Employing tumor hypoxia to enhance oncolytic viral therapy in breast cancer Journal Article
| Authors: | Pin, R. H.; Reinblatt, M.; Fong, Y. |
| Article Title: | Employing tumor hypoxia to enhance oncolytic viral therapy in breast cancer |
| Abstract: | Background Hypoxia is a common tumor condition correlated with therapeutic resistance. Ribonucleotide reductase (RR) is a rate-limiting enzyme for viral replication. We hypothesize that hypoxia-driven transcription of UL39, the gene encoding the large subunit of RR, would enhance herpes oncolytic viral therapy in breast cancer. Methods Hypoxia-inducible factor 1α (HIF-1α) ELISA was performed on MCF7 human breast cancer cells in hypoxia (1% O 2) or normoxia (21% O 2). A multimerized hypoxia-responsive enhancer was constructed (10xHRE) and functionally tested in a luciferase assay. 10xHRE was cloned upstream of the UL39 gene (10xHRE-UL39). MCF7 cells were transfected with 10xHRE-UL39, incubated in hypoxia or normoxia, and infected with G207. Cytotoxicity assays and viral titers were performed. Results HIF-1α levels increased 7-fold in hypoxic MCF7 cells (P <.001). 10xHRE increased luciferase gene expression 61-fold in hypoxia versus controls (P <.01). G207 cytotoxicity of 10xHRE-UL39-transfected, hypoxic MCF7 cells increased 74% versus mock-transfected, hypoxic MCF7 cells (P <.001). In normoxia, 10xHRE-UL39 transfection did not significantly improve G207 cytotoxicity. 10xHRE-UL39 transfection improved peak viral titers 69-fold in hypoxia (P <.005), with no significant difference in normoxia. Conclusion Hypoxia-driven RR production significantly enhances G207 cytotoxicity in hypoxic breast cancer cells, which would otherwise be resistant to herpes viral therapy alone. |
| Keywords: | controlled study; human cell; nonhuman; animal cell; breast cancer; gene expression; luciferase; cytotoxicity; cell line, tumor; breast neoplasms; enzyme linked immunosorbent assay; transcription factors; hypoxia; molecular cloning; statistical significance; genetic transfection; cancer cell; oncolytic virus; simplexvirus; cell hypoxia; virus replication; luciferases; cell strain mcf 7; hypoxia inducible factor 1alpha; enzyme assay; hypoxia-inducible factor 1, alpha subunit; humans; human; female; priority journal; article |
| Journal Title: | Surgery |
| Volume: | 136 |
| Issue: | 2 |
| ISSN: | 0039-6060 |
| Publisher: | Elsevier Inc. |
| Date Published: | 2004-08-01 |
| Start Page: | 199 |
| End Page: | 204 |
| Language: | English |
| DOI: | 10.1016/j.surg.2004.04.016 |
| PROVIDER: | scopus |
| PUBMED: | 15300180 |
| DOI/URL: | |
| Notes: | Surgery -- Cited By (since 1996):9 -- Export Date: 16 June 2014 -- CODEN: SURGA -- Source: Scopus |
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