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

被引：15
|
作者：
Zhou, Huicong [1 ]
He, Zhiliang [1 ]
Wang, Changdong [1 ]
Xie, Tingting [1 ]
Liu, Lin [1 ]
Liu, Chuanyang [1 ]
Song, Fangzhou [1 ]
Ma, Yongping [1 ]
机构：
[1] Chongqing Med Univ, Dept Biochem & Mol Biol, Mol Med & Canc Res Ctr, Yi XueYuan Rd, Chongqing 400016, Peoples R China
来源：
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES | 2016年 / 17卷 / 06期
关键词：
cancer; gene therapy; Bifidobacterium; safety; thymidine kinase; ganciclovir; vascular endothelial growth factor (VEGF); INNATE IMMUNE-RESPONSE; DELIVERY-SYSTEM; ADENOVIRUS; EXPRESSION; VECTORS; ANGIOGENESIS; LONGUM; ENDOSTATIN; BACTERIA; VACCINE;
D O I：
10.3390/ijms17060891
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
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.
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页数：18
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