Tirone Thomas A, Wang Xaio-Ping, Templeton Nancy S, Lee Tim, Nguyen Liz, Fisher William, Brunicardi F Charles
Michael E. DeBakey Department of Surgery, Baylor College of Medicine, 6550 Fannin, Suite 1661, 77030, Houston, Texas, USA.
World J Surg. 2004 Aug;28(8):826-33. doi: 10.1007/s00268-004-7291-x. Epub 2004 Aug 3.
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.
正常胰腺的形成和胰岛素分泌的激活部分依赖于胰腺十二指肠同源盒基因1（PDX-1）的表达和激活。在多种人胰腺导管腺癌（PDA）细胞系中也检测到了PDX-1的表达。这使得构建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，我们利用大鼠胰岛素启动子（RIP-TK）控制下的单纯疱疹病毒胸苷激酶（TK）的表达，建立了PDA细胞的细胞特异性细胞毒性模型。我们已经表明，人PDA细胞中的细胞特异性细胞毒性取决于PDX-1的存在。我们的结果还证明，在严重联合免疫缺陷（SCID）小鼠中，通过腹腔脂质体基因递送方法给予RIP-TK并在短时间内进行更昔洛韦治疗，可以实现体内PDA特异性细胞毒性。此外，在所有六个新鲜分离的人胰腺癌标本和两个进行分组检测的肝转移样本中都发现了PDX-1蛋白，这表明在人类中使用RIP-TK基因治疗具有可行性。本研究可能为未来胰腺癌的治疗提供一种替代策略。
