullman 99164-6510.
Raha
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Springer
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Meadows
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D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D019328:Buthionine Sulfoximine; D002455:Cell Division / Q000187:drug effects; D005978:Glutathione / Q000032:analysis*; D005982:Glutathione Transferase / Q000032:analysis; D008544:Melanocytes / Q000737:chemistry / Q000187:drug effects*; D008546:Melanoma, Experimental / Q000737:chemistry / Q000473:pathology*; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051379:Mice; D014407:Tumor Cells, Cultured
D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; D005982:Glutathione Transferase; D005978:Glutathione