This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gollob, J. A. Articles by Sciambi, C. J. Search for Related Content PubMed PubMed Citation Articles by Gollob, J. A. Articles by Sciambi, C. J.

Decitabine Up-regulates S100A2 Expression and Synergizes with IFN- to Kill Uveal Melanoma Cells

Authors' Affiliations: ¹ Division of Medical Oncology, Department of Medicine, Duke University, and ² Division of Hematology and Oncology, Geriatrics Research, Education and Clinical Center, Department of Medicine, Durham VA Medical Center, Durham, North Carolina

Requests for reprints: Jared A. Gollob, Duke University Medical Center, DUMC Box 3441, Durham, NC 27710. Phone: 919-668-3979; Fax: 919-668-2163; E-mail: jared.gollob{at}duke.edu.

Purpose: Metastatic uveal melanoma is resistant to conventional chemotherapy and immunotherapy. In this study, we investigated the responsiveness of uveal melanoma cell lines to IFNs and the hypomethylating agent decitabine.

Experimental Design: The uveal melanoma cell lines 92-1, UW-1, OCM-1, and MKT-BR were exposed to varying concentrations of IFN-, IFN-, and decitabine, alone and in combination. The effects of decitabine on gene expression were examined using DNA microarray analysis.

Results: We found that IFN- and decitabine induced cell death in uveal melanoma. Whereas a high concentration of IFN- (1,000 units/mL) was required to induce cell death, we observed a dose-related increase in cell death when decitabine was used at a range of 0.1 to 10 µmol/L. Strikingly, 1 µmol/L decitabine synergized with 10 to 1,000 units/mL IFN- to induce massive cell death. In contrast, decitabine had no effect on three cutaneous melanoma cell lines and exhibited no synergy with either IFN. In uveal melanoma, decitabine up-regulated the expression of genes involved in growth control and apoptosis and down-regulated genes that have been implicated in the malignant phenotype of cutaneous melanoma. The gene up-regulated to the greatest degree by decitabine and whose expression showed a dose-effect across the three concentrations of decitabine was S100A2, a putative tumor suppressor. The genes modulated by decitabine in uveal melanoma were largely unaffected in cutaneous melanoma.

Conclusions: These findings form a basis for testing the decitabine/IFN- combination in metastatic uveal melanoma and for exploring the role of S100A2 in the susceptibility of uveal melanoma to IFN-mediated cell death.

This article has been cited by other articles:

				J. Begley and A. Ribas Targeted Therapies to Improve Tumor Immunotherapy Clin. Cancer Res., July 15, 2008; 14(14): 4385 - 4391. [Abstract] [Full Text] [PDF]