Intravenous Administration Is an Effective and Safe Route for Cancer Gene Therapy Using the Bifidobacterium-Mediated Recombinant HSV-1 Thymidine Kinase and Ganciclovir.
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.
Molecular Medicine &amp; Cancer Research Center, Department of Biochemistry &amp; Molecular Biology, Chongqing Medical University, Yuzhong District, Yi XueYuan Road, Number 1, Chongqing 400016, China. zhczb@163.com.
Huicong
H
Zhou
Molecular Medicine &amp; Cancer Research Center, Department of Biochemistry &amp; Molecular Biology, Chongqing Medical University, Yuzhong District, Yi XueYuan Road, Number 1, Chongqing 400016, China. jk0072007@163.com.
Zhiliang
Z
He
Molecular Medicine &amp; Cancer Research Center, Department of Biochemistry &amp; Molecular Biology, Chongqing Medical University, Yuzhong District, Yi XueYuan Road, Number 1, Chongqing 400016, China. cdwhust@163.com.
Changdong
C
Wang
Molecular Medicine &amp; Cancer Research Center, Department of Biochemistry &amp; Molecular Biology, Chongqing Medical University, Yuzhong District, Yi XueYuan Road, Number 1, Chongqing 400016, China. 18716461018@163.com.
Tingting
T
Xie
Molecular Medicine &amp; Cancer Research Center, Department of Biochemistry &amp; Molecular Biology, Chongqing Medical University, Yuzhong District, Yi XueYuan Road, Number 1, Chongqing 400016, China. 15086785450@163.com.
Lin
L
Liu
Molecular Medicine &amp; Cancer Research Center, Department of Biochemistry &amp; Molecular Biology, Chongqing Medical University, Yuzhong District, Yi XueYuan Road, Number 1, Chongqing 400016, China. 13883688451@163.com.
Chuanyang
C
Liu
Molecular Medicine &amp; Cancer Research Center, Department of Biochemistry &amp; Molecular Biology, Chongqing Medical University, Yuzhong District, Yi XueYuan Road, Number 1, Chongqing 400016, China. fzsongcq@163.com.
Fangzhou
F
Song
Molecular Medicine &amp; Cancer Research Center, Department of Biochemistry &amp; Molecular Biology, Chongqing Medical University, Yuzhong District, Yi XueYuan Road, Number 1, Chongqing 400016, China. yongpingm@yahoo.com.
Yongping
Y
Ma
D061605:Administration, Intravenous; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001644:Bifidobacterium / Q000502:physiology*; D015415:Biomarkers; D053181:Caspase 8 / Q000378:metabolism; D045744:Cell Line, Tumor; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D015774:Ganciclovir / Q000008:administration & dosage / Q000494:pharmacology*; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000008:administration & dosage / Q000009:adverse effects / Q000235:genetics*; D018259:Herpesvirus 1, Human / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D015398:Signal Transduction / Q000187:drug effects; D013937:Thymidine Kinase / Q000235:genetics*; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
D015415:Biomarkers; D016207:Cytokines; D051195:Toll-Like Receptor 2; D013937:Thymidine Kinase; C092717:thymidine kinase 1; D053181:Caspase 8; D015774:Ganciclovir
Bifidobacterium; cancer; ganciclovir; gene therapy; safety; thymidine kinase; vascular endothelial growth factor (VEGF)