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HSV-tk/GCV gene therapy mediated by EBV-LMP1 for EBV-associated cancer.

Lifang Y, Min T, Midan A, Ya C - J. Exp. Clin. Cancer Res. (2008)

Bottom Line: To investigate the feasibility of gene therapy in treating Epstein-Barr virus (EBV)-associated cancer by employing the suicide gene, herpes simplex virus thymidine kinase/ganciclovir (HSV-tk/GCV), which uses the signaling pathway through the HIV-long terminal repeat (LTR) gene which is expressed from a nuclear factor-kappaB (NF-kappaB)-binding motif-containing promoter that is regulated by EBV-latent membrane protein 1 (LMP1) via NF-kappaB.The activation of TK was increased after transfection of the pVLTR-tk into the EBV-LMP1 positive cells.After GCV treatment, the clonogenicity and survival of the cells substantially declined, and a bystander effect was also observed.

View Article: PubMed Central - HTML - PubMed

Affiliation: Molecular Biology Research Center, Cancer Research Institute, XiangYa School of Medicine, Central South University, ChangSha, Hunan, 410078, PR China. anglifang99@hotmail.com

ABSTRACT

Background: To investigate the feasibility of gene therapy in treating Epstein-Barr virus (EBV)-associated cancer by employing the suicide gene, herpes simplex virus thymidine kinase/ganciclovir (HSV-tk/GCV), which uses the signaling pathway through the HIV-long terminal repeat (LTR) gene which is expressed from a nuclear factor-kappaB (NF-kappaB)-binding motif-containing promoter that is regulated by EBV-latent membrane protein 1 (LMP1) via NF-kappaB.

Methods: First, we constructed the plasmid pVLTR-tk, which was regulated by EBV-LMP1 via NF-kappaB, and then investigated the cytotoxic effect of the pVLTR-tk/GCV on cancer cells, using MTT assays, clonogenic assays, flow cytometry, and animal experiments.

Results: The activation of TK was increased after transfection of the pVLTR-tk into the EBV-LMP1 positive cells. After GCV treatment, the clonogenicity and survival of the cells substantially declined, and a bystander effect was also observed. The LMP1 positive cells exhibited remarkable apoptosis following pVLTR-tk/GCV treatment, and the pVLTR-tk/GCV restrained tumor growth in vivo for EBV-LMP1 positive cancers.

Conclusion: The pVLTR-tk/GCV suicide gene system may be used as a new gene targeting strategy for EBV-associated cancer.

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Histopathological analysis of tumor tissues after pVLTR-tk/GCV treatment. A: CNE1+TK (400×); B: CNE1+TK+GCV (400×); C: CNE1-LMP1+TK (400×); D: CNE1-LMP1+TK+GCV (400×).
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Figure 7: Histopathological analysis of tumor tissues after pVLTR-tk/GCV treatment. A: CNE1+TK (400×); B: CNE1+TK+GCV (400×); C: CNE1-LMP1+TK (400×); D: CNE1-LMP1+TK+GCV (400×).

Mentions: Hematoxylin and eosin staining showed that the tumor status of the CNE1+TK group and that of the CNE1-LMP1+TK group were concordant with the pathology of the tissue. In the CNE1+TK+GCV group, there were some putrescence cells, whereas in the CNE1-LMP1+TK+GCV group, there were a great number of putrescence cells. Therefore, EBV-LMP1 is capable of enhancing the cytotoxic effect of pVLTR-tk/GCV (Figure 7).


HSV-tk/GCV gene therapy mediated by EBV-LMP1 for EBV-associated cancer.

Lifang Y, Min T, Midan A, Ya C - J. Exp. Clin. Cancer Res. (2008)

Histopathological analysis of tumor tissues after pVLTR-tk/GCV treatment. A: CNE1+TK (400×); B: CNE1+TK+GCV (400×); C: CNE1-LMP1+TK (400×); D: CNE1-LMP1+TK+GCV (400×).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2562992&req=5

Figure 7: Histopathological analysis of tumor tissues after pVLTR-tk/GCV treatment. A: CNE1+TK (400×); B: CNE1+TK+GCV (400×); C: CNE1-LMP1+TK (400×); D: CNE1-LMP1+TK+GCV (400×).
Mentions: Hematoxylin and eosin staining showed that the tumor status of the CNE1+TK group and that of the CNE1-LMP1+TK group were concordant with the pathology of the tissue. In the CNE1+TK+GCV group, there were some putrescence cells, whereas in the CNE1-LMP1+TK+GCV group, there were a great number of putrescence cells. Therefore, EBV-LMP1 is capable of enhancing the cytotoxic effect of pVLTR-tk/GCV (Figure 7).

Bottom Line: To investigate the feasibility of gene therapy in treating Epstein-Barr virus (EBV)-associated cancer by employing the suicide gene, herpes simplex virus thymidine kinase/ganciclovir (HSV-tk/GCV), which uses the signaling pathway through the HIV-long terminal repeat (LTR) gene which is expressed from a nuclear factor-kappaB (NF-kappaB)-binding motif-containing promoter that is regulated by EBV-latent membrane protein 1 (LMP1) via NF-kappaB.The activation of TK was increased after transfection of the pVLTR-tk into the EBV-LMP1 positive cells.After GCV treatment, the clonogenicity and survival of the cells substantially declined, and a bystander effect was also observed.

View Article: PubMed Central - HTML - PubMed

Affiliation: Molecular Biology Research Center, Cancer Research Institute, XiangYa School of Medicine, Central South University, ChangSha, Hunan, 410078, PR China. anglifang99@hotmail.com

ABSTRACT

Background: To investigate the feasibility of gene therapy in treating Epstein-Barr virus (EBV)-associated cancer by employing the suicide gene, herpes simplex virus thymidine kinase/ganciclovir (HSV-tk/GCV), which uses the signaling pathway through the HIV-long terminal repeat (LTR) gene which is expressed from a nuclear factor-kappaB (NF-kappaB)-binding motif-containing promoter that is regulated by EBV-latent membrane protein 1 (LMP1) via NF-kappaB.

Methods: First, we constructed the plasmid pVLTR-tk, which was regulated by EBV-LMP1 via NF-kappaB, and then investigated the cytotoxic effect of the pVLTR-tk/GCV on cancer cells, using MTT assays, clonogenic assays, flow cytometry, and animal experiments.

Results: The activation of TK was increased after transfection of the pVLTR-tk into the EBV-LMP1 positive cells. After GCV treatment, the clonogenicity and survival of the cells substantially declined, and a bystander effect was also observed. The LMP1 positive cells exhibited remarkable apoptosis following pVLTR-tk/GCV treatment, and the pVLTR-tk/GCV restrained tumor growth in vivo for EBV-LMP1 positive cancers.

Conclusion: The pVLTR-tk/GCV suicide gene system may be used as a new gene targeting strategy for EBV-associated cancer.

Show MeSH
Related in: MedlinePlus