| Cyclooxygenase(COX) is a rate-limiting enzyme in the conversion of arachidonic acid to prostaglandins and other eicosanoids. Two isoforms of COX have been identified, COX-1 and COX-2. COX-2 activity could be increased during chronic inflammation. COX-2 is highly expressed in gastrointestinal carcinomas. COX-2 inhibitors have shown the effects of anti-cancer. In spite of considerable progress in image diagnostics, early diagnosis of pancreatic cancer is still difficult due to the lack of symptoms and the elusive workup. Pancreatic tumour remains a major therapeutic challenge because of very poor prognosis. Radiotherapy and chemotherapy are usually ineffective. Therefore, other therapeutic approaches for treatment of pancreatic tumour need to be explored. No expression of COX-2 has been detected in normal pancreatic tissue. However, COX-2 expression is up-regulated in human pancreatic cancer. Thus, the effects of COX-2 inhibitors on the growth of pancreatic cancer and their mechanisms would be interesting. Frequent alcohol intake is one of risk factors for pancreatic cancer. The data regarding with effects of alcohol on pancreas mainly focus in acute or chronic pancreatitis. Besides these, what damages else would happen in pancreas because of frequent alcohol intake. In addition, are these damages related to pancreatic cancer? We were not successful to establish chronic pancreatitis in rat by alcohol intake for long time during the primary experiment. However, we found some early damages inultrastructures of acinar cells companying with decreasing of pancreatic exocrine function.It is not know whether the expression of COX-2, one of inflammation parameters would be changed when pancreatic acinar cells affected by alcohol. The effects of COX-2 inhibitors on ultrastructures and exocrine function of acinar cells have not been reported. Aims of the study1. Do the different selective cyclooxygenase-2 inhibitors have different effects on the growth of human pancreatic cellular carcinoma?2. If highly selective COX-2 inhibitor-rofecoxib could inhibit the growth of pancreatic cancer? What are its mechanisms?3. Chronically fed ethanol diets effects on pancreatic acinar cells functions and morphology and their COX-2 expression. 4. Dietary protein content's effects on alcoholic acinar cells involution and COX-2 expression.5. Rofecoxib effects on alcoholic acinar cells retrogression.Methods1. Cell proliferation is evaluated by 3H-thymidine incorporation into DNA. 2. Apoptosis was used by the TdT-mediated dUTP nick end labeling assay(TUNEL).3. Pancreatic cancer xenograft model was established and the growth of pancreatic cancer was investigated in vivo.4. The expression of COX-2, PCNA, c-Fos, VEGF, â…§-related antigen on pancreatic cancer tissue, pancreatic cancer cell line, acinar cell were detected by immunocytochemistry or immunohistochemistry.5. The expression of c-Fos or ERK was determined by western blot.6. Gelatin Zymography and RT-PCR technology were used to detect the expression of matrix metalloproteinase-2 (MMP-2) progelatinase and MMP-2 gene.AP-1 binding activity was mesured by electrophoretic mobility sift7. assay(EMSA).8. Acinar cell structure and histological changes were evaluated by light microscopy(LM ). 9. Acinar cell ultrastructure changes were studied by electron microscopy (EM). 10. Evaluation of detection pancreatic homogenate amylase and lipase by Somogyi and colorimetry, respectively. Results1. Pancreatic cancer cell line BXPC-3 have COX-2 expression. Three selective COX-2 inhibitors down regulate COX-2 expression in vitro and in vivo.2. Three selective COX-2 inhibitors could inhibit 3H-thymidine incorporation into DNA, the inhibit rate is positively related to the dose of drugs and the ability of selective inhibition on COX-2 expression. 3. Rofecoxib could induce BXPC-3 cell apoptosis, the apopotosis index was 25%(0.6%, only few apoptosis cells was observed in control. Rofecoxib down-regulated th... |
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