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

点击翻译按钮获取中文摘要

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