| Autor: |
Post DE; Department of Neurosurgery, Winship Cancer Institute, Emory University School of Medicine, 1365C Clifton Road, Atlanta, GA 30322, USA. postd@upstate.ede, Sandberg EM, Kyle MM, Devi NS, Brat DJ, Xu Z, Tighiouart M, Van Meir EG |
| Jazyk: |
angličtina |
| Zdroj: |
Cancer research [Cancer Res] 2007 Jul 15; Vol. 67 (14), pp. 6872-81. |
| DOI: |
10.1158/0008-5472.CAN-06-3244 |
| Abstrakt: |
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. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
|
