Document Detail

Relationship between melanogenesis, glutathione levels and melphalan toxicity in human melanoma cells.
MedLine Citation:
PMID:  1337997     Owner:  NLM     Status:  MEDLINE    
Resistance to alkylating agents has been correlated with cellular levels of reduced glutathione (GSH) and glutathione-S-transferase (GST). GSH is also involved in regulation of melanin synthesis. Therefore, we examined sensitivity to melphalan as a function of differentiation and GSH/GST levels in three human melanoma cell lines. The Me8 cell line, classified as undifferentiated on the basis of cell shape, absence of pigment, insignificant dopa oxidase activity and presence of inhibitors of dopa-melanin formation, showed the lowest GST activity among the cell lines investigated. GLL19 cells exhibited normal differentiation as indicated by the presence of dendrites, typical eumelanosomes, melanin granules and dopa oxidase activity. These cells showed the highest GSH content and the highest GST activity. The JUSO cell line showed incomplete differentiation, and its dopa oxidase and GST activities were intermediate between the Me8 and GLL19 cell lines. The sensitivity of melanoma cell lines to melphalan increased with their degree of differentiation; it was lowest for Me8, intermediate for JUSO and highest for GLL19. Dibutyryl cyclic AMP (dbcAMP) enhanced melphalan toxicity against Me8 cells. Depletion of intracellular GSH with buthionine sulphoximine (BSO) resulted in a three-fold increase in melphalan sensitivity in all three cell lines. Our results indicate that melphalan toxicity is related to cell differentiation and GSH status of melanoma cells. Based on the observed relationship between dopa oxidase, GSH/GST levels and drug toxicity, it is proposed that competition for the GSH pool between quinonoid melanin intermediates and melphalan could diminish drug conjugation and increase cytotoxicity.
M Benathan; H Alvero-Jackson; A M Mooy; C Scaletta; E Frenk
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Melanoma research     Volume:  2     ISSN:  0960-8931     ISO Abbreviation:  Melanoma Res.     Publication Date:  1992 Dec 
Date Detail:
Created Date:  1993-04-02     Completed Date:  1993-04-02     Revised Date:  2004-11-17    
Medline Journal Info:
Nlm Unique ID:  9109623     Medline TA:  Melanoma Res     Country:  ENGLAND    
Other Details:
Languages:  eng     Pagination:  305-14     Citation Subset:  IM    
Department of Dermatology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
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MeSH Terms
Bucladesine / pharmacology
Buthionine Sulfoximine
Cell Differentiation / drug effects
Cell Division / drug effects
Cell Survival / drug effects
Dose-Response Relationship, Drug
Eye Neoplasms / metabolism*,  pathology
Glutathione / metabolism*
Glutathione Transferase / metabolism*
Melanins / biosynthesis*
Melanoma / metabolism*,  pathology,  ultrastructure
Melphalan / pharmacology*
Methionine Sulfoximine / analogs & derivatives,  pharmacology
Microscopy, Electron
Monophenol Monooxygenase / metabolism*
Neoplasm Staging
Skin Neoplasms / metabolism*,  pathology
Tumor Cells, Cultured
Reg. No./Substance:
0/Melanins; 148-82-3/Melphalan; 1982-67-8/Methionine Sulfoximine; 362-74-3/Bucladesine; 5072-26-4/Buthionine Sulfoximine; 70-18-8/Glutathione; EC Monooxygenase; EC Transferase

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