Department of Urology, First Affiliated Hospital, Chongqing Medical University, Chongqing, China.
J Exp Clin Cancer Res. 2009 Dec 16;28(1):155. doi: 10.1186/1756-9966-28-155.
Bladder cancer is the ninth most common malignancy in the world. Successful clinical management remains a challenge. In order To search for novel targeted and efficacious treatment, we sought to investigate anti-tumor activity of BI-TK suicide gene therapy system in a rat model of bladder tumors. We first constructed and tested an anaerobic Bifidobacterium infantis-mediated thymidine kinase (BI-TK) suicide gene therapy system. To test the in vivo efficacy of this system, we established a rat model of bladder tumors, which was induced by N-methyl-nitrosourea perfusion. Bifidobacterium infantis containing the HSV-TK (i.e., BI-TK) were constructed by transformation of recombinant plasmid pGEX - TK. The engineered BI-TK was injected into tumor-bearing rats via tail vein, followed by intraperitoneal injection of ganciclovir (GCV). Using the rat model of bladder tumors, we found that bladder tumor burdens were significantly lower in the rats treated with BI-TK/GCV group than that treated with normal saline control group (p <0.05). While various degrees of apoptosis of the tumor cells were detected in all groups using in situ TUNEL assay, apoptosis was mostly notable in the BI-TK/GCV treatment group. Immunohistochemical staining further demonstrated that the BI-TK/GCV treatment group had the highest level of caspase3 protein expression than that of the empty plasmid group and normal saline group (p < 0.05). Thus, our results demonstrate that the Bifidobacterium infantis-mediated TK/GCV suicide gene therapy system can effectively inhibit rat bladder tumor growth, possibly through increasing caspase 3 expression and inducing apoptosis.
膀胱癌是全球第 9 大常见恶性肿瘤。成功的临床管理仍然是一个挑战。为了寻找新的靶向和有效的治疗方法，我们试图在膀胱癌大鼠模型中研究 BI-TK 自杀基因治疗系统的抗肿瘤活性。我们首先构建并测试了一种厌氧双歧杆菌介导的胸苷激酶（BI-TK）自杀基因治疗系统。为了测试该系统的体内疗效，我们建立了膀胱癌大鼠模型，该模型通过 N-甲基-N-亚硝脲灌注诱导。通过转化重组质粒 pGEX-TK，构建了含有单纯疱疹病毒胸苷激酶（即 BI-TK）的双歧杆菌婴儿。将工程化的 BI-TK 通过尾静脉注射到荷瘤大鼠中，然后腹腔内注射更昔洛韦（GCV）。使用膀胱癌大鼠模型，我们发现 BI-TK/GCV 治疗组的膀胱癌负担明显低于生理盐水对照组（p<0.05）。虽然原位 TUNEL 检测显示所有组的肿瘤细胞均有不同程度的凋亡，但 BI-TK/GCV 治疗组的凋亡最为明显。免疫组织化学染色进一步表明，BI-TK/GCV 治疗组的 caspase3 蛋白表达水平高于空质粒组和生理盐水组（p<0.05）。因此，我们的结果表明，双歧杆菌介导的 TK/GCV 自杀基因治疗系统可以有效抑制大鼠膀胱癌的生长，可能通过增加 caspase3 表达和诱导细胞凋亡。
