Modulation of resistance to regional chemotherapy in the extremity melanoma model.
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.
Grubbs
Elizabeth G
EG
Departments of General Surgery, Internal Medicine, and Neurosurgery, Duke University Medical Center, Durham, NC 27710, USA.
Ueno
Tomio
T
Abdel-Wahab
Omar
O
Cheng
Tsung-Yen
TY
Pruitt
Scott K
SK
Michael Colvin
O
O
Friedman
Henry S
HS
Tyler
Douglas S
DS
D000818:Animals; D019328:Buthionine Sulfoximine / Q000008:administration & dosage; D010478:Chemotherapy, Cancer, Regional Perfusion / Q000379:methods*; D019008:Drug Resistance, Neoplasm; D005260:Female; D005978:Glutathione / Q000032:analysis; D008545:Melanoma / Q000188:drug therapy*; D008558:Melphalan / Q000008:administration & dosage; D051381:Rats
D019328:Buthionine Sulfoximine; D005978:Glutathione; D008558:Melphalan