Cell-specific cytotoxicity of human pancreatic adenocarcinoma cells using rat insulin promoter thymidine kinase-directed gene therapy.
Cell-specific cytotoxicity of human pancreatic adenocarcinoma cells using rat insulin promoter thymidine kinase-directed gene therapy.
复制标题
使用大鼠胰岛素启动子胸苷激酶定向基因治疗对人胰腺腺癌细胞的细胞特异性细胞毒性。
DOI：
10.1007/s00268-004-7291-x
复制
发表时间：
2004
影响因子：
2.6
通讯作者：
Brunicardi,FCharles
中科院分区：
文献类型：
--
作者：
Tirone,ThomasA;Wang,Xaio-Ping;Templeton,NancyS;Lee,Tim;Nguyen,Liz;Fisher,William;Brunicardi,FCharles
正常胰腺的形成和胰岛素产生的激活在一定程度上依赖于胰腺十二指肠同源框基因1(PDX-1)的表达和激活。PDX-1在多种人胰腺导管腺癌(PDA)细胞系中也有表达。这使得产生一种癌细胞特异性基因表达系统来治疗人类胰腺癌成为可能。在本研究中，我们建立了一种在大鼠胰岛素启动子(RIP-TK)控制下表达单纯疱疹病毒胸苷激酶(TK)的PDA细胞特异性细胞毒模型。我们已经证明，人PDA细胞的细胞特异性细胞毒性依赖于PDX-1的存在。我们的结果还表明，在严重联合免疫缺陷(SCID)小鼠中，RIP-TK使用脂质体基因传递方法，然后短期使用更昔洛韦治疗，可以实现体内PDA特异性细胞毒性。此外，在所有6例新鲜分离的人胰腺癌标本和2例肝转移瘤标本中都发现了PDX-1蛋白，这表明在人类中使用RIP-TK基因治疗是可行的。本研究可能为今后胰腺癌的治疗提供一种替代策略。
The formation of a normal pancreas and the activation of insulin production are, in part, dependent on the expression and activation of the pancreatic duodenal homeobox gene 1 (PDX-1). The expression of PDX-1 also has been detected in various human pancreatic ductal adenocarcinoma (PDA) cell lines. This has made it possible to generate a cancer cell-specific gene expression system to treat human pancreatic cancer. In this study, we have developed a cell-specific cytotoxic model of PDA cells using the expression of herpes simplex virus thymidine kinase (TK) under the control of the rat insulin promoter (RIP-TK). We have shown that the cell-specific cytotoxicity in human PDA cells depends on the presence of PDX-1. Our results also demonstrate that in vivo PDA-specific cytotoxicity can be achieved with RIP-TK using an intraperitoneal liposomal gene delivery method followed by a short period of ganciclovir treatment in severe combined immunodeficient (SCID) mice. Furthermore, PDX-1 protein was found in all six freshly isolated human pancreas cancer specimens and two liver metastasis samples that were group-tested, suggesting the feasibility of using RIP-TK gene therapy in humans. This study may provide an alternative strategy for the future treatment of pancreatic cancer.