Research Articles: Therapeutics, Targets, and Development

Adenovirus type 5 E1A gene therapy for ovarian clear cell carcinoma: a potential treatment strategy

^{1 1}Department of Obstetrics and Gynecology, Tottori University School of Medicine, Nishicho, Yonago, Japan; ²Breast Cancer Translational Research Laboratory and Departments of ³Breast Medical Oncology, ⁴Molecular and Cellular Oncology, ⁵Pathology, and ⁶Stem Cell Transplantation and Cellular Therapy, The University of Texas M. D. Anderson Cancer Center, Houston, Texas

^* To whom correspondence should be addressed. E-mail: nueno{at}mdanderson.org.

	Abstract

Resistance of ovarian clear cell carcinoma (CCC) to platinum-based chemotherapy is associated with poor prognosis, and an effective treatment for advanced disease is urgently needed. HER2/neu is up-regulated more often in CCC than in other histologic types of epithelial ovarian cancer. The purpose of this study was to assess possible treatment for ovarian CCC with the anti-HER2 antibody trastuzumab or human adenovirus type 5 E1A. We treated 10 CCC cell lines with trastuzumab or E1A and assessed cell viability, proliferation, and colony formation and the expression of HER2 and wild-type p53 proteins and molecules downstream of those signaling pathways. HER2 protein was detected at various levels in all 10 cell lines by Western blotting and in 5 CCC cell lines by immunohistochemical staining; HER2 gene amplification was detected (by fluorescence in situ hybridization) in only one cell line (RMG-I). Trastuzumab did not inhibit proliferation in any of the four CCC cell lines tested (RMG-I, SKOV-2, OVTOKO, and OVSAYO). However, transfection with E1A (as compared with control vectors) reduced colony formation in all 10 CCC cell lines regardless of HER2 expression level. Infection of RMG-I and SMOV-2 cells with an adenoviral vector encoding E1A led to significant (P < 0.05) suppression of proliferation and enhancement of cell death; this effect required stabilization of p53 (but not p73) protein and was associated with the up-regulation of Bax and the cleavage of caspase-9. Other mechanisms, such as p53-independent apoptosis, may also be involved in E1A-mediated cell death in CCC. Finally, treatment with E1A prolonged survival in a CCC xenograft model (P < 0.001). E1A gene therapy, becAuthorListse of its ability to stabilize wild-type p53, is worth exploring as a treatment modality for women with ovarian CCC, which typically expresses wild-type p53. [Mol Cancer Ther 2007;6(1):227-35]

Key Words: ovarian carcinoma, clear cell, E1A, gene therapy, Her-2/neu

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