Bcl-2 and glutathione depletion sensitizes B16 melanoma to combination therapy and eliminates metastatic disease.
Clin Cancer Res
; 13(9): 2658-66, 2007 May 01.
Article
em En
| MEDLINE
| ID: mdl-17473197
ABSTRACT
PURPOSE:
Advanced melanoma resists all current therapies, and metastases in the liver are particularly problematic. Prevalent resistance factors include elevated glutathione (GSH) and increased expression of bcl-2 in melanoma cells. GSH has pleiotropic effects promoting cell growth and broad resistance to therapy, whereas Bcl-2 inhibits the activation of apoptosis and contributes to elevation of GSH. This study determined the in vivo efficacy of combination therapies administered while GSH and Bcl-2 were individually and simultaneously decreased in metastatic melanoma lesions. EXPERIMENTALDESIGN:
Highly metastatic murine B16 melanoma (B16M-F10) cells have elevated levels of both GSH and Bcl-2. B16M-F10 cells were injected i.v. to establish metastatic lesions in vivo. GSH was decreased using an L-glutamine--enriched diet and administration of verapamil and acivicin, whereas Bcl-2 was reduced using oligodeoxynucleotide G3139. Paclitaxel, X-rays, tumor necrosis factor-alpha, and IFN-gamma were administered as a combination therapy.RESULTS:
Metastatic cells were isolated from liver to confirm the depletion of GSH and Bcl-2 in vivo. Reduction of Bcl-2 and GSH, combined with partial therapies, decreased the number and volume of invasive B16M-F10 foci in liver by up to 99% (P<0.01). The full combination of paclitaxel, X-rays, and cytokines eliminated B16M-F10 cells from liver and all other systemic disease, leading to long-term survival (>120 days) without recurrence in 90% of mice receiving the full therapy. Toxicity was manageable; the mice recovered quickly, and hematology and clinical chemistry data were representative of accepted clinical toxicities.CONCLUSIONS:
Our results suggest a new strategy to induce regression of late-stage metastatic melanoma.
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Base de dados:
MEDLINE
Assunto principal:
Neoplasias Cutâneas
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Melanoma Experimental
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Fator de Necrose Tumoral alfa
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Paclitaxel
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Proteínas Proto-Oncogênicas c-bcl-2
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Glutationa
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Antineoplásicos Fitogênicos
Idioma:
En
Ano de publicação:
2007
Tipo de documento:
Article