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Int. J. Mol. Sci. 2016, 17(6), 891; doi:10.3390/ijms17060891

Intravenous Administration Is an Effective and Safe Route for Cancer Gene Therapy Using the Bifidobacterium-Mediated Recombinant HSV-1 Thymidine Kinase and Ganciclovir

Molecular Medicine & Cancer Research Center, Department of Biochemistry & Molecular Biology, Chongqing Medical University, Yuzhong District, Yi XueYuan Road, Number 1, Chongqing 400016, China
These authors contributed equally to this work.
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Author to whom correspondence should be addressed.
Academic Editor: Ge Zhang
Received: 20 April 2016 / Revised: 25 May 2016 / Accepted: 26 May 2016 / Published: 6 June 2016
(This article belongs to the Special Issue Translational Molecular Medicine & Molecular Drug Discovery)
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Abstract

The herpes simplex virus thymidine kinase/ganciclovir (HSV TK/GCV) system is one of the best studied cancer suicide gene therapy systems. Our previous study showed that caspase 3 expression was upregulated and bladder tumor growth was significantly reduced in rats treated with a combination of Bifidobacterium (BF) and HSV TK/GCV (BF-rTK/GCV). However, it was raised whether the BF-mediated recombinant thymidine kinase combined with ganciclovir (BF-rTK/GCV) was safe to administer via venous for cancer gene therapy. To answer this question, the antitumor effects of BF-rTK/GCV were mainly evaluated in a xenograft nude mouse model bearing MKN-45 gastric tumor cells. The immune response, including analysis of cytokine profiles, was analyzed to evaluate the safety of intramuscular and intravenous injection of BF-rTK in BALB/c mice. The results suggested that gastric tumor growth was significantly inhibited in vivo by BF-rTK/GCV. However, the BF-rTK/GCV had no effect on mouse body weight, indicating that the treatment was safe for the host. The results of cytokine profile analysis indicated that intravenous injection of a low dose of BF-rTK resulted in a weaker cytokine response than that obtained with intramuscular injection. Furthermore, immunohistochemical analysis showed that intravenous administration did not affect the expression of immune-associated TLR2 and TLR4. Finally, the BF-rTK/GCV inhibited vascular endothelial growth factor (VEGF) expression in mouse model, which is helpful for inhibiting of tumor angiogenesis. That meant intravenous administration of BF-rTK/GCV was an effective and safe way for cancer gene therapy. View Full-Text
Keywords: cancer; gene therapy; Bifidobacterium; safety; thymidine kinase; ganciclovir; vascular endothelial growth factor (VEGF) cancer; gene therapy; Bifidobacterium; safety; thymidine kinase; ganciclovir; vascular endothelial growth factor (VEGF)
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Zhou, H.; He, Z.; Wang, C.; Xie, T.; Liu, L.; Liu, C.; Song, F.; Ma, Y. Intravenous Administration Is an Effective and Safe Route for Cancer Gene Therapy Using the Bifidobacterium-Mediated Recombinant HSV-1 Thymidine Kinase and Ganciclovir. Int. J. Mol. Sci. 2016, 17, 891.

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