Modulation of resistance to regional chemotherapy in the extremity melanoma model.

Journal Article (Journal Article)

BACKGROUND: The presence of resistance to chemotherapy is associated with poor tumor response and patient survival in a variety of tumors. Attempts to modulate resistance in conjunction with systemic chemotherapy have been limited by the toxicity of combined therapy, particularly gastrointestinal or hematopoetic toxicity. This study explored systemic modulation of resistance in conjunction with intra-arterial regional therapy to determine if tumor responses to melphalan could be improved with acceptable toxicity. METHODS: Using a nude rat human xenograft model of extremity melanoma,we analyzed tumors for glutathione (GSH), the main protein in the melphalan resistance pathway. Modulation of GSH was performed with intraperitoneal buthionine sulfoximine (BSO). In parallel, BSO-modulated and nonmodulated animals underwent survival studies after regional intra-arterial perfusion with melphalan or saline. Rats were monitored daily for tumor growth and toxicity. RESULTS: BSO depleted tumor GSH levels by 71.8% with minimal toxicity. Survival studies using increasing melphalan concentrations demonstrated similar tumor growth. The combined use of modulator and chemotherapeutic agent showed a significant tumor growth delay as compared to control and drug-alone group without enhanced toxicity. CONCLUSIONS: Modulation of resistance in conjunction with regional chemotherapy allows for improved tumor responses with minimal toxicity. These results demonstrate that BSO can potentiate the cytotoxic effects of regional melphalan therapy in the setting of extremity melanoma.

Full Text

Duke Authors

Cited Authors

  • Grubbs, EG; Ueno, T; Abdel-Wahab, O; Cheng, T-Y; Pruitt, SK; Michael Colvin, O; Friedman, HS; Tyler, DS

Published Date

  • August 2004

Published In

Volume / Issue

  • 136 / 2

Start / End Page

  • 210 - 218

PubMed ID

  • 15300182

Pubmed Central ID

  • 15300182

International Standard Serial Number (ISSN)

  • 0039-6060

Digital Object Identifier (DOI)

  • 10.1016/j.surg.2004.04.021


  • eng

Conference Location

  • United States