环氧合酶-2与肿瘤
作者：谷兰 刘桂琴
单位：中国医科大学附属第三临床学院内科 沈阳 110021
关键词：
解剖科学进展000403 摘要 环氧合酶(COX)是一种膜结合蛋白，具有双重酶的功能，是PGs(前列腺素类)生物合成的限速酶。目前发现它有两个亚型，即COX-1和COX-2。近4、5年来，欧美、日本等国科学家通过对COX-2的广泛研究，发现COX-2在肿瘤发生、发展、分化、转移及预后等方面可能有重要作用，并开发了COX-2特异性抑制剂应用于抗肿瘤研究，取得了初步成效。但国内在此方面尚未见文献报导，本篇就国外此项研究的现状进行综述，旨在使国人了解此项研究的进展，推动该项研究在国内的开展，为人类征服癌症，提供新的手段。
参考文献
1，Williams CS,DuBois RN. Prostaglandin endoperoxide synthase:why two isoforms? Am J Physiol,1996,270(3Pt1)：G393
, http://www.100md.com
2，Dewitt DL,Smith WL.Primary structure of prostaglandin G/H synthase from sheep vesicular gland determined from the complementary DNA sequence. Proc Natl Acad Sci USA,1988,85:1412
3，Kosaka T,Miyata Y,Ihara H,et al. Characterization of the human gene(PTGS2) encoding prostaglandin-endoperoxide synthases-2. Eur J Biochem,1994,221(3):889
4，Smith WL,Marnett LT. Prostaglandin-endoperoxide synthase structure and catalysis. Biochem Biophys Acta,1991,1083:1
, 百拇医药
5，Lecomte M,Laneuville Q,Ji C,et al.Acetylation of human prostaglandin endoperoxide synthase-2(COX-2) by aspirin. J Biol Chem,1994,269:13207
6，Xie W,Chipman TG,Robertson DL,et al. Expression of a mitogen-responsive gene endoing prostaglandin synthase is regulated by mRNA splicing. Proc Natl Acad Sci USA,1991,88:2692
7，Kujubu DA,Fletcher BS,Varnum BC,et al. TIS10 a phorbol ester tumor promoter-inducible mRNA from Swiss 3T3 cells encodes a novel prostaglandin synthase/cox homologue. J Biol Chem,1991,266:12866
, http://www.100md.com
8，O'Banion MK,Winn VD,Young DA.cDNA cloning and funtional activity of a glucocorticoid-regulated inflammatory cyclooxygenase. Proc Natl Acad Sci USA,1992,89:4888
9，Gilbert RS,Reddy ST,Kjubu DA,et al.Transforming growth factor bata 1 augments mitogen-induced prostaglandin synthesis and expression of the TIS10/prostaglandin synthase 2 gene both in Swiss 3T3 cells and in murine embryo fibroblasts. J Cell Physiol,1994,159:67
10，DuBois RN,Tsujii M,Bishop P,et al. Cloning and characterization of a growth factor-inducible cyclooxygenase gene from rat intestinal epithelial cells. Am J Physiol,1994,266:G822
, 百拇医药
11，DuBois RN,Awad J,Morrow J, et al. Regulation of eicosanoid production and mitogenesis in rat intestinal epithelial cells by transforming growth factor-alpha and phorbol ester. J Clin Invest,1994,93:493
12，Newman SP,Flower RJ,Croxtal JD.Dexamethasone suppression of IL-1β induced cyclooxygenase-expression is not mediated by lipocortin-1 in A549 cells. Biochem Biophys Res Commun,1994,202(2):931
13，Asano K,Lilly CM,Drazen JM.Prostaglandin G/S synthase-2 is the constitutive and dominant isoform in cultured human lung epithelial cells. Am J Physiol,1996,271(1):L126
, http://www.100md.com
14，Leong J,Hughes FM,Rakhlin N,et al. Cyclooxygenases in human and mouse skin and cultured human keratinocytes:association keratinocyte differentiation. Exp Cell Res,1996,224(1):79
15，Kargman S,Charleson S,Cartwright M,et al. Characterization of prostaglandin G/S synthase 1 and 2 in rat dog monkey and human gastrointestinal tract. Gastroenterology,1996,111:445
16，Langenbach R,Loftin C,Lee C,et al. Cyclooxygenase Knockout mice:models for elucidating isoform-specific functions.Biochem Pharmacol,1999,58(8):1217
, http://www.100md.com
17，Morham SG,Langenbach R,Loftin CD,et al. Prostaglandin synthase 2 gene disruption causes sever renal pathology in the mouse. Cell,1995,83(3):473
18，Silver RM, Edwin SS, Trautman MS, et al. Bacterial lipopolysaccharide-mdeiated fatal death production of a newly recognized form of inducible cyclooxygnase(COX-2) in murine decidua in response to lipopolysaccharide. J Clin Invest,1995,95(2):725
19，Wilborn J,Crofford LJ,Burdick MD,et al. Cultured lung fibroblasts isolated from patients with idiopathic pulmonary fibrosis have a diminished capacity to synthesize prostaglandin E2 and to express cyclooxygenaes-2. J Clin Invest,1995,95(4):1861
, http://www.100md.com
20，DuBois RN,Radhika A,Reddy BS,et al.Increased cox-2 levels in carcinogen-induced rat colonic tumors. Gastroenterology,1996,110:1259
21，Parker J,Kaplon MK,Alvarez CJ,et al. Prostaglandin H synthase expression is variable in human colorectal adenocarcinoma cell lines. Exp Cell Res,1997,236(1):321
22，Sawaoka H,Kawano S,Tsuji S,et al.Effects of NSAIDs on proliferation of gastric cancer cells in vitro:possible implication of cox-2 in cancer development. J Clin Gastroenterol,1998,27(Suppl 1):S47
, 百拇医药
23，Molina MA,Sitja AM,Lemoine MG.Increased cox-2 expression in human pancreatic carcinomas and cell lines:growth inhibition by NSAIDs.Cancer Res, 1999,59(17):4356
24，Tsujii M,DuBois RN. Alterations is cellular adhesion and apoptosis in epithelial cells overexpression cox-2. Cell,1995,83:493
25，Tsujii M,Kawano S,DuBois RN,et al. Cyclooxygenase regulation angiogenesis induced by colon cancer cells. Cell,1998,93(5):705
, http://www.100md.com
26，Uefuji K,Ickikura T,Mochizuki H,et al.Expression of cox-2 protein in gastric adenocarcinoma. J Surg Oncol,1998,69(3):168
27，Eberhart CE,Coffey RJ,DuBois RN,et al. Up-regulation of cyclooxygenase 2 gene expression in human colorectal adenomas. Gastroenterology,1994,107:1183
28，Kargman SL,O'Neill GP,Vickers PJ,et al.Expression of prostaglandin G/H synthase-1 and-2 protein in human colon cancer. Cancer Res,1995,55:2556
, http://www.100md.com
29，Zimmermann KC,Sarbia M,Weber AA,et al. Cox-2 expression in human esophageal carcinoma. Cancer Res,1999,59(1):198
30，Tucker ON, Yang EK, Zhang F,et al. Cyclooxygenase-2 expression is upregulated in human pancreatic cancer. Cancer Res,1999,59(5):987
31，Koga H,Sakisaka S,Ohishi M,et al. Expression of cyclooxygenase-2 in human hepatocellular carcinoma:relevance to tumor dedifferentiation. Hepatology,1999,29:688
, 百拇医药
32，Wolff H,Saukkonen K,Anttila S,et al. Expression of cyclooxygenase-2 in human lung carcinoma. Cancer Res,1998,58:4997
33，Hwang D,Scollard D,Byrne J,et al.Expression of cyclooxygenase-1 and-2 in human breast cancer. J Natl Cancer Inst,1998,90(6):455
34，Muller DK,Reinerth G,Krieg P,et al.Prostaglandin-H-Synthase isozyme expression in normal and neoplastic human skin. Int J Cancer,1999,82(5):648
, 百拇医药 35，Karnes WE,Burgart LJ,DuBois RN,et al. Reduced cox-2 protein in colorectal cancer with defective mismatch repair. Cancer Res,1998,58(23):5473
36，Yamamoto H,Itoh F,Fukushima H. Overexpression of cyclooxygenase-2 protein is less frequent in gastric cancers with microsatellita instability. Int J Cancer,1999,84(4):400
37，Oshima M,Dinchuk JE,Kargman SL,et al.Suppression of intestinal polyposis in APC knockout mice by inhibition of cox-2. Cell,1996,87:803
, 百拇医药
38，Murata H,Kawano S,Tsuji S,et al.Cyclooxygenase-2 overexpression enhances lymphatic invasion and metastasis in human gastric carcinoma. Am J Gastroenterology,1999,94(2):451
39，Romano M,Ricci V,Memoli A,et al. Helicobacter pylori upregulates cox-2 mRNA expression and prostaglandin E2 synthesis in MKN28 gastric mucosal cells in vitro. J Biol Chem,1998,273(44):28560
40，Thun MJ,Namboodiri MM,Calle EE,et al.Aspirin use and risk of fatal cancer. Cancer Res,1993,53:1322
, 百拇医药
41，Peleg II,Maibach HT,Brown SH,et al.Asprin and nonsteroidal anti-inflammatory drug use and the risk of subsequent colorectal cancer. Arch Intern Med,1994,154:394
42，Waddell WR,Loughry RW. Sulindac for polyposis of the colon. J Surg Oncol,1983,24:83
43，Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action of the aspirin-like drugs. Nature New Biol,1971,231:232
44，Sheng H,Shao J,DuBois RN,et al. Inhibition of human colon cancer cell growth by selective inhibition of cox-2. J Clin Invest,1997,99(9):2254
, 百拇医药
45，Reddy BS,Rao CV,Seibert K,et al.Evaluation of cyclooxyxygenase-2 inhibitor for potential chempreventive properties in colon carcinogenesis. Cancer Res,1996,56:4566
46，Fukuda KY,Mutoh M.Inhibition by berberine of cox-2 transcriptional activity in human colon cancer cells. J Ethnopharmacol,1999,66(2):227
47，Pugh S,Thomas G.Patients with adenomatous polyps and carcinomas have increased colonic mucosal prostaglandin E2. Gut,1994,35:675, http://www.100md.com
单位：中国医科大学附属第三临床学院内科 沈阳 110021
关键词：
解剖科学进展000403 摘要 环氧合酶(COX)是一种膜结合蛋白，具有双重酶的功能，是PGs(前列腺素类)生物合成的限速酶。目前发现它有两个亚型，即COX-1和COX-2。近4、5年来，欧美、日本等国科学家通过对COX-2的广泛研究，发现COX-2在肿瘤发生、发展、分化、转移及预后等方面可能有重要作用，并开发了COX-2特异性抑制剂应用于抗肿瘤研究，取得了初步成效。但国内在此方面尚未见文献报导，本篇就国外此项研究的现状进行综述，旨在使国人了解此项研究的进展，推动该项研究在国内的开展，为人类征服癌症，提供新的手段。
参考文献
1，Williams CS,DuBois RN. Prostaglandin endoperoxide synthase:why two isoforms? Am J Physiol,1996,270(3Pt1)：G393
, http://www.100md.com
2，Dewitt DL,Smith WL.Primary structure of prostaglandin G/H synthase from sheep vesicular gland determined from the complementary DNA sequence. Proc Natl Acad Sci USA,1988,85:1412
3，Kosaka T,Miyata Y,Ihara H,et al. Characterization of the human gene(PTGS2) encoding prostaglandin-endoperoxide synthases-2. Eur J Biochem,1994,221(3):889
4，Smith WL,Marnett LT. Prostaglandin-endoperoxide synthase structure and catalysis. Biochem Biophys Acta,1991,1083:1
, 百拇医药
5，Lecomte M,Laneuville Q,Ji C,et al.Acetylation of human prostaglandin endoperoxide synthase-2(COX-2) by aspirin. J Biol Chem,1994,269:13207
6，Xie W,Chipman TG,Robertson DL,et al. Expression of a mitogen-responsive gene endoing prostaglandin synthase is regulated by mRNA splicing. Proc Natl Acad Sci USA,1991,88:2692
7，Kujubu DA,Fletcher BS,Varnum BC,et al. TIS10 a phorbol ester tumor promoter-inducible mRNA from Swiss 3T3 cells encodes a novel prostaglandin synthase/cox homologue. J Biol Chem,1991,266:12866
, http://www.100md.com
8，O'Banion MK,Winn VD,Young DA.cDNA cloning and funtional activity of a glucocorticoid-regulated inflammatory cyclooxygenase. Proc Natl Acad Sci USA,1992,89:4888
9，Gilbert RS,Reddy ST,Kjubu DA,et al.Transforming growth factor bata 1 augments mitogen-induced prostaglandin synthesis and expression of the TIS10/prostaglandin synthase 2 gene both in Swiss 3T3 cells and in murine embryo fibroblasts. J Cell Physiol,1994,159:67
10，DuBois RN,Tsujii M,Bishop P,et al. Cloning and characterization of a growth factor-inducible cyclooxygenase gene from rat intestinal epithelial cells. Am J Physiol,1994,266:G822
, 百拇医药
11，DuBois RN,Awad J,Morrow J, et al. Regulation of eicosanoid production and mitogenesis in rat intestinal epithelial cells by transforming growth factor-alpha and phorbol ester. J Clin Invest,1994,93:493
12，Newman SP,Flower RJ,Croxtal JD.Dexamethasone suppression of IL-1β induced cyclooxygenase-expression is not mediated by lipocortin-1 in A549 cells. Biochem Biophys Res Commun,1994,202(2):931
13，Asano K,Lilly CM,Drazen JM.Prostaglandin G/S synthase-2 is the constitutive and dominant isoform in cultured human lung epithelial cells. Am J Physiol,1996,271(1):L126
, http://www.100md.com
14，Leong J,Hughes FM,Rakhlin N,et al. Cyclooxygenases in human and mouse skin and cultured human keratinocytes:association keratinocyte differentiation. Exp Cell Res,1996,224(1):79
15，Kargman S,Charleson S,Cartwright M,et al. Characterization of prostaglandin G/S synthase 1 and 2 in rat dog monkey and human gastrointestinal tract. Gastroenterology,1996,111:445
16，Langenbach R,Loftin C,Lee C,et al. Cyclooxygenase Knockout mice:models for elucidating isoform-specific functions.Biochem Pharmacol,1999,58(8):1217
, http://www.100md.com
17，Morham SG,Langenbach R,Loftin CD,et al. Prostaglandin synthase 2 gene disruption causes sever renal pathology in the mouse. Cell,1995,83(3):473
18，Silver RM, Edwin SS, Trautman MS, et al. Bacterial lipopolysaccharide-mdeiated fatal death production of a newly recognized form of inducible cyclooxygnase(COX-2) in murine decidua in response to lipopolysaccharide. J Clin Invest,1995,95(2):725
19，Wilborn J,Crofford LJ,Burdick MD,et al. Cultured lung fibroblasts isolated from patients with idiopathic pulmonary fibrosis have a diminished capacity to synthesize prostaglandin E2 and to express cyclooxygenaes-2. J Clin Invest,1995,95(4):1861
, http://www.100md.com
20，DuBois RN,Radhika A,Reddy BS,et al.Increased cox-2 levels in carcinogen-induced rat colonic tumors. Gastroenterology,1996,110:1259
21，Parker J,Kaplon MK,Alvarez CJ,et al. Prostaglandin H synthase expression is variable in human colorectal adenocarcinoma cell lines. Exp Cell Res,1997,236(1):321
22，Sawaoka H,Kawano S,Tsuji S,et al.Effects of NSAIDs on proliferation of gastric cancer cells in vitro:possible implication of cox-2 in cancer development. J Clin Gastroenterol,1998,27(Suppl 1):S47
, 百拇医药
23，Molina MA,Sitja AM,Lemoine MG.Increased cox-2 expression in human pancreatic carcinomas and cell lines:growth inhibition by NSAIDs.Cancer Res, 1999,59(17):4356
24，Tsujii M,DuBois RN. Alterations is cellular adhesion and apoptosis in epithelial cells overexpression cox-2. Cell,1995,83:493
25，Tsujii M,Kawano S,DuBois RN,et al. Cyclooxygenase regulation angiogenesis induced by colon cancer cells. Cell,1998,93(5):705
, http://www.100md.com
26，Uefuji K,Ickikura T,Mochizuki H,et al.Expression of cox-2 protein in gastric adenocarcinoma. J Surg Oncol,1998,69(3):168
27，Eberhart CE,Coffey RJ,DuBois RN,et al. Up-regulation of cyclooxygenase 2 gene expression in human colorectal adenomas. Gastroenterology,1994,107:1183
28，Kargman SL,O'Neill GP,Vickers PJ,et al.Expression of prostaglandin G/H synthase-1 and-2 protein in human colon cancer. Cancer Res,1995,55:2556
, http://www.100md.com
29，Zimmermann KC,Sarbia M,Weber AA,et al. Cox-2 expression in human esophageal carcinoma. Cancer Res,1999,59(1):198
30，Tucker ON, Yang EK, Zhang F,et al. Cyclooxygenase-2 expression is upregulated in human pancreatic cancer. Cancer Res,1999,59(5):987
31，Koga H,Sakisaka S,Ohishi M,et al. Expression of cyclooxygenase-2 in human hepatocellular carcinoma:relevance to tumor dedifferentiation. Hepatology,1999,29:688
, 百拇医药
32，Wolff H,Saukkonen K,Anttila S,et al. Expression of cyclooxygenase-2 in human lung carcinoma. Cancer Res,1998,58:4997
33，Hwang D,Scollard D,Byrne J,et al.Expression of cyclooxygenase-1 and-2 in human breast cancer. J Natl Cancer Inst,1998,90(6):455
34，Muller DK,Reinerth G,Krieg P,et al.Prostaglandin-H-Synthase isozyme expression in normal and neoplastic human skin. Int J Cancer,1999,82(5):648
, 百拇医药 35，Karnes WE,Burgart LJ,DuBois RN,et al. Reduced cox-2 protein in colorectal cancer with defective mismatch repair. Cancer Res,1998,58(23):5473
36，Yamamoto H,Itoh F,Fukushima H. Overexpression of cyclooxygenase-2 protein is less frequent in gastric cancers with microsatellita instability. Int J Cancer,1999,84(4):400
37，Oshima M,Dinchuk JE,Kargman SL,et al.Suppression of intestinal polyposis in APC knockout mice by inhibition of cox-2. Cell,1996,87:803
, 百拇医药
38，Murata H,Kawano S,Tsuji S,et al.Cyclooxygenase-2 overexpression enhances lymphatic invasion and metastasis in human gastric carcinoma. Am J Gastroenterology,1999,94(2):451
39，Romano M,Ricci V,Memoli A,et al. Helicobacter pylori upregulates cox-2 mRNA expression and prostaglandin E2 synthesis in MKN28 gastric mucosal cells in vitro. J Biol Chem,1998,273(44):28560
40，Thun MJ,Namboodiri MM,Calle EE,et al.Aspirin use and risk of fatal cancer. Cancer Res,1993,53:1322
, 百拇医药
41，Peleg II,Maibach HT,Brown SH,et al.Asprin and nonsteroidal anti-inflammatory drug use and the risk of subsequent colorectal cancer. Arch Intern Med,1994,154:394
42，Waddell WR,Loughry RW. Sulindac for polyposis of the colon. J Surg Oncol,1983,24:83
43，Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action of the aspirin-like drugs. Nature New Biol,1971,231:232
44，Sheng H,Shao J,DuBois RN,et al. Inhibition of human colon cancer cell growth by selective inhibition of cox-2. J Clin Invest,1997,99(9):2254
, 百拇医药
45，Reddy BS,Rao CV,Seibert K,et al.Evaluation of cyclooxyxygenase-2 inhibitor for potential chempreventive properties in colon carcinogenesis. Cancer Res,1996,56:4566
46，Fukuda KY,Mutoh M.Inhibition by berberine of cox-2 transcriptional activity in human colon cancer cells. J Ethnopharmacol,1999,66(2):227
47，Pugh S,Thomas G.Patients with adenomatous polyps and carcinomas have increased colonic mucosal prostaglandin E2. Gut,1994,35:675, http://www.100md.com