This Article Full Text Full Text (PDF) Supplementary Data Correction (v67,p8422) 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 Post, D. E. Articles by Van Meir, E. G. Search for Related Content PubMed PubMed Citation Articles by Post, D. E. Articles by Van Meir, E. G.

Targeted Cancer Gene Therapy Using a Hypoxia Inducible Factor–Dependent Oncolytic Adenovirus Armed with Interleukin-4

Departments of ¹ Neurosurgery, ² Pathology, ³ Hematology/Oncology, and ⁴ Biostatistics Research and Informatics, ⁵ Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, and Departments of ⁶ Neurosurgery and ⁷ Microbiology & Immunology, State University of New York Upstate Medical University, Syracuse, New York

Requests for reprints: Dawn E. Post or Erwin G. Van Meir, Laboratory of Molecular Neuro-Oncology, Department of Neurosurgery, Winship Cancer Institute, 1365C Clifton Rd., N.E., Emory University, Atlanta, GA 30322. Phone: 404-778-5563; Fax: 404-778-5550; E-mail: postd{at}upstate.edu or evanmei{at}emory.edu.

There is a need for novel therapies targeting hypoxic cells in tumors. These cells are associated with tumor resistance to therapy and express hypoxia inducible factor-1 (HIF-1), a transcription factor that mediates metabolic adaptation to hypoxia and activates tumor angiogenesis. We previously developed an oncolytic adenovirus (HYPR-Ad) for the specific killing of hypoxic/HIF-active tumor cells, which we now armed with an interleukin-4 gene (HYPR-Ad-IL4). We designed HYPR-Ad-IL4 by cloning the Ad E1A viral replication and IL-4 genes under the regulation of a bidirectional hypoxia/HIF-responsive promoter. The IL-4 cytokine was chosen for its ability to induce a strong host antitumor immune response and its potential antiangiogenic activity. HYPR-Ad-IL4 induced hypoxia-dependent IL-4 expression, viral replication, and conditional cytolysis of hypoxic, but not normoxic cells. The treatment of established human tumor xenografts with HYPR-Ad-IL4 resulted in rapid and maintained tumor regression with the same potency as that of wild-type dl309-Ad. HYPR-Ad-IL4–treated tumors displayed extensive necrosis, fibrosis, and widespread viral replication. Additionally, these tumors contained a distinctive leukocyte infiltrate and prominent hypoxia. The use of an oncolytic Ad that locally delivers IL-4 to tumors is novel, and we expect that HYPR-Ad-IL4 will have broad therapeutic use for all solid tumors that have hypoxia or active HIF, regardless of tissue origin or genetic alterations. [Cancer Res 2007;67(14):6872–81]

This article has been cited by other articles:

				E. Ramakrishna, N. Woller, B. Mundt, S. Knocke, E. Gurlevik, M. Saborowski, N. Malek, M. P. Manns, T. Wirth, F. Kuhnel, et al. Antitumoral Immune Response by Recruitment and Expansion of Dendritic Cells in Tumors Infected with Telomerase-Dependent Oncolytic Viruses Cancer Res., February 15, 2009; 69(4): 1448 - 1458. [Abstract] [Full Text] [PDF]

				R L Cowen, E J Garside, B Fitzpatrick, M V Papadopoulou, and K J Williams Gene therapy approaches to enhance bioreductive drug treatment Br. J. Radiol., October 1, 2008; 81(Special_Issue_1): S45 - S56. [Abstract] [Full Text] [PDF]

				Correction: Oncolytic and Gene Therapy Using HYPR-Ad-IL4 Cancer Res., September 1, 2007; 67(17): 8422 - 8423. [Full Text] [PDF]