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Technical Knockdown in Melanoma

Oblimersen sodium improved the efficacy of systemic chemotherapy in patients with advanced melanoma.

The survival rate of patients with advanced melanoma has not improved in more than 30 years. Drug-resistant melanoma is common and has been partially attributed to overexpression of Bcl-2, an antiapoptotic protein localized to the mitochondria. Previous small studies suggested that pharmacologic reduction or targeted inactivation of Bcl-2 can amplify anticancer responses to chemotherapy. Oblimersen sodium is an 18-base antisense oligonucleotide that has been shown to downregulate Bcl-2 expression and increase chemotherapy-induced apoptosis in human cancer xenografts. The antisense pharmacologic strategy decreases expression of specific proteins by blocking their translation from mRNA.

To evaluate whether oblimersen sodium improved the efficacy of systemic chemotherapy for advanced melanoma, researchers randomized 771 patients to receive either oblimersen-dacarbazine or dacarbazine alone. After at least 24 months of follow-up, median survival in the oblimersen-dacarbazine group was 9.0 months, compared with 7.8 months in the dacarbazine-alone group (hazard ratio, 0.87; 95% confidence interval, 0.75–1.01; P=0.077). The overall response rate (complete plus partial responses) was 13.5% for oblimersen-dacarbazine recipients and 7.5% for dacarbazine-only recipients (P=0.007). The addition of oblimersen significantly increased survival in patients whose baseline serum lactate dehydrogenase (LDH) levels were not elevated. However, among patients with elevated LDH, no significant between-group differences were found, which suggests that baseline LDH value should be used to identify the patients most likely to benefit from oblimersen. Oblimersen increased the incidence of neutropenia and thrombocytopenia, but the incidences of severe neutropenia (21%) and thrombocytopenia (16%) were substantially lower than the incidences associated with other therapies for advanced melanoma.

Comment: Oblimersen should not be viewed as a home run in melanoma treatment, but it does represent some success for the new strategy of using whole-body antisense chemotherapy against selected proteins (here, Bcl-2). Where traditional combined approaches have not proven beneficial, more-targeted approaches hold promise. For example, this year’s Nobel Prize in Medicine was awarded for another form of "knockdown" technology — RNA interference to selectively reduce the expression of an individual protein in a cell. With a better understanding of the proteins or oncogenes that drive melanoma tumorigenesis, more-refined methodologies for inhibiting or eliminating these proteins might become the next generation of molecular therapeutics.

— Hensin Tsao, MD, PhD

Published in Journal Watch Dermatology December 8, 2006

Citation(s):

Bedikian AY et al. Bcl-2 antisense (oblimersen sodium) plus dacarbazine in patients with advanced melanoma: The Oblimersen Melanoma Study Group. J Clin Oncol 2006 Oct 10; 24:4738-45.

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