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In-transit melanoma: the role of alkylating-agent resistance in regional therapy.

Publication ,  Journal Article
Grubbs, EG; Abdel-Wahab, O; Cheng, T-Y; Abdel-Wahab, Z; Peterson, B; Pruitt, SK; Colvin, OM; Friedman, HS; Tyler, DS
Published in: J Am Coll Surg
September 2004

BACKGROUND: Regional perfusion treatments for melanoma, using the alkylating agent melphalan, show variable responses in magnitude and duration. Surprisingly, the potential contribution of alkylating-agent resistance mechanisms to diminish tumor responses, especially the crucial cellular detoxifying system formed by glutathione (GSH) and its associated enzyme glutathione-S-transferase (GST), has remained unexplored. Objectives of this study were to characterize GSH levels and GST activity in melanoma of patients undergoing regional perfusion and examine the effect of melphalan concentration in both an in vitro human melanoma cell line and in the extremity melanoma of an in vivo rodent limb infusion model. STUDY DESIGN: Human in-transit melanoma, muscle, subcutaneous tissue, and skin (n = 9) and metastatic regional lymph nodes (n = 7) were evaluated for GSH level and GST activity. Effects of increasing melphalan exposure on GSH and GST were studied in an in vitro human melanoma cell line. A survival human melanoma xenograft model of isolated limb infusion using increasing dosages of melphalan was used, with evaluation of GSH and GST in the recurrent tumor. RESULTS: GSH levels in human in-transit lesions and muscle were significantly higher than that of skin and subcutaneous tissue. Four of 9 patients had tumor-to-muscle GSH ratio > 1. A strong correlation was seen between in vitro melphalan dose and resultant GSH level and GST activity. In vivo recurrent tumor GSH levels correlated with increasing melphalan infusion dose. CONCLUSIONS: A GSH-based resistance pathway may play a role in effecting response and toxicity to regional melphalan perfusion.

Duke Scholars

Published In

J Am Coll Surg

DOI

ISSN

1072-7515

Publication Date

September 2004

Volume

199

Issue

3

Start / End Page

419 / 427

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Transplantation, Heterologous
  • Surgery
  • Rats, Nude
  • Rats
  • Melphalan
  • Melanoma, Experimental
  • Melanoma
  • Lymphatic Metastasis
  • Inactivation, Metabolic
 

Citation

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MLA
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Grubbs, E. G., Abdel-Wahab, O., Cheng, T.-Y., Abdel-Wahab, Z., Peterson, B., Pruitt, S. K., … Tyler, D. S. (2004). In-transit melanoma: the role of alkylating-agent resistance in regional therapy. J Am Coll Surg, 199(3), 419–427. https://doi.org/10.1016/j.jamcollsurg.2004.05.271
Grubbs, Elizabeth G., Omar Abdel-Wahab, Tsung-Yen Cheng, Zeinab Abdel-Wahab, Bercedis Peterson, Scott K. Pruitt, O Michael Colvin, Henry S. Friedman, and Douglas S. Tyler. “In-transit melanoma: the role of alkylating-agent resistance in regional therapy.J Am Coll Surg 199, no. 3 (September 2004): 419–27. https://doi.org/10.1016/j.jamcollsurg.2004.05.271.
Grubbs EG, Abdel-Wahab O, Cheng T-Y, Abdel-Wahab Z, Peterson B, Pruitt SK, et al. In-transit melanoma: the role of alkylating-agent resistance in regional therapy. J Am Coll Surg. 2004 Sep;199(3):419–27.
Grubbs, Elizabeth G., et al. “In-transit melanoma: the role of alkylating-agent resistance in regional therapy.J Am Coll Surg, vol. 199, no. 3, Sept. 2004, pp. 419–27. Pubmed, doi:10.1016/j.jamcollsurg.2004.05.271.
Grubbs EG, Abdel-Wahab O, Cheng T-Y, Abdel-Wahab Z, Peterson B, Pruitt SK, Colvin OM, Friedman HS, Tyler DS. In-transit melanoma: the role of alkylating-agent resistance in regional therapy. J Am Coll Surg. 2004 Sep;199(3):419–427.
Journal cover image

Published In

J Am Coll Surg

DOI

ISSN

1072-7515

Publication Date

September 2004

Volume

199

Issue

3

Start / End Page

419 / 427

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Transplantation, Heterologous
  • Surgery
  • Rats, Nude
  • Rats
  • Melphalan
  • Melanoma, Experimental
  • Melanoma
  • Lymphatic Metastasis
  • Inactivation, Metabolic