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.

Abstract

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.

• Authors: F Alena, T Iwashina, A Gili, K Jimbow
• Journal: Cancer research (Cancer Res) Vol. 54 Issue 10 Pg. 2661-6 (May 15 1994) ISSN: 0008-5472 [Print] United States
• PMID: 8168094 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Phenols
• Methionine Sulfoximine
• Buthionine Sulfoximine
• Cysteamine
• N-acetyl-4-S-cysteaminylphenol
• Glutathione

Topics

• Animals
• Autoradiography
• Buthionine Sulfoximine
• Cysteamine (analogs & derivatives, pharmacokinetics, pharmacology)
• Dose-Response Relationship, Drug
• Drug Synergism
• Female
• Glutathione (metabolism)
• Lung Neoplasms (metabolism, secondary)
• Melanoma, Experimental (metabolism, secondary)
• Methionine Sulfoximine (analogs & derivatives, pharmacology)
• Mice
• Mice, Inbred C57BL
• Phenols (pharmacokinetics, pharmacology)