Modulation of resistance to regional chemotherapy in the extremity melanoma model

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

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)210-218
Number of pages9
JournalSurgery
Volume136
Issue number2
DOIs
StatePublished - Aug 2004
Externally publishedYes

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Melanoma
Extremities
Melphalan
Drug Therapy
Buthionine Sulfoximine
Neoplasms
Survival
Growth
Nude Rats
Drug and Narcotic Control
Heterografts
Glutathione
Therapeutics
Perfusion
Proteins

ASJC Scopus subject areas

  • Surgery

Cite this

Grubbs, E. G., Ueno, T., Abdel-Wahab, O., Cheng, T. Y., Pruitt, S. K., Michael Colvin, O., ... Tyler, D. (2004). Modulation of resistance to regional chemotherapy in the extremity melanoma model. Surgery, 136(2), 210-218. https://doi.org/10.1016/j.surg.2004.04.021

Modulation of resistance to regional chemotherapy in the extremity melanoma model. / Grubbs, Elizabeth G.; Ueno, Tomio; Abdel-Wahab, Omar; Cheng, Tsung Yen; Pruitt, Scott K.; Michael Colvin, O.; Friedman, Henry S.; Tyler, Douglas.

In: Surgery, Vol. 136, No. 2, 08.2004, p. 210-218.

Research output: Contribution to journalArticle

Grubbs, EG, Ueno, T, Abdel-Wahab, O, Cheng, TY, Pruitt, SK, Michael Colvin, O, Friedman, HS & Tyler, D 2004, 'Modulation of resistance to regional chemotherapy in the extremity melanoma model', Surgery, vol. 136, no. 2, pp. 210-218. https://doi.org/10.1016/j.surg.2004.04.021
Grubbs EG, Ueno T, Abdel-Wahab O, Cheng TY, Pruitt SK, Michael Colvin O et al. Modulation of resistance to regional chemotherapy in the extremity melanoma model. Surgery. 2004 Aug;136(2):210-218. https://doi.org/10.1016/j.surg.2004.04.021
Grubbs, Elizabeth G. ; Ueno, Tomio ; Abdel-Wahab, Omar ; Cheng, Tsung Yen ; Pruitt, Scott K. ; Michael Colvin, O. ; Friedman, Henry S. ; Tyler, Douglas. / Modulation of resistance to regional chemotherapy in the extremity melanoma model. In: Surgery. 2004 ; Vol. 136, No. 2. pp. 210-218.
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AU - Friedman, Henry S.

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N2 - 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.

AB - 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.

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