Treatment of pancreatic cancer by HGF antagonist, NK4, through new drug delivery system. -Approach from bench to practice

肝细胞生长因子（HGF）作为肿瘤-间质相互作用的主要介质，通过促进肿瘤侵袭和转移参与胰腺癌的恶性行为。NK4是HGF的4个kringle片段，同时具有HGF拮抗剂和血管生成抑制剂的功能。在这一系列的实验中，我们已经清楚地表明，NK4可能是一个有希望的胰腺癌基因治疗分子。记录的结果如下：体外实验表明，8种人胰腺癌细胞均不同程度表达c-Met/HGF受体。HGF强烈刺激这些细胞的迁移和侵袭。重组NK4消除了胰腺癌细胞侵袭的增加。（中国医学杂志，2001）重组NK4腹腔注射抑制人胰腺癌移植到裸鼠胰腺的生长、侵袭和转移。NK4延长小鼠存活时间。(, 2001)。3.腺病毒介导的NK4（Ad-NK4）转染可显著抑制胰腺癌细胞的扩散和侵袭。此外，Ad-NK4显著抑制裸鼠皮下移植肿瘤的生长。（临床实验，2001）。4.在原位植入和肝转移模型中，基因工程分泌NK4的胰腺癌细胞的生长均受到显著抑制。其抗肿瘤作用主要是通过NK4作为血管生成抑制剂而非HGF拮抗剂来实现的。（临床癌症研究，2002）。5.在裸鼠腹膜播散模型中，每周腹腔注射Ad-NK4可抑制肿瘤结节的发展，并显著提高Ad-NK4处理小鼠的存活率。（癌症基因治疗，2002）。6.为了开发新的局部递送系统，我们制作了nk4转导的口腔黏膜上皮细胞（OMEC）片。omc片分泌的NK4抑制成纤维细胞诱导的胰腺癌细胞侵袭。nk4 -sheet抑制体内血管生成和生长。(临床癌症研究，2003

Hepatocyte growth factor(HGF) is involved in malignant behavior of pancreatic cancer as a major mediator in tumor-stromal interaction through enhancing tumor invasion and metastasis. NK4, a four kringle fragment of HGF, functions as both an HGF-antagonist and an angiogenesis inhibitor. In this series of the experiments, we have clearly indicated that NK4 could be a promising molecule for gene therapy for pancreatic cancer. Documented results are as follows.1.In vitro experiments showed that all of eight human pancreatic cancer cells expressed c-Met/HGF receptor at varying level. HGF strongly stimulated migration and invasion of these cells. Recombinant NK4 abolished the increased invasion of pancreatic cancer cells. (Br J Cancer,2001) 2.Intraperitoneal administration of recombinant NK4 inhibited the growth, invasion, and metastasis of human pancreatic cancer implanted into the pancreas of nude mice. NK4 prolonged survival time of mice. (Cancer Res,2001). 3.Adenovirally-mediated transfe … More r of NK4(Ad-NK4) markedly inhibited scattering and invasion of pancreatic cancer cells. Furthermore, Ad-NK4 significantly inhibited the growth of tumors subcutaneously transplanted to nude mice. (Clin Exp Metastas,2001). 4.Growth of pancreatic cancer cells genetically engineered to secrete NK4 were significantly inhibited in both the orthotopic implantation and liver metastasis models. The anti-tumor effect is mainly obtained by NK4's function as an angiogenesis inhibitor rather than as an HGF antagonist. (Clin Cancer Res,2002). 5.Weekly intraperitoneal injection of Ad-NK4 Suppress the development of tumor nodules in a nude mouse peritoneal dissemination model and survival of the AD-NK4-treated mice was significantly imporoved. (Cancer Gene Therapy,2002). 6.For the development of new local delivery system, NK4-transduced oral mucosal epithelial cell(OMEC) sheet was made. NK4 secreted from OMEC sheet suppressed fibroblast-induced invasion of pancreatic cancer cells. NK4-sheets inhibited both angiogenesis and growth in vivo. (Clin Cancer Res,2003) Less