Co-expression of herpes simplex virus thymidine kinase and Escherichia coli nitroreductase by an hTERT-driven adenovirus vector in breast cancer cells results in additive anti-tumor effects
| Autor: | Xianghui Yu, Qingzhe Dong, Yang Zhan, Bin Yu, Xiao Zha, Wei Kong, Xizhen Zhang, Yu Zhang, Yonege Wu |
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| Rok vydání: | 2011 |
| Předmět: |
Cancer Research
viruses Aziridines Genetic Vectors Antineoplastic Agents Breast Neoplasms medicine.disease_cause Thymidine Kinase Adenoviridae Viral vector Mice Retrovirus Cell Line Tumor Escherichia coli medicine Animals Humans Simplexvirus Telomerase reverse transcriptase Telomerase Mice Inbred BALB C Oncogene biology Cancer General Medicine Suicide gene Flow Cytometry biology.organism_classification medicine.disease Herpes simplex virus Oncology Thymidine kinase Cancer research Female HeLa Cells |
| Zdroj: | Oncology Reports. |
| ISSN: | 1791-2431 1021-335X |
| DOI: | 10.3892/or.2011.1285 |
| Popis: | Breast cancers especially in the late and metastatic stages remain refractory to treatment despite advances in surgical techniques and chemotherapy. Tumor-specific promoter-directed suicide gene therapy and adenoviral technology can be promising strategies for such advanced disease. Previous studies suggested that combining herpes simplex virus thymidine kinase (HSV-TK) and ganciclovir (GCV) with Escherichia coli nitroreductase (Coli.NTR) and 5-(azaridin-1-yl)-2, 4-dinitrobenzamide (CB1954) by a recombinant retrovirus delivery system resulted in a co-operative killing effect in vitro. We constructed a bicistronic adenovirus type 5 (Ad5)-based vector which co-expresses herpes HSV-TK and Coli.NTR under the control of the human telomerase reverse transcriptase (hTERT) promoter and SV40 enhancer. NTR gene expression mediated by an internal ribosome entry site (IRES) was inserted after the hTERT and HSV-TK sequences. Anti-tumor activities of the novel vector, Ad-hT-TK/NTR-enh, combined with prodrugs were evaluated in human breast cancer cells (ZR-75-30, MCF-7) in vitro and in vivo. We showed that expression of HSV-TK and NTR genes by Ad-hT-TK/NTR-enh in combination with GCV and CB1954 resulted in specific and significant cytotoxic effects in breast cancer cells in vitro. The anti-tumor activity of this system was more efficient than that from a single suicide gene, and only slightly lower than by HSV-TK and NTR driven from separate hTERT promoters in vitro and in vivo while the total amount of adenovirus of Ad-hT-TK/NTR-enh was half that of Ad-hT-TK-enh+Ad-hT-NTR-enh. These results suggest that suicide genes HSV-TK and NTR mediated by a single adenovirus vector under the control of an enhanced hTERT promoter results in additive anti-tumor effects and may provide a relatively safe strategy for the treatment of breast cancer by tumor-specific targeting. |
| Databáze: | OpenAIRE |
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