<i>E1A</i> Is an Oncogene and May Immortalize Normal Cells, Especially in Combination With Other Oncoproteins
Authors: Arnold Meisler, Gabriel N. Hortobagyi, Naoto Ueno, Mien-Chie Hung
Journal: Journal of Clinical Oncology (2001)

Article Tools SPECIAL DEPARTMENTS Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2001.19.21.4183 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 11689591 E1A Is an Oncogene and May Immortalize Normal Cells, Especially in Combination With Other Oncoproteins Arnold MeislerxArnold MeislerSearch for articles by this author Gabriel N. HortobagyixGabriel N. HortobagyiSearch for articles by this author , Naoto UenoxNaoto UenoSearch for articles by this author , Mien-Chie HungxMien-Chie HungSearch for articles by this author Show More Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PAThe University of Texas M.D. Anderson Cancer Center, Houston, TX https://doi.org/10.1200/JCO.2001.19.21.4183 First Page Full Text PDF Figures and Tables © 2001 by American Society of Clinical OncologyjcoJ Clin OncolJournal of Clinical OncologyJCO0732-183X1527-7755American Society of Clinical OncologyResponse01112001In Reply:We understand Dr Meisler’s relevant concerns and thank him for bringing this topic for discussion. We had similar concerns at the beginning of this project1 nearly 10 years ago when the antitumor activity of adenoviral types 2 and 5 E1A was initially suggested.2-4 Because of E1A’s ability to immortalize cells, its antitumor activity was overlooked and has not been fully appreciated. In the past decade, we and others have accumulated a significant amount of preclinical data demonstrating that E1A has multiple antitumor activities.E1A, similar to LT and c-myc, was originally shown to cooperate with E1B or the ras oncogene to immortalize primary cell cultures.5 However, recent studies indicate that the immortalization function is actually much more complicated than this. Immortalization requires LT (which inactivates both Rb and p53), ras, and telomerase activity.6 E1A, similar to LT in its ability to inactivate Rb, can stabilize p53. Furthermore, immortalization is a long-term process that usually requires a gene such as E1A to be expressed constitutively in the cell; eg, integration of E1A into the chromosome might be required for the gene to be consistently expressed and allow immortalization to occur. However, the E1A/liposome gene therapy described in our article is based on “transient expression,” which does not require E1A gene integration into the chromosome.Regarding the concern about ras and p53, the metastatic phenotypes induced by the ras oncogene in tumor cells were actually found to be suppressed by E1A.2 It has also been established that E1A can induce apoptosis through a p53-independent mechanism.7 In addition, we would like to emphasize that E1A has been shown to be associated with multiple antitumor activities, including downregulated HER2/neu, induction of apoptosis, and inhibition of metastasis and angiogenesis. Indeed, E1A has been reviewed and recognized as a tumor suppressor gene.8-10Although the type 2/5 E1A was initially classified as an “immortalizing oncogene,” the “immortalizing phenotypes” are really not synonymous with “transforming phenotypes.” In fact, many established epithelial cell lines have been immortalized but are not tumorigenic. Expression of the type 2/5 E1A gene itself does not induce transforming phenotypes in normal fibroblast cell lines,4 which is different from type 12 E1A. Before initiating a phase I clinical trial, we had demonstrated in nude mice that E1A-DC-Chol liposome had strong tumor-suppressing activity, resulting in almost 70% tumor-free survival in multiple orthotopic animal models11,12; however, 100% of the animals in the control group died within a short period of time. We also conducted studies in normal mice to evaluate the safety of the E1A-DC-Chol complex therapy. Cumulative doses of E1A-DC-Chol up to 40 times that proposed for the phase I clinical trial had no adverse effects.13,14 Based on the above findings, the phase I trial was reviewed by the Recomfinant DNA Advisory Committee, the United States Food and Drug Administration, and our institutional review board, and it was considered appropriate to proceed with its implementation. These reviews included extensive discussions of the various proposed biologic effects of E1A, including the concern voiced by Dr Meisler.Multiple clinical trials using an adenoviral competent virus, eg, Onyx 015,15 also introduced the E1A gene into the human body (E1A gene is required for replication of adenovirus). The results from these studies are encouraging and demonstrate the feasibility of this treatment without significant adverse effects.In conclusion, we appreciate the opportunity to discuss Dr Meisler’s concerns. However, no preclinical data suggest that E1A is tumorigenic; rather, they demonstrate that the E1A gene is associated with potent antitumor activities, providing justification for conducting this clinical trial. In addition, all appropriate safety studies were performed and appropriate regulatory processes were followed before the initiation of the phase I clinical trial.1. 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