Selective in vivo accumulation of N-acetyl-4-S-cysteaminylphenol in B16F10 murine melanoma and enhancement of its in vitro and in vivo antimelanoma effect by combination of buthionine sulfoximine.
In order to develop a new chemotherapeutic agent based on exploitation of the specific metabolic pathway of malignant melanoma, a phenolic thioether, N-acetyl-4-S-cysteaminylphenol (NA-CAP), the substrate of melanin-forming enzyme, tyrosinase was developed. Our previous in vivo studies have clearly shown that this compound has a significant and selective melanocytotoxicity and antimelanoma effect. This study further examined the specificity of the antimelanoma effect of NA-CAP through the study of biodistribution and accumulation of NA-CAP in B16F10 melanoma-bearing mice. We also tested the antimelanoma effect of NA-CAP by combination treatment with buthionine sulfoximine on the growth of in vitro culture cells and in vivo B16F10 melanoma lung colonies. We found a selective accumulation of 14C-labeled NA-CAP into s.c. transplants and lung colonies of melanoma grown in C57BL mice. This accumulation was mediated by selective covalent binding of NA-CAP to the melanoma tissues. The combination of NA-CAP and buthionine sulfoximine significantly increased the chemosensitivity of B16F10 melanoma cells in vitro and reduced the number of in vivo melanoma lung colonies. We conclude that NA-CAP acts as an alkylating agent to melanoma tissue and that the combination of buthionine sulfoximine enhances the therapeutic index of this potent melanoma-specific drug through the depletion of tissue glutathione.
Alena
F
F
Division of Dermatology and Cutaneous Sciences, University of Alberta, Edmonton, Canada.
Iwashina
T
T
Gili
A
A
Jimbow
K
K
D000818:Animals; D001345:Autoradiography; D019328:Buthionine Sulfoximine; D003543:Cysteamine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D005978:Glutathione / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism* / Q000556:secondary; D008546:Melanoma, Experimental / Q000378:metabolism* / Q000556:secondary; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D010636:Phenols / Q000493:pharmacokinetics* / Q000494:pharmacology*
D010636:Phenols; D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; D003543:Cysteamine; C066420:N-acetyl-4-S-cysteaminylphenol; D005978:Glutathione