Investigation for pancreatic cancer associated with hypoxia-inducible factor

手术是胰腺癌患者最有效的治疗方法。然而，几乎所有的胰腺癌患者都是因为远处转移而被诊断为不可切除的疾病，而可切除的胰腺癌患者的胰腺癌复发率很高。因此，开发有效的化疗药物治疗耐药胰腺癌是十分必要的。胰腺癌是一种低血供肿瘤，通过计算机断层扫描和对比剂显示为缺氧。胰腺癌细胞对化疗药物敏感，胰腺癌细胞的耐药是胰腺癌微环境的一个重要因素，本研究采用体外实验方法，测定了吉西他滨（GEM）、顺铂（CDDP）和5-氟尿嘧啶（5-FU）对胰腺癌细胞株MiaPaCa 2和PANC 1的IC_（50）。缺氧条件下MiapaCa 2对GEM的IC 50为72.1±12.1 ng/ml，常氧条件下为30.5±1.5 ng/ml（P=0.03）;缺氧条件下PANC 1对GEM的IC 50为5884.4±4590.0 ng/ml，常氧条件下为890.3±78.0 ng/ml（P=0.0006）。缺氧组与常氧组对顺铂和5-FU的敏感性无显著差异。此外，我们还利用微阵列技术对基因表达进行了研究。虽然缺氧诱导因子基因芯片未检测到，但缺氧诱导蛋白2、CXCR 4、血管生成素样4、内皮素2、胎盘生长因子和血管内皮生长因子相关蛋白等与缺氧和缺氧血管生成有关的基因在缺氧时表达增强，提示这些基因有可能成为胰腺癌治疗的新药。

Surgery is the most effective treatment for pancreatic cancer patients. However, almost pancreatic cancer patients have been diagnosed as unresectable disease by distant metastasis, and resectable pancreatic cancer patients have a high incidence of recurrence of pancreatic cancer. Therefore, it is necessary to develop the effective chemotherapy for chemoresistant pancreatic cancer. Pancreatic cancer is hypo-vascular tumor suggesting hypoxia by computed tomography with a contrast medium. It was thought that microenvironment of pancreas makes cancer cells induce chemoresistance of pancreatic cancer cells having chemosensitivity in vitro.We demonstrated the IC50 against pancreatic cancer cells line, MiaPaCa2 and PANC1 by Gemcitabine (GEM), CDDP and 5-FU. The IC50 of MiapaCa2 for GEM under hypoxia was 72.1±12.1 ng/ml compared with 30.5±1.5 ng/ml under normoxia (P=0.03), and that of PANC1 under hypoxia was 5884.4±4590.0 ng/ml compared with 890.3±78.0 ng/m under normoxia (P=0.0006). There was no significant difference between hypoxia and normoxia in chemosensitivities for CDDP and 5-FU. In addition, we conducted that the investigation of gene expression using microarray. Although hypoxia-inducible factor was not detected by microarray, the genes of hypoxia -inducible protein 2, CXCR4, angiopoietin-like 4, endothelin2, placental growth factor and cascular endothelial growth factor-related protein which were involved in hypoxia and angiogenesis expressed strongly by hypoxia.It was concluded that these genes have potential for the new drugs for pancreatic cancer.