This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend 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 Bartholomeusz, C. Articles by Ueno, N. T. Search for Related Content PubMed PubMed Citation Articles by Bartholomeusz, C. Articles by Ueno, N. T.

Bcl-2 Antisense Oligonucleotide Overcomes Resistance to E1A Gene Therapy in a Low HER2-Expressing Ovarian Cancer Xenograft Model

¹ Breast Cancer Translational Research Laboratory and Departments of ² Blood and Marrow Transplantation, ³ Breast Medical Oncology, ⁴ Urology, and ⁵ Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center; ⁶ Graduate School of Biomedical Sciences, The University of Texas Health Science Center, Houston, Texas; and ⁷ Department of Obstetrics and Gynecology, Tottori University School of Medicine, Yonago, Japan

Requests for reprints: Naoto T. Ueno, Department of Blood and Marrow Transplantation, Unit 448, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-792-8750; Fax: 713-794-4747; E-mail: nueno{at}mdanderson.org.

We are currently conducting clinical trials of E1A gene therapy for patients with ovarian cancer. The adenovirus type 5 E1A gene suppresses growth of ovarian cancer cells that overexpress HER-2/neu (HER2) and growth of some—but not all—that express low HER2. In HER2-overexpressing cells, suppression by E1A is predominantly by down-regulation of HER2, but the mechanism in low HER2-expressing cells is not fully understood. The adenoviral E1B protein has sequential and functional homology to Bcl-2 and prolongs the viability of adenovirus host cells by inhibiting E1A-induced apoptosis. Bcl-2 is overexpressed in ovarian cancer and participates in chemoresistance; we hypothesized that Bcl-2 inhibits E1A-induced apoptosis leading to resistance to E1A gene therapy. E1A suppressed colony formation of ovarian cancer cells that express low levels of Bcl-2 and HER2 (OVCAR-3 and OVCA 433), but enhanced colony formation in low HER2-, high Bcl-2–expressing ovarian cancer cells (2774 and HEY). Treating 2774 or HEY cells with antisense oligonucleotide Bcl-2 (Bcl-2-ASO) did not reduce cell viability. E1A combined with Bcl-2-ASO led to significant decreases in cell viability resulting from increased apoptosis relative to cells treated with E1A alone (P < 0.05). The increase in apoptosis was partly due to cytochrome c release and subsequently caspase-9 activation by Bcl-2-ASO. Finally, in an ovarian cancer xenograft model, treatment with Bcl-2-ASO did not prolong survival, but E1A plus Bcl-2-ASO did (P < 0.001). In conclusion, ovarian tumors overexpressing Bcl-2 may not respond well to E1A gene therapy, but treatment with a combination of E1A and Bcl-2-ASO may overcome this resistance.

This article has been cited by other articles:

				J. Low, Shuguang Huang, M. Dowless, W. Blosser, T. Vincent, S. Davis, J. Hodson, E. Koller, E. Marcusson, K. Blanchard, et al. High-Content Imaging Analysis of the Knockdown Effects of Validated siRNAs and Antisense Oligonucleotides J Biomol Screen, September 1, 2007; 12(6): 775 - 788. [Abstract] [PDF]

				H. Itamochi, J. Kigawa, Y. Kanamori, T. Oishi, C. Bartholomeusz, R. Nahta, F. J. Esteva, N. Sneige, N. Terakawa, and N. T. Ueno Adenovirus type 5 E1A gene therapy for ovarian clear cell carcinoma: a potential treatment strategy Mol. Cancer Ther., January 1, 2007; 6(1): 227 - 235. [Abstract] [Full Text] [PDF]