title: Adenovirus type 5 E1A gene therapy for ovarian clear cell carcinoma: a potential treatment strategy.
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, because 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.
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, Unit 448, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Itamochi
authors.forename: Junzo
authors.initials: J
authors.lastname: Kigawa
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Kanamori
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Oishi
authors.forename: Chandra
authors.initials: C
authors.lastname: Bartholomeusz
authors.forename: Rita
authors.initials: R
authors.lastname: Nahta
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Esteva
authors.forename: Nour
authors.initials: N
authors.lastname: Sneige
authors.forename: Naoki
authors.initials: N
authors.lastname: Terakawa
authors.forename: Naoto T
authors.initials: NT
authors.lastname: Ueno
mesh_terms: D018262:Adenocarcinoma, Clear Cell / Q000473:pathology / Q000628:therapy*; D017500:Adenovirus E1A Proteins / Q000235:genetics*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000187:drug effects; D010051:Ovarian Neoplasms / Q000473:pathology / Q000628:therapy*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D016019:Survival Analysis; D013816:Thermodynamics; D000068878:Trastuzumab; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D017500:Adenovirus E1A Proteins; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; D016159:Tumor Suppressor Protein p53