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

Elizabeth G. Grubbs, Omar Abdel-Wahab, Tsung Yen Cheng, Zeinab Abdel-Wahab, Bercedis Peterson, Scott K. Pruitt, O. Michael Colvin, Henry S. Friedman, Douglas Tyler

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)419-427
Number of pages9
JournalJournal of the American College of Surgeons
Volume199
Issue number3
DOIs
StatePublished - Sep 2004
Externally publishedYes

Fingerprint

Melphalan
Alkylating Agents
Glutathione Transferase
Melanoma
Extremities
Perfusion
Subcutaneous Tissue
Muscles
Therapeutics
Neoplasms
Cell Line
Skin
Heterografts
Glutathione
Rodentia
Lymph Nodes
Enzymes
In Vitro Techniques

Keywords

  • glutathione
  • glutathione-S-transferase
  • GSH
  • GST
  • L-PAM
  • L-phenylalanine mustard
  • SC
  • subcutaneous

ASJC Scopus subject areas

  • Surgery

Cite this

In-transit melanoma : The role of alkylating-agent resistance in regional therapy. / Grubbs, Elizabeth G.; Abdel-Wahab, Omar; Cheng, Tsung Yen; Abdel-Wahab, Zeinab; Peterson, Bercedis; Pruitt, Scott K.; Colvin, O. Michael; Friedman, Henry S.; Tyler, Douglas.

In: Journal of the American College of Surgeons, Vol. 199, No. 3, 09.2004, p. 419-427.

Research output: Contribution to journalArticle

Grubbs, EG, Abdel-Wahab, O, Cheng, TY, Abdel-Wahab, Z, Peterson, B, Pruitt, SK, Colvin, OM, Friedman, HS & Tyler, D 2004, 'In-transit melanoma: The role of alkylating-agent resistance in regional therapy', Journal of the American College of Surgeons, vol. 199, no. 3, pp. 419-427. https://doi.org/10.1016/j.jamcollsurg.2004.05.271
Grubbs, Elizabeth G. ; Abdel-Wahab, Omar ; Cheng, Tsung Yen ; Abdel-Wahab, Zeinab ; Peterson, Bercedis ; Pruitt, Scott K. ; Colvin, O. Michael ; Friedman, Henry S. ; Tyler, Douglas. / In-transit melanoma : The role of alkylating-agent resistance in regional therapy. In: Journal of the American College of Surgeons. 2004 ; Vol. 199, No. 3. pp. 419-427.
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abstract = "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.",
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AU - Abdel-Wahab, Omar

AU - Cheng, Tsung Yen

AU - Abdel-Wahab, Zeinab

AU - Peterson, Bercedis

AU - Pruitt, Scott K.

AU - Colvin, O. Michael

AU - Friedman, Henry S.

AU - Tyler, Douglas

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N2 - 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.

AB - 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.

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