5-lox和cox-2在结直肠癌中表达及5-lox抑制剂相关性应用
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摘要
结肠癌是胃肠道中常见的恶性肿瘤,以41-65岁发病率高。在我国近20年来,尤其在大城市发病率明显上升,且结肠癌多于直肠癌的趋势,结肠癌病因虽未明确,但其相关的高危因素逐渐被认识,如过多的动物脂肪及动物蛋白饮食,缺乏新鲜蔬菜及维生素食品;缺乏适度的体力活动。遗传易感性在结直肠癌的发病中也具有重要地位,结肠腺瘤,溃疡性结肠炎以及结肠血吸虫病肉芽肿,与结肠癌的发生有较密切的关系。中国人直肠癌与西方人比较有三个流行病学特点:①直肠癌比结肠癌发生率高,约1.5:1;②低位直肠癌所占比例高,约占直肠癌的60%-75%;③青年人(<30)直肠癌比例高,约10%-15%。癌的发生发展是一个多步骤、多阶段及多基因参与的细胞遗传性疾病[141]。随着分子生物学技术快速发展,进一步研究大肠癌发病机理、生物学诊断和治疗,成为目前研究的热点。
高脂肪饮食与特定器官包括乳腺、胰腺、结肠、前列腺等发病率及肿瘤生长相关联。也证实花生四烯酸、多不饱和脂肪酸代谢是通过环氧合酶(cox)途径或脂氧合酶(lox)途径,产生一系列促炎性反应物质类花生酸类物质,包括前列腺素、血栓烷素、白细胞三烯等.这些物质在人类癌症发生、发展中发挥重要生物效应。环氧合酶在人许多恶性肿瘤发生、发展起到重要作用,它的抑制剂相应被呈现出。脂氧合酶和其代谢产物在人类癌细胞组织中明显增多,这一过度表达对于肿瘤细胞增殖、抵抗吞噬作用和血管发生更具有理论及实践意义。
本实验通过RT-PCR、Western-blot和免疫组织化学法不同方法对结直肠癌患者切除标本进行5-lox和cox-2测定及5-lox抑制剂对5-loxmRNA与bcl-2mRNA和baxmRNA表达的影响,在国内尚未见报道。结果表明5-loxmRNA和cox-2mRNA在结直肠癌组织中表达增高,与结直肠癌临床分期、肿瘤大小、肿瘤分化程度有关;5-lox蛋白和cox-2蛋白表达癌肿组织明显高于癌旁组织(western-blot),5-lox和cox-2表达水平与微血管密度相关联;5-loxmRNA表达与bcl-2mRNA表达相一致,而与baxmRNA表达呈负相关;5-lox抑制剂MK886对5-loxmRNA、bcl-2mRNA表达有抑制作用,表明对环氧合酶和脂氧合酶的深入研究具有临床实用性和先进性,为今后结直肠癌诊断和治疗提供了很好理论和实践意义。
Objective: To study expressions of 5-Lipoxygenase and Cyclooxygenase-2 in human colorectal cancer, and approach potential mechanism of 5-lox in the promotion and progression of human colorectal cancer, it provides a good theoretical and practical significance For the future diagnosis and treatment of colorectal cancer.
Background:
Evidence from epidemiological and animal studies suggests that a high-fat consumption is associated with an increased incidence and growth of tumors at several specific organ sites, it has been demonstrated that the metabolism of arachidonic acid, a polyunsaturated fatty acid by either the Cyclooxygenase (cox) pathway or the Lipoxygenase (lox) pathway, generates a host of pro-inflammatory substances called eicosanoids including prostaglandins, thromboxanes, leukotrienes, etc. that act as significance effect of biological in the promotion and progression of many types of human neoplasms. it suggests that the deep investigation ofcyclooxygenase and lipoxygenase possess clinical utility and advanced ,for the future diagnosis and treatment of colorectal cancer provides a good theoretical and practical significance.
Part 1 Expressions of 5-Lipoxygenase and Cyclooxygenase-2 in human colorectal tumor and adjacent normal mucosa
Method:
1、To investigate the expressions of 5-loxmRNA and cox-2mRNA in paired 39 colorectal cancer samples and their relationship by RT-PCR.
2、The relative quantity of protein 5-lox and cox-2 in colorectal tumor and adjacent normal mucosa samples was determined by western-blot.
3、Expressions of 5-Lipoxygenase and Cyclooxygenase-2 in human colorectal cancer samples is related with microvessel density by immunohistochemical staining methods.
Result:
There were 33 cases of 5-loxmRNA amplified bands of 504bp in39 cases of colorectal cancer tissues, positive expression ratio was 84.6% (33/39); there were 30 cases cox-2mRNA amplified bands of 540bp in 39 cases of colorectal cancer tissues, positive expression ratio was 76.9% (30/39). Expressions of 5-loxmRNA and cox-2mRNA in colorectal cancer tissue were remarkably elevated,and correlated with clinical stage, tumor size,differentiation degree. Expressions of both were not coordinated. Expressions of 5-lox and cox-2 were remarkably elevated in human colorectal tumor tissue in comparison with normal colon mucosa. And the over expression level of 5-lox and cox-2 was positively correlated with microvessel density.
Part 2 Expressions of 5-loxmRNA is correlated with expression of bcl-2mRNA and bax mRNA in paired 39 colorectal tumor and adjacent normal mucosa samples and the effect of 5-lox MK886 inhibitor on expression of 5-loxmRNA、bcl-2mRNA and baxmRNA
Method:
1、Expressions of 5-loxmRNA、bcl-2mRNA and baxmRNA in paired 39 colorectal tumor and adjacent normal mucosa samples by RT-PCR.
2、Expressions of 5-lox mRNA、bcl-2mRNA and baxmRNA compared with before and after MK886 in HT29 colon cancer cell lines.
Result:
Expressions of 5-loxmRNA、bcl-2mRNA and baxmRNA are separately 33/39, 29/39, 10/39 and 14/39, 10/39, 26/39in paired 39 colorectal tumor and adjacent normal mucosa samples.Expressions of 5-loxmRNA and bcl-2mRNA were more elevated than expression of baxmRNA in human colorectal tumor tissue, Expression of baxmRNA were more higher than expressions of 5-loxmRNA and bcl-2mRNA in human adjacent normal mucosa tissue, Expressions of 5-loxmRNA and bcl-2mRNA were lower by after Mk886 in comparison with befor Mk886 in HT29 colon cancer cell lines. Expressions of baxmRNA were higher by after Mk886 in comparison with before Mk886 in HT29 colon cancer cell lines. Expressions of 5-lox mRNA, bcl-2mRNA are gradually reduced with augmentation of drug concentration, Expression of baxmRNA is gradually increased With augmentation of drug concentration.
Conclusion:
1、Expressions of 5-loxmRNA and cox-2mRNA were simultaneously up- regulated in human colorectal cancer tissue, Expressions of both were not coordinated.
2、Protein expressions of 5-lox and cox-2 were remarkably elevated in human colorectal tumor tissue in comparison with normal colon mucosa.
3、The over expressions level of 5-lox and cox-2 was positively correlated with microvessel density.
4、5-lox may play a role of promoter in the promotion and development of colorectal cancer by influencing the balance of between cell proliferation and apoptosis.
高脂肪饮食与特定器官包括乳腺、胰腺、结肠、前列腺等发病率及肿瘤生长相关联。也证实花生四烯酸、多不饱和脂肪酸代谢是通过环氧合酶(cox)途径或脂氧合酶(lox)途径,产生一系列促炎性反应物质类花生酸类物质,包括前列腺素、血栓烷素、白细胞三烯等.这些物质在人类癌症发生、发展中发挥重要生物效应。环氧合酶在人许多恶性肿瘤发生、发展起到重要作用,它的抑制剂相应被呈现出。脂氧合酶和其代谢产物在人类癌细胞组织中明显增多,这一过度表达对于肿瘤细胞增殖、抵抗吞噬作用和血管发生更具有理论及实践意义。
本实验通过RT-PCR、Western-blot和免疫组织化学法不同方法对结直肠癌患者切除标本进行5-lox和cox-2测定及5-lox抑制剂对5-loxmRNA与bcl-2mRNA和baxmRNA表达的影响,在国内尚未见报道。结果表明5-loxmRNA和cox-2mRNA在结直肠癌组织中表达增高,与结直肠癌临床分期、肿瘤大小、肿瘤分化程度有关;5-lox蛋白和cox-2蛋白表达癌肿组织明显高于癌旁组织(western-blot),5-lox和cox-2表达水平与微血管密度相关联;5-loxmRNA表达与bcl-2mRNA表达相一致,而与baxmRNA表达呈负相关;5-lox抑制剂MK886对5-loxmRNA、bcl-2mRNA表达有抑制作用,表明对环氧合酶和脂氧合酶的深入研究具有临床实用性和先进性,为今后结直肠癌诊断和治疗提供了很好理论和实践意义。
Objective: To study expressions of 5-Lipoxygenase and Cyclooxygenase-2 in human colorectal cancer, and approach potential mechanism of 5-lox in the promotion and progression of human colorectal cancer, it provides a good theoretical and practical significance For the future diagnosis and treatment of colorectal cancer.
Background:
Evidence from epidemiological and animal studies suggests that a high-fat consumption is associated with an increased incidence and growth of tumors at several specific organ sites, it has been demonstrated that the metabolism of arachidonic acid, a polyunsaturated fatty acid by either the Cyclooxygenase (cox) pathway or the Lipoxygenase (lox) pathway, generates a host of pro-inflammatory substances called eicosanoids including prostaglandins, thromboxanes, leukotrienes, etc. that act as significance effect of biological in the promotion and progression of many types of human neoplasms. it suggests that the deep investigation ofcyclooxygenase and lipoxygenase possess clinical utility and advanced ,for the future diagnosis and treatment of colorectal cancer provides a good theoretical and practical significance.
Part 1 Expressions of 5-Lipoxygenase and Cyclooxygenase-2 in human colorectal tumor and adjacent normal mucosa
Method:
1、To investigate the expressions of 5-loxmRNA and cox-2mRNA in paired 39 colorectal cancer samples and their relationship by RT-PCR.
2、The relative quantity of protein 5-lox and cox-2 in colorectal tumor and adjacent normal mucosa samples was determined by western-blot.
3、Expressions of 5-Lipoxygenase and Cyclooxygenase-2 in human colorectal cancer samples is related with microvessel density by immunohistochemical staining methods.
Result:
There were 33 cases of 5-loxmRNA amplified bands of 504bp in39 cases of colorectal cancer tissues, positive expression ratio was 84.6% (33/39); there were 30 cases cox-2mRNA amplified bands of 540bp in 39 cases of colorectal cancer tissues, positive expression ratio was 76.9% (30/39). Expressions of 5-loxmRNA and cox-2mRNA in colorectal cancer tissue were remarkably elevated,and correlated with clinical stage, tumor size,differentiation degree. Expressions of both were not coordinated. Expressions of 5-lox and cox-2 were remarkably elevated in human colorectal tumor tissue in comparison with normal colon mucosa. And the over expression level of 5-lox and cox-2 was positively correlated with microvessel density.
Part 2 Expressions of 5-loxmRNA is correlated with expression of bcl-2mRNA and bax mRNA in paired 39 colorectal tumor and adjacent normal mucosa samples and the effect of 5-lox MK886 inhibitor on expression of 5-loxmRNA、bcl-2mRNA and baxmRNA
Method:
1、Expressions of 5-loxmRNA、bcl-2mRNA and baxmRNA in paired 39 colorectal tumor and adjacent normal mucosa samples by RT-PCR.
2、Expressions of 5-lox mRNA、bcl-2mRNA and baxmRNA compared with before and after MK886 in HT29 colon cancer cell lines.
Result:
Expressions of 5-loxmRNA、bcl-2mRNA and baxmRNA are separately 33/39, 29/39, 10/39 and 14/39, 10/39, 26/39in paired 39 colorectal tumor and adjacent normal mucosa samples.Expressions of 5-loxmRNA and bcl-2mRNA were more elevated than expression of baxmRNA in human colorectal tumor tissue, Expression of baxmRNA were more higher than expressions of 5-loxmRNA and bcl-2mRNA in human adjacent normal mucosa tissue, Expressions of 5-loxmRNA and bcl-2mRNA were lower by after Mk886 in comparison with befor Mk886 in HT29 colon cancer cell lines. Expressions of baxmRNA were higher by after Mk886 in comparison with before Mk886 in HT29 colon cancer cell lines. Expressions of 5-lox mRNA, bcl-2mRNA are gradually reduced with augmentation of drug concentration, Expression of baxmRNA is gradually increased With augmentation of drug concentration.
Conclusion:
1、Expressions of 5-loxmRNA and cox-2mRNA were simultaneously up- regulated in human colorectal cancer tissue, Expressions of both were not coordinated.
2、Protein expressions of 5-lox and cox-2 were remarkably elevated in human colorectal tumor tissue in comparison with normal colon mucosa.
3、The over expressions level of 5-lox and cox-2 was positively correlated with microvessel density.
4、5-lox may play a role of promoter in the promotion and development of colorectal cancer by influencing the balance of between cell proliferation and apoptosis.
引文
[1] Romano M, Claria J. Cyclooxygenase-2 and 5-lipoxygenase converging functions on cell proliferation and tumor angiogenesis: implications for cancer therapy. FASEB J 2003;17:1986-95.
[2] Wang D, Mann JR, DuBois RN. The role of prostaglandins and other eicosanoids in the gastrointestinal tract. Gastroenterology 2005;128:1445-61.
[3] Hase T, Yoshimura R, Matsuyama M, et al. Cyclooxygenase-1 and-2 in human testicular tumours. Eur J Cancer 2003;39:2043-49.
[4] Steinbach G, Lynch PM, Phillips RK, Wallace MH, Hawk E, Gordon GB, Wakabayashi N, Saunders B, Shen Y, Fujimura T, Su LK, Levin B. The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N Engl J Med 2000;342:1946-52.
[5] Sandler RS, Halabi S, Baron JA, Budinger S, Paskett E, Keresztes R, Petrelli N, Pipas JM, Karp DD, Loprinzi CL, Steinbach G, Schilsky R. A randomized trial of aspirin to prevent colorectal adenomas in patients with previous colorectal cancer. N Engl J Med 2003;348:883-890.
[6] Reardon DA, Quinn JA, Vredenburgh J, Rich JN, Gururangan S, Badruddoja M, Herndon JE 2nd, Dowell JM, Friedman AH, Friedman HS. Phase II trial of irinotecan plus celecoxib in adults with recurrent malignant glioma. Cancer 2005; 103:329-338.
[7] Milella M, Gelibter A, Di Cosimo S, Bria E, Ruggeri EM, Carlini P, Malaguti P, Pellicciotta M, Terzoli E, Cognetti F. Pilot study of celecoxib and infusional 5-fluorouracil as second-line treatment for advanced pancreatic carcinoma. Cancer 2004;101:133-138.
[8] Steele VE, Holmes CA, Hawk ET, Kopelovich L, Lubet RA, Crowell JA, Sigman CC, Kelloff GJ. Lipoxygenase inhibitors as potential cancer chemopreventives. Cancer Epidemiol Biomarkers Prev 1999; 8: 467-483.
[9] Gupta S, Srivastava M, Ahmad N, Sakamoto K, Bostwick DG, Mukhtar H. Lipoxygenase-5 is overexpressed in prostate adenocarcinoma. Cancer 2001; 91:737-743.
[10] Yoshimura R, Matsuyama M, Tsuchida K, Kawahito Y, Sano H, Nakatani T. Expression of lipoxygenase inhuman bladder carcinoma and growth inhibition by its inhibitors. J Urol 2003;170:1994-1999.
[11] Hong SH, Avis I, Vos MD, Martinez A, Treston AM, Mulshine JL. Relationship of arachidonic acid metabolizing enzyme expression in epithelial cancer cell lines to the growth effect of selective biochemical inhibitors. Cancer Res 1999; 59: 2223-2228.
[12] Ohd JF, Nielsen CK, Campbell J, Landberg G, Lofberg H, Sjolander A. Expression of the leukotriene D4 receptor CysLT1, cox-2, and other cell sur- vival factors in colorectal adenocarcinomas. Gastroenterology 2003; 124: 57-70.
[13] Hennig R, Grippo P, Ding XZ, Rao SM, Buchler MW, Friess H, Talamonti MS, Bell RH, Adrian TE. 5-Lipoxygenase, a marker for early pancreatic intraepithelial neoplastic lesions. Cancer Res 2005;65:6011-6016.
[14] Li N, Sood S, Wang S, Fang M, Wang P, Sun Z, Yang CS, Chen X. Overexp- ression of 5-lipoxygenase and cyclooxygenase 2 in hamster and human oral cancer and chemopreventive effects of zileuton and celecoxib. Clin Cancer Res 2005;11:2089-2096.
[15] Chen X, Wang S, Wu N, Sood S, Wang P, Jin Z, Beer DG, Giordano TJ, Lin Y, Shih WC, Lubet RA, Yang CS. Overexpression of 5-lipoxygenase in rat and human esophageal adenocarcinoma and inhibitory effects of zileuton and celecoxib on carcinogenesis. Clin Cancer Res 2004;10:6703-6709.
[16] Avis I, Hong SH, Martinez A, Moody T, Choi YH, Trepel J, Das R, Jett M, Mulshine JL. Five-lipoxygenase inhibitors can mediate apoptosis in human breast cancer cell lines through complex eicosanoid interactions. FASEB J 2001;15: 2007-2009.
[17] Romano M, Catalano A, Nutini M, D’Urbano E, Crescenzi C, Claria J, Libner R, Davi G, Procopio A. 5-lipoxygenase regulates malignant mesothelial cell survival: involvement of vascular endothelial growth factor. FASEB J 2001;15:2326-2336.
[18] Hoque A, Lippman SM, Wu TT, Xu Y, Liang ZD, Swisher S, Zhang H, Cao L, Ajani JA, Xu XC. Increased 5-lipoxygenase expression and induction of apo- ptosis by itsinhibitors in esophageal cancer: a potential target for prevention. Carcinogenesis 2005;26:785-791.
[19]徐天宇.利用生物技术生产二十碳五烯酸和二十二碳六烯酸.食品与发酵工业, 1995,1:56-65。
[20]包建新,楼亚平.花生四烯酸及其代谢物的第二信使作用.中国药理学通报, 1991,7(5):321-323。
[21] Morrow JD, Haris TM, Roberts II LJ. Noncyclooxygenase oxidative formation of a series of novel prostaglandins: Analytical ramification for measurement of eicosanoids. Anal Biochem, 1990,184:1-10.
[22] Piomelli D, Volterra A, Siegelbaum SA, et al. Lipoxygenase metabolites of arachidonic acid as second messengers for presynaptic inhibition of aplysia sensory cells. Nature, 1987,328:38-43.
[23]王治荣.白细胞的花生四烯酸代谢.生理科学进展, 1986,17(3):250-253.
[24] Bliss TVP, Douglas RM, Errington ML, et al. Correlation between long-term potentiatin and release of endogenous amino acids from dentate gyrus of aesth- etized rats. J Physiol, 1986,377:391-408.
[25]李春海.花生四烯酸衍生物与造血和免疫调节.军事医学科学院院刊, 1989,13(4):259-265。
[26] Mong S, Chi-Rosso G,Miller J, etal. Leukotriene B4 induces formation of inositol phosphates in rat peritoneal polymorphonuclear leukocytes. Mol Pharmacol, 1986,30:235-242.
[27]孙庆伟.花生四烯酸代谢物与胆肝.生理科学进展, 1992,23(2):177-180.
[28]吴升华.花生四烯酸非环氧合酶产物与肾脏疾病.国外医学-泌尿系统分册, 1994,14(5):208-211。
[29] Nigam S, Fiore S, Luscinskas FW, etal. Lipoxin A4 and lipoxin B4 stimulate the release but not oxygenation of arachidonic acid inhuman neutrophils:dissociation between lipid remoseling and adhesion. J Cell Physiol, 1990,143:512-523.
[30] Wang D, Dubois RN. Prostaglandins and cancer. Gut 2006;55:115-122.
[31] Aggarwal S, Taneja N, Lin L, Orringer MB, Rehemtulla A, Beer DG. Indom- ethacin-induced apoptosis in esophageal adenocarcinoma cells involves upregul- ation of Bax and translocation of mitochondrial cytochrome C independent of cox-2 expression. Neoplasia 2000;2:346-356.
[32] He Q, Luo X, Huang Y, Sheikh MS. Apo2L/TRAIL differentially modulates the apoptotic effects of sulindac and a cox-2 selective non-steroidal anti-inflame- matory agent in Bax-deficient cells. Oncogene 2002;21:6032-6040.
[33] Dohadwala M, Batra RK, Luo J, Lin Y, Krysan K, Pold M, Sharma S, Dubinett SM. Autocrine/paracrine prostaglandin E2 production by non-small cell lung cancer cells regulates matrix metalloproteinase-2 and CD44 in cyclooxygenase- 2-dependent invasion. J Biol Chem 2002;277:50828-50833.
[34] Pan MR, Chuang LY, Hung WC. Non-steroidal anti-inflammatory drugs inhibit matrix metalloproteinase-2 expression via repression of transcription in lung cancer cells. FEBS Lett 2001;508:365-368.
[35] Farrow B, Evers BM. Inflammation and the development of pancreatic cancer. Surg Oncol 2002;10:153-169.
[36] Liyanage UK, Moore TT, Joo HG, Tanaka Y,Herrmann V, Doherty G, Drebin JA, Strasberg SM, Eberlein TJ, Goedegebuure PS, Linehan DC.Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma. J Immunol 2002;169:2756- 2761.
[37] Morita I, Schindler M, Regier MK, et al. Different intracekkular locations for prostaglandin endoperoxide H synthase-1 and–2. J Biol Chem. 1995;270(18): 10902-10908.
[38] Inoue H, Yokoyama C, Hara S, et al. Transcriptional regulation of human prostaglandin endoperoxide synthase-2 gene by lipopolysaccharide and phorbol ester in vascular enlothelial cells. J Biol Chem. 1995;270(42):24965-24971.
[39] Hla T, Neilson K. Human Cyclo-oxygenase-2 CDNA. Proc Natl Acad Sci USA. 1992;89(16):7384-7388.
[40] Jones DA, Carlton DP, McIntyre TM, et al. Molecular cloning of human prostaglandin endoperoxide synthase typeⅡand demonstration of expression in response to cytokines. J Biol Chem. 1993;268(12):9049-9054.
[41] Rudnick DA, Perlmutter DH, Muglia LJ. Prostaglandins are required for CREB activation and cellular proliferation during liver regeneration [J]. Proc Natl Acad Sci USA,2001,98(15):8885-8890.
[42] ShengH, Shao J, Washington MK, et al. Prostaglandin E2 increases growth andmotility of colorectal carcinoma cells [J]. J Biol Chem,2001,276(21): 18075-18081.
[43] Dermott JM, ReddyMR, Onesime D, et al. Oncogenic mutant of Galpha12 stimulates cell proliferation through cycloxygenase-2 signaling pathway [J]. Oncogene, 1999,18(51):7185-7189.
[44] Mann M, Sheng H, Shao J,et al. Targeting cyclooxygenase 2 and HER-2/neu pathways inhibits colorectal carcinoma growth [J]. Gas troenterology, 2001,120 (7):1713-1719.
[45] Ding XZ, Tong WG, AdrianTE. Blockade of cyclooxygenase-2 inhibits proliferation and induces apoptosis in human pancreatic cancer cells [J]. Antica- ncer Res, 2000,20(4):2625-2631.
[46] Joki T, Heese O, Nikas DC, et al. Expression of cyclooxygenase 2 (cox-2) in human glioma and in vitro inhibition by a specific cox-2 inhibitor, NS-398 [J]. Cancer Res, 2000,60(17):4926-4931.
[47] Li M, Wu X, Xu XC. Induction of apoptosis in colon cancer cells by cyclooxygenase-2 inhibitor NS398 through a cytochrome c-dependent pathway [J]. Clin Cancer Res, 2001,7(4):1010-1016.
[48] Sun Y, Tang XM, Half E, et al. Cyclooxygenase-2 overexpression reduces apoptotic susceptibility by inhibiting the cytochrome c-dependent apoptotic pathway in human colon cancer cells [J]. Cancer Res, 2002,62(21):6323-6328.
[49] Scorrano L, Penzo D, Petronilli V, et al. Arachidonic acid causes celldeath thro- ugh the mitochondrial permeability transition. Implications for tumor necrosis factor-alpha aopototic signaling [J]. J Biol Chem, 2001,276(15):12035-12040.
[50] Cao Y, Dave KB, DoanTP,et al. Fatty acid CoA ligase 4 is up-regulated in colon adenocarcinoma [J]. Cancer Res, 2001,61(23):8429-8434.
[51] Cao Y, Pearman AT, Zimmerman GA, et al. Intracellular unesterified arachidonic acid signals apoptosis [J]. Proc Natl Acad Sci USA, 2000,97(21):11280-11285.
[52] Kundu N, Smyth MJ, Samsel L,et al. Cyclooxygenase inhibitors blockcell growth, increase ceramide and inhibit cell cycle [J]. Breast Cancer ResTreat, 2002,76 (1):57-64.
[53] Yamamoto Y, Yin MJ, Lin KM, et al. Sulindac inhibits activation of the NF-kappaB pathway [J]. J Biol Chem, 1999,274(38):27307-27314.
[54] Hsu AL, Ching TT, Wang DS,et al. The cyclooxygenase-2 inhibitor celecoxib induces apoptosis by blockingAkt activation in human prostate cancer cells independently of Bcl-2[J].J Biol Chem, 2000,275(15):11397-11403.
[55] Poligone B, BaldwinAS. Positive and negative regulation of NF-kappaB by cox-2: roles of different prostaglandins [J]. J Biol Chem, 2001,276(42):38658 -38664.
[56] Noda M, Tatsumi Y, TomizawaM, et al. Effects of etodolac, a selective cyclooxygenase-2 inhibitor, on the expression of E-cadherin-catenin complexes in gastrointestinal cell lines [J]. J Gastroenterol, 2002,37(11):896-904.
[57] Dohadwala M, Batra RK, LuoJ,et al. Autocrine/paracrine prostaglandin E2 production by non-small cell lung cancer cellsregulates matrix metalloproteinase-2 and CD44 in cyclooxygenase-2-dependent invasion [J]. J Biol Chem, 2002,277(52):50828-50833.
[58] Dohadwala M, Luo J, Zhu L,et al. Non-small cell lung cancer cyclooxygenase- 2-dependent invasion is mediated by CD44 [J]. J Biol Chem, 2001,276(24): 20809-20812.
[59] Masferrer JL, Leahy KM, Koki AT, et al. Antiangiogenic and antitu-mor activities of cyclooxygenase-2 inhibitors [J]. Cancer Res,2000,60(5):1306-1311.
[60] Sonoshita M, Takaku K, Sasaki N,et al. Acceleration of intestinal polyposis through prostaglandin receptor EP2 in Apc (Delta 716) knock out mice [J]. Nat Med, 2001,7(9):1048-1051.
[61] Leval X, Julemont F, Delarge J, Pirotte B, Dogne JM. New trends in dual 5-lox/coxinhibition. Curr Med Chem 2002;9:941-962.
[62] Ikawa H, Kamitani H, Calvo BF, Foley JF, Eling TE. Expression of 15- lipoxygenase-1 in human colorectal cancer. Cancer Res 1999;59:360-366.
[63] Yamamoto S. Mammalian lipoxygenases: molecular structures and functions. Biochim Biophys Acta 1992;1128:117-131.
[64] Matsuyama M, Yoshimura R, Tsuchida K, Takemoto Y, Segawa Y, Shinnka T, Kawahito Y, Sano H, Nakatani T. Lipoxygenase inhibitors prevent urological cancer cell growth. Int J Mol Med 2004; 13: 665-668.
[65] Shureiqi I, Wojno KJ, Poore JA, Reddy RG, Moussalli MJ, Spindler SA, Greenson JK, Normolle D, Hasan AA, Lawrence TS, Brenner DE.Decreased 13-S-hydroxyoctadecadienoic acid levels and 15-lipoxygenase-1 expression in human colon cancers. Carcinogenesis 1999;20:1985-1995.
[66] Heslin MJ, Hawkins A, Boedefeld W, Arnoletti JP, Frolov A, Soong R, Urist MM, Bland KI. Tumor-associated down-regulation of 15-lipoxygenase-1 is reversed by celecoxib in colorectal cancer. Ann Surg 2005;241:941-946; discu- ssion 946-947.
[67] Jack GS, Brash AR, Olson SJ, Manning S, Coffey CS, Smith JA Jr, Shappell SB. Reduced 15-lipoxygenase-2 immunostaining in prostate adenocarcinoma: correlation with grade and expression in high-grade prostatic intraepithelial neoplasia. Hum Pathol 2000;31:1146-1154.
[68] Werz O. 5-lipoxygenase cellular biology and molecular pharmacology.Curr Drug Targets Inflamm Allergy 2002;1:23-44.
[69] Claria J, Romano M. Pharmacological intervention of cyclooxygenase-2 and 5-lipoxygenase pathways impact on inflammation and cancer.Curr Pharm Des 2005;11:3431-3447.
[70] Hoshiko S,Radmark O,Samuelsson B.Characterization of the human 5-lipoxygen- ase gene promoter.Proc Natl Acad Sci USA 1990;87:9073-9077.
[71] Funk CD. Prostaglandins and leukotrienes: advances in eicosanoid biology. Science 2001;294:1871-1875.
[72] Cao Y, Prescott SM. Many actions of cyclooxygenase-2 in cellular dynamics and in cancer. J Cell Physiol 2002;190:279-286.
[73] Werz O, Burkert E, Samuelsson B, Radmark O, Steinhilber D. Activation of 5-lipoxygenase by cell stress is calcium independent in human polymorph- onuclear leukocytes. Blood 2002;99:1044-1052.
[74] Hammarberg T, Reddy KV, Persson B, Radmark O. Calcium binding to 5- lipoxygenase. Adv Exp Med Biol 2002;507:117-121.
[75] Fischer L, Poeckel D, Buerkert E, Steinhilber D, Werz O. Inhibitors of actin polymerisation stimulate arachidonic acid release and 5-lipoxygenase activation by upregulation of Ca2+ mobilisation in polymorphonuclear leukocytes involving Src family kinases.Biochim Biophys Acta 2005;1736:109-119.
[76] Peters-Golden M, Brock TG. 5-lipoxygenase and FLAP. Prostaglandins Leukot Essent Fatty Acids 2003;69:99-109.
[77] Werz O, Steinhilber D. Development of 5-lipoxygenase inhibitors-lessons from cellular enzyme regulation. Biochem Pharmacol 2005;70:327-333.
[78] Hong SH, Avis I, Vos MD, Martinez A, Treston AM, Mulshine JL. Relationship of arachidonic aicd metabolizing enzyme expression in epithelial cancer cell lines to the growth effect of selective biochemical inhibitors. Cancer Res 1999;59: 2223-2228.
[79] Hennig R, Ding XZ, Tong WG, Schneider MB, Standop J, Friess H, Buchler MW, Pour PM, Adrian TE. 5-lipoxygenase and leukotriene B (4) receptor are expr- essed in human pancreatic cancers but not in pancreatic ducts in normal tissue. Am J Pathol 2002;161:421-428.
[80] Hoque A, Lippman SM, Wu TT, Xu Y, Liang ZD, Swisher S, Zhang H, Cao L, Ajani JA, Xu XC, Increased 5-lipoxygenase expression and induction of apoptosis by its inhibitors in esophageal cancer.a potential target for prevention. Carcinogenesis 2005; 26: 785-791.
[81] Chen X, Li N, Wang S, Hong J, Fang M, YousselfsonJ, Yang P, NewmanRA, Lubet RA, Yang CS. Aberrant arachidonic acid metabolism in esophageal adenocarcinogenesis,and the effects of sulindac, nordihydroguaiaretic acid, and alpha-difluoromethylomithine on tumorigenesis in a rat surgicalmodel. Carcino- genesis 2002;23:2095-2102.
[82] Rioux N, Castongvay A. Inhibitors of lipoxygenase: a new class of cancer chemopreventive agents. CarcinoRenesis 1998;19:1393-1400.
[83] Ginning WT, Kramer PM, Steele VE, Pereira MA. Chemoprevention by lipoxygenase and leukotriene pathway inhibitors of vinyl carbamate-induced lung tumors in mice. Cancer Res 2002;62:4199-4201.
[84] Ghosh J, Myers CE. Inhibition of arachidonate 5-1ipoxygenase triggers massive apoptosis in human prostate cancer cells. Proc Natl Acad Sci USA 1998;95:13182 -13187.
[85] Matsuyama M, Yoshimura R, Mitsuhashi M, Tsuchida K, Takemoto Y, Kawahito Y, Sano H, Nakatani T. 5-Lipoxygenase inhibitors attenuate growth of human renal cell carcinoma and induce apoptosis through arachidonic acid pathway. Oncol Rep 2005;14: 73-79.
[86] Schwartz GK, Weitzman A, O'Reilly E, Brail L, de Alwis DP, Cleverly A, Barile-Thiem B, Vinciguerra V, Budman DR Phase I and pharmacokinetic study LY293111, an orally bioavailable LTB4 receptor antagonist, in patients with advanced solid tumors. ] clin Oncol 2005; 23: 5365-5373.
[87] Ding XZ, Talamonri MS, Bell RH Jr, Adrian TE. Anovel anti-pancreatic cancer agent, LY293111. Anti-cancer Drugs 2005;16:467-473.
[88] Ghosh J, Myers CE. Central role of arachidonate 5-lipoxygenase in the regulation of cell growth and apoptosis in human prostate cancer cells. Adv ExpMed Biol 1999:469:577-582.
[89] Steele VE, Holmes CA, Hawk ET, Kopelovich L, Lubet RA, Crowell JA, Sigman CC, Kelloff GJ. Lipoxygenase inhibitors as potential cancer chemopreventives. Cancer Epidemiol Biomarkers Prev 1999; 8:467-483.
[90] Tong WG, Ding XZ, Witt RC, Adrian TE. Lipoxygenase inhibitors attenuate growth ofhuman pancreatic cancer xenografts and induce apoptosis through the mitochondrial pathway. Mol Cancer Ther 2002;1:929-935.
[91] Tong WG, Ding XZ, Adrian TE. The mechanisms of lipoxygenase inhibitor- induced apoptosis in human breast cancer cells. Biochem Biophys Res Commun 2002;296:942-948.
[92] Fan XM, Tu SP, Lam SK, Wang WP, Wu J, Wong WM, Yuen MF, Lin MC, Kung HF, Wong BC. Five-lipoxygenase-activating protein inhibitor MK-886 induces apoptosis in gastric cancer through upregulation of p27kip1 and bax. J Gastroent- erol Hepatol 2004;19:31-37.
[93] Tong WG, Ding XZ, Hennig R, Witt RC, Standop J, Pour PM, Adrian TE. Leukotriene B4 receptor antagonist LY293111 inhibits proliferation and induces apoptosis in human pancreatic cancer cells. Clin Cancer Res 2002;8:3232-3242.
[94] Werz O, Burkert E, Fischer L, Szellas D, Dishart D, Samuelsson B, Radmark O, Steinhilber D. Extracellular signal-regulated kinases phosphorylate 5- lipoxygenase and stimulate 5-lipoxygenase product formation in leukocytes. FASEB J 2002;16:1441-1443.
[95] del Peso L, Gonzalez-Garcia M, Page C, Herrera R,Nunez G. Interleukin-3- induced phosphorylation ofBAD through the protein kinase Akt. Science 1997;278:687-689.
[96] Datta SR, Dudek H, Tao X, Masters S, Fu H, GotohY, Greenberg ME. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 1997;91:231-241.
[97] Kane LP, Mollenauer MN, Xu Z, Turck CW, Weiss A. Akt-dependent phosphorylation specifically regulates Cot induction of NF-kappa B-dependent transcription. Mol Cell Biol 2002;22:5962-5974.
[98] Tyers M, Rachubinski RA, Stewart MI, Varrichio AM, Shorr RG, Haslam RJ, Harley CB. Molecular cloning and expression of the major protein kinase C substrate of platelets. Nature 1988; 333: 470-473.
[99] Szekeres CK, Tang K, Trikha M, Honn KV. Eicosanoid activation of extracellularsignal-regulated kinasel/2 in human epidermoid carcinoma cells. Biol Chem 2000; 275:38831-38841.
[100] Zeng ZZ, Yellaturu CR, Neeli I, Rao GN. 5 (S)-hydroxyeicosatetraenoic acid stimulates DNA synthesis in human microvascular endothelial cells via activation of Jak/STAT and phosphatidylinositol 3-kinase/Akt signaling, leading to induction of expression of basic fibroblast growth factor 2.]Biol Chem 2002;277: 41213-41219.
[101] Romano M, Claria J. Cyclooxygenase-2 and 5-lipoxygenase converging functions on cell proliferation and tumor angiogenesis: implications for cancer therapy. FASEB 2003;17:1986-1995.
[102] Liotta LA, Steeg PS, Stetler-Stevenson WG. Cancer metastasis and angiogenesis: an imbalance of posifive and negative regulation. Cell 1991;64:327 -336.
[103] Wang Y, Zhou B, Li J, Cao YB, Chen XS, Cheng MH, Yin M. Inhibitors of 5-lipoxygenase inhibit expression of intercellular adhesion molecule-1 in human melanoma cells. Acta Pharmacol Sin 2004;25:672-677.
[104]贾旭东,韩弛.生物学标志物在大肠癌化学预防中的应用研究[J].卫生研究, 2000,29(2):109.
[105] Reed JC, Tsujimoto Y, Alpers JD, et al. Regulations of bcl-2 pro-to-oncogene expression during normal human lymphocyte proliferation [J]. Science, 1987,236: 1295.
[106]徐晓丽.大肠癌及腺瘤中细胞凋亡和bcl-2, bax基因的表达[J].中华病理学杂志, 1998,27(2):141.
[107] Wastson AJ, Merritt AJ, Jones LS, et al. Evidence for reciprocity of bcl-2 and p53 expression in human colorectal adenomas and cinomas [J]. Br J Cancer, 1996,73(8):889
[108]侯宝华.热疗联合DDP诱导大肠癌细胞凋亡和bcl-2表达的实验研究[J].湖北医科大学学报, 2000,21(2):133.
[109] Hockenbery D, Nunez G, Milliman C, et al. bcl-2 as inner mito chondrial membrane protein that blocks programmed cell death [J]. Nature,1990,384:334.
[110]孙方利.大肠肿瘤bcl-2和c-myc基因的表达及其意义[J].齐鲁医学杂志, 1999,155:316.
[111]肖小炜. Bcl-2, cmyc和p53致癌蛋白的共同表达对大肠癌预后的评价[J].四川肿瘤防治, 1999,12(4):5.
[112]曹立宇.大肠肿瘤中p53和bcl-2蛋白的表达方式[J].临床与实验病理学杂志, 2000,16(3):214.
[113] Pilotti S, Collini P, Rilke F, et al. Bcl-2 protein expression in carcinomas originating from the follicular epithelium of the thyroidgland [J]. JPathol, 1994,172:337.
[114] Joensun H, Pylkanen L, Toikkqnens. bcl-2 protein expression and long-tern surviral in breast cancer [J]. Am J Pathol, 1994,145(5):1191.
[115] Villuendas R, Riris MA, Orradre JL, et al. Different bcl-2 protein expression in hight grade B-cell lymphomas derived from lymph node of mucosa-associated lymphoid tissue [J]. Am J Pathol,1991,139:989 .
[116]梁智勇,柳凤轩,刘丽梅. p53及bcl-2蛋白在大肠腺瘤及腺癌中的表达[J].第三军医大学学报, 1998,20(6):516.
[117]骆成玉,李世拥.大肠癌bcl-2基因表达和重排的研究[J].中国普外基础与临床杂志, 1999,6(1):4.
[118] Garcia R L, Coltrera M D, Gown A N. Analysis of proliferating grade using anti-PCNA/cyxlin monoclonal antibodies in fixed, embeded tissue: comparison with flow cytometric analysis [J]. Am JPathol, 1989,134:733.
[119] Hsu B, Marin MC, Brisbay S, et al. Expression of bcl-2 gene con-fers multidrug resistance to chemotherapy-induced cell death [J]. Cancer Bull, 1994,46(1):125.
[120] Fisher TC, Milner AE, Gregory CD, et al. Bcl-2 modulation of apoptosis induced by anticancer drugs: resistance to thymidylate stress is independent of classical resistance pathways [J]. Cancer Res,1993,53(15):3321.
[121] Yin XY, Oltval ZN, Korsmeyer SJ. BH1 and BH2 domains of bcl-2 are required for inhibition of apoptosis and heterodimerization with bax [J]. Nature, 1994,369:321.
[122]乔庆,吴金生.凋亡相关基因bcl-2, bax在人类大肠腺癌中的表达意义[J].世界华人消化杂志, 1999,7(11):936.
[123] DuBois RN, Abramson SB, Crofford LRAG, et al. Cyclooxygenase in biology anddisease [J]. FASEB J 1998;12:1063-73.
[124] Samuelsson B, Dahlen SE, Lindgren JA, et al Leukotrienes and lipoxins: structures, biosynthesis, and biological effects [J]. Science 1987;237:1171-6.
[125] Wang D, DuBois RN. Prostaglandins and cancer [J]. Gut 2006;55:115-22.
[126] Shureiqi I, Lippman SM. Lypoxygenase modulation to reverse carcinog- enesis [J]. Cancer Res 2001;61:6307-12.
[127] Gupta RA, DuBois RN. Colorectal cancer prevention and treatment by inhibition of cyclooxygenase-2 [J]. Nat Rev Cancer 2001;1:11-21.
[128] Rikio Yoshimura, Hajime Sano, Chikayosi Masuda, etal. Expression of Cyclooxygenase-2 in prostate carcinoma. Cancer. 2000;89(3):589-596.
[129] Levy GN.Prostaglandin H synthases, nonsteroidal anti-fiammtory drugs, and colon cancer. FASEB J.1997;11(4):234-247.
[130] Lim HY. Joo HJ, etal. Increased expression of cyclooxygenase-2 protein in human gastric cancinoma. Clin cancer Res. 2000;6(2):519-525.
[131] Half E, Tang XM, Gwyn K, et al, Cyclooxygenase-2 expression in human breast cancers and adjacent ductal carcinoma in situ. Cancer Res. 2002;62(6): 1676-1681.
[132] Cao Y, Prescott SM. Many actions of cyclooxygenase-2 in cellular dynamics and in cancer. J Cell Physiol 2002; 190: 279-286.
[133] Ye YN, Liu ES, Shin VY, Wu WK, Cho CH. Contributory role of 5- lipoxygenase and its association with angiogenesis in the promotion of inflammation- associated colonic tumorigenesis by cigarette smoking. Toxicology 2004;203:179-188.
[134] Ikawa H, Kamitani H, Calvo BF, Foley JF, Eling TE. Expression of 15-lipoxygenase-1 in human colorectal cancer. Cancer Res 1999;59:360-366.
[135] Shureiqi I, Wojno KJ, Poore JA, Reddy RG, Moussalli MJ, Spindler SA, Greenson JK, Normolle D, Hasan AA, Lawrence TS, Brenner DE. Decreased 13-S-hydroxyoctadecadienoic acid levels and 15-lipoxygenase-1 expression in human colon cancers. Carcinogenesis 1999;20:1985-1995.
[136] Heslin MJ, Hawkins A, Boedefeld W, Arnoletti JP, Frolov A, Soong R, Urist MM,Bland KI. Tumor-associated down-regulation of 15-lipoxygenase-1 is reversed by celecoxib in colorectal cancer. Ann Surg 2005;241:941-946; discussion 946-947.
[137] Jack GS, Brash AR, Olson SJ, Manning S, Coffey CS, Smith JA Jr, Shappell SB. Reduced 15-lipoxygenase-2 immunostaining in prostate adenocarcinoma: correlation with grade and expression in high-grade prostatic intraepithelial neoplasia. Hum Pathol 2000;31:1146-1154.
[138] Reed JC. Bcl-2 family proteins: regulators of apoptosis and chemoresistance in hematologic malignancies [J]. Sem in Hematol, 1997,34(4):9-19.
[139] Gibson LF, Fortney J, Magro G, et al. Regulation of BAX and Bcl-2 expression in breast cancer cells by chemotherapy [J]. Breast Cancer Res Treat, 1999,55(2):107-17.
[140] Cianchi F, Cortesini C, Magnelli L, et al. Inhibition of 5-lipoxygenase by MK886 augments the antitumor activity of celecoxib in human colon cancer cells Mol Cancer Ther, 2006,5(11):2716-26.
[141]吴在德,吴肇汉.外科学[M].第7版.北京:人民卫生出版社, 2008: 487-92.
[142] WeidnerN. Current pathologic methods formeasuring intratumoral microvessel density within breast carcinoma and other solid tumors [J]. BreastC- ancerResTreat, 1995,36:169.
[2] Wang D, Mann JR, DuBois RN. The role of prostaglandins and other eicosanoids in the gastrointestinal tract. Gastroenterology 2005;128:1445-61.
[3] Hase T, Yoshimura R, Matsuyama M, et al. Cyclooxygenase-1 and-2 in human testicular tumours. Eur J Cancer 2003;39:2043-49.
[4] Steinbach G, Lynch PM, Phillips RK, Wallace MH, Hawk E, Gordon GB, Wakabayashi N, Saunders B, Shen Y, Fujimura T, Su LK, Levin B. The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N Engl J Med 2000;342:1946-52.
[5] Sandler RS, Halabi S, Baron JA, Budinger S, Paskett E, Keresztes R, Petrelli N, Pipas JM, Karp DD, Loprinzi CL, Steinbach G, Schilsky R. A randomized trial of aspirin to prevent colorectal adenomas in patients with previous colorectal cancer. N Engl J Med 2003;348:883-890.
[6] Reardon DA, Quinn JA, Vredenburgh J, Rich JN, Gururangan S, Badruddoja M, Herndon JE 2nd, Dowell JM, Friedman AH, Friedman HS. Phase II trial of irinotecan plus celecoxib in adults with recurrent malignant glioma. Cancer 2005; 103:329-338.
[7] Milella M, Gelibter A, Di Cosimo S, Bria E, Ruggeri EM, Carlini P, Malaguti P, Pellicciotta M, Terzoli E, Cognetti F. Pilot study of celecoxib and infusional 5-fluorouracil as second-line treatment for advanced pancreatic carcinoma. Cancer 2004;101:133-138.
[8] Steele VE, Holmes CA, Hawk ET, Kopelovich L, Lubet RA, Crowell JA, Sigman CC, Kelloff GJ. Lipoxygenase inhibitors as potential cancer chemopreventives. Cancer Epidemiol Biomarkers Prev 1999; 8: 467-483.
[9] Gupta S, Srivastava M, Ahmad N, Sakamoto K, Bostwick DG, Mukhtar H. Lipoxygenase-5 is overexpressed in prostate adenocarcinoma. Cancer 2001; 91:737-743.
[10] Yoshimura R, Matsuyama M, Tsuchida K, Kawahito Y, Sano H, Nakatani T. Expression of lipoxygenase inhuman bladder carcinoma and growth inhibition by its inhibitors. J Urol 2003;170:1994-1999.
[11] Hong SH, Avis I, Vos MD, Martinez A, Treston AM, Mulshine JL. Relationship of arachidonic acid metabolizing enzyme expression in epithelial cancer cell lines to the growth effect of selective biochemical inhibitors. Cancer Res 1999; 59: 2223-2228.
[12] Ohd JF, Nielsen CK, Campbell J, Landberg G, Lofberg H, Sjolander A. Expression of the leukotriene D4 receptor CysLT1, cox-2, and other cell sur- vival factors in colorectal adenocarcinomas. Gastroenterology 2003; 124: 57-70.
[13] Hennig R, Grippo P, Ding XZ, Rao SM, Buchler MW, Friess H, Talamonti MS, Bell RH, Adrian TE. 5-Lipoxygenase, a marker for early pancreatic intraepithelial neoplastic lesions. Cancer Res 2005;65:6011-6016.
[14] Li N, Sood S, Wang S, Fang M, Wang P, Sun Z, Yang CS, Chen X. Overexp- ression of 5-lipoxygenase and cyclooxygenase 2 in hamster and human oral cancer and chemopreventive effects of zileuton and celecoxib. Clin Cancer Res 2005;11:2089-2096.
[15] Chen X, Wang S, Wu N, Sood S, Wang P, Jin Z, Beer DG, Giordano TJ, Lin Y, Shih WC, Lubet RA, Yang CS. Overexpression of 5-lipoxygenase in rat and human esophageal adenocarcinoma and inhibitory effects of zileuton and celecoxib on carcinogenesis. Clin Cancer Res 2004;10:6703-6709.
[16] Avis I, Hong SH, Martinez A, Moody T, Choi YH, Trepel J, Das R, Jett M, Mulshine JL. Five-lipoxygenase inhibitors can mediate apoptosis in human breast cancer cell lines through complex eicosanoid interactions. FASEB J 2001;15: 2007-2009.
[17] Romano M, Catalano A, Nutini M, D’Urbano E, Crescenzi C, Claria J, Libner R, Davi G, Procopio A. 5-lipoxygenase regulates malignant mesothelial cell survival: involvement of vascular endothelial growth factor. FASEB J 2001;15:2326-2336.
[18] Hoque A, Lippman SM, Wu TT, Xu Y, Liang ZD, Swisher S, Zhang H, Cao L, Ajani JA, Xu XC. Increased 5-lipoxygenase expression and induction of apo- ptosis by itsinhibitors in esophageal cancer: a potential target for prevention. Carcinogenesis 2005;26:785-791.
[19]徐天宇.利用生物技术生产二十碳五烯酸和二十二碳六烯酸.食品与发酵工业, 1995,1:56-65。
[20]包建新,楼亚平.花生四烯酸及其代谢物的第二信使作用.中国药理学通报, 1991,7(5):321-323。
[21] Morrow JD, Haris TM, Roberts II LJ. Noncyclooxygenase oxidative formation of a series of novel prostaglandins: Analytical ramification for measurement of eicosanoids. Anal Biochem, 1990,184:1-10.
[22] Piomelli D, Volterra A, Siegelbaum SA, et al. Lipoxygenase metabolites of arachidonic acid as second messengers for presynaptic inhibition of aplysia sensory cells. Nature, 1987,328:38-43.
[23]王治荣.白细胞的花生四烯酸代谢.生理科学进展, 1986,17(3):250-253.
[24] Bliss TVP, Douglas RM, Errington ML, et al. Correlation between long-term potentiatin and release of endogenous amino acids from dentate gyrus of aesth- etized rats. J Physiol, 1986,377:391-408.
[25]李春海.花生四烯酸衍生物与造血和免疫调节.军事医学科学院院刊, 1989,13(4):259-265。
[26] Mong S, Chi-Rosso G,Miller J, etal. Leukotriene B4 induces formation of inositol phosphates in rat peritoneal polymorphonuclear leukocytes. Mol Pharmacol, 1986,30:235-242.
[27]孙庆伟.花生四烯酸代谢物与胆肝.生理科学进展, 1992,23(2):177-180.
[28]吴升华.花生四烯酸非环氧合酶产物与肾脏疾病.国外医学-泌尿系统分册, 1994,14(5):208-211。
[29] Nigam S, Fiore S, Luscinskas FW, etal. Lipoxin A4 and lipoxin B4 stimulate the release but not oxygenation of arachidonic acid inhuman neutrophils:dissociation between lipid remoseling and adhesion. J Cell Physiol, 1990,143:512-523.
[30] Wang D, Dubois RN. Prostaglandins and cancer. Gut 2006;55:115-122.
[31] Aggarwal S, Taneja N, Lin L, Orringer MB, Rehemtulla A, Beer DG. Indom- ethacin-induced apoptosis in esophageal adenocarcinoma cells involves upregul- ation of Bax and translocation of mitochondrial cytochrome C independent of cox-2 expression. Neoplasia 2000;2:346-356.
[32] He Q, Luo X, Huang Y, Sheikh MS. Apo2L/TRAIL differentially modulates the apoptotic effects of sulindac and a cox-2 selective non-steroidal anti-inflame- matory agent in Bax-deficient cells. Oncogene 2002;21:6032-6040.
[33] Dohadwala M, Batra RK, Luo J, Lin Y, Krysan K, Pold M, Sharma S, Dubinett SM. Autocrine/paracrine prostaglandin E2 production by non-small cell lung cancer cells regulates matrix metalloproteinase-2 and CD44 in cyclooxygenase- 2-dependent invasion. J Biol Chem 2002;277:50828-50833.
[34] Pan MR, Chuang LY, Hung WC. Non-steroidal anti-inflammatory drugs inhibit matrix metalloproteinase-2 expression via repression of transcription in lung cancer cells. FEBS Lett 2001;508:365-368.
[35] Farrow B, Evers BM. Inflammation and the development of pancreatic cancer. Surg Oncol 2002;10:153-169.
[36] Liyanage UK, Moore TT, Joo HG, Tanaka Y,Herrmann V, Doherty G, Drebin JA, Strasberg SM, Eberlein TJ, Goedegebuure PS, Linehan DC.Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma. J Immunol 2002;169:2756- 2761.
[37] Morita I, Schindler M, Regier MK, et al. Different intracekkular locations for prostaglandin endoperoxide H synthase-1 and–2. J Biol Chem. 1995;270(18): 10902-10908.
[38] Inoue H, Yokoyama C, Hara S, et al. Transcriptional regulation of human prostaglandin endoperoxide synthase-2 gene by lipopolysaccharide and phorbol ester in vascular enlothelial cells. J Biol Chem. 1995;270(42):24965-24971.
[39] Hla T, Neilson K. Human Cyclo-oxygenase-2 CDNA. Proc Natl Acad Sci USA. 1992;89(16):7384-7388.
[40] Jones DA, Carlton DP, McIntyre TM, et al. Molecular cloning of human prostaglandin endoperoxide synthase typeⅡand demonstration of expression in response to cytokines. J Biol Chem. 1993;268(12):9049-9054.
[41] Rudnick DA, Perlmutter DH, Muglia LJ. Prostaglandins are required for CREB activation and cellular proliferation during liver regeneration [J]. Proc Natl Acad Sci USA,2001,98(15):8885-8890.
[42] ShengH, Shao J, Washington MK, et al. Prostaglandin E2 increases growth andmotility of colorectal carcinoma cells [J]. J Biol Chem,2001,276(21): 18075-18081.
[43] Dermott JM, ReddyMR, Onesime D, et al. Oncogenic mutant of Galpha12 stimulates cell proliferation through cycloxygenase-2 signaling pathway [J]. Oncogene, 1999,18(51):7185-7189.
[44] Mann M, Sheng H, Shao J,et al. Targeting cyclooxygenase 2 and HER-2/neu pathways inhibits colorectal carcinoma growth [J]. Gas troenterology, 2001,120 (7):1713-1719.
[45] Ding XZ, Tong WG, AdrianTE. Blockade of cyclooxygenase-2 inhibits proliferation and induces apoptosis in human pancreatic cancer cells [J]. Antica- ncer Res, 2000,20(4):2625-2631.
[46] Joki T, Heese O, Nikas DC, et al. Expression of cyclooxygenase 2 (cox-2) in human glioma and in vitro inhibition by a specific cox-2 inhibitor, NS-398 [J]. Cancer Res, 2000,60(17):4926-4931.
[47] Li M, Wu X, Xu XC. Induction of apoptosis in colon cancer cells by cyclooxygenase-2 inhibitor NS398 through a cytochrome c-dependent pathway [J]. Clin Cancer Res, 2001,7(4):1010-1016.
[48] Sun Y, Tang XM, Half E, et al. Cyclooxygenase-2 overexpression reduces apoptotic susceptibility by inhibiting the cytochrome c-dependent apoptotic pathway in human colon cancer cells [J]. Cancer Res, 2002,62(21):6323-6328.
[49] Scorrano L, Penzo D, Petronilli V, et al. Arachidonic acid causes celldeath thro- ugh the mitochondrial permeability transition. Implications for tumor necrosis factor-alpha aopototic signaling [J]. J Biol Chem, 2001,276(15):12035-12040.
[50] Cao Y, Dave KB, DoanTP,et al. Fatty acid CoA ligase 4 is up-regulated in colon adenocarcinoma [J]. Cancer Res, 2001,61(23):8429-8434.
[51] Cao Y, Pearman AT, Zimmerman GA, et al. Intracellular unesterified arachidonic acid signals apoptosis [J]. Proc Natl Acad Sci USA, 2000,97(21):11280-11285.
[52] Kundu N, Smyth MJ, Samsel L,et al. Cyclooxygenase inhibitors blockcell growth, increase ceramide and inhibit cell cycle [J]. Breast Cancer ResTreat, 2002,76 (1):57-64.
[53] Yamamoto Y, Yin MJ, Lin KM, et al. Sulindac inhibits activation of the NF-kappaB pathway [J]. J Biol Chem, 1999,274(38):27307-27314.
[54] Hsu AL, Ching TT, Wang DS,et al. The cyclooxygenase-2 inhibitor celecoxib induces apoptosis by blockingAkt activation in human prostate cancer cells independently of Bcl-2[J].J Biol Chem, 2000,275(15):11397-11403.
[55] Poligone B, BaldwinAS. Positive and negative regulation of NF-kappaB by cox-2: roles of different prostaglandins [J]. J Biol Chem, 2001,276(42):38658 -38664.
[56] Noda M, Tatsumi Y, TomizawaM, et al. Effects of etodolac, a selective cyclooxygenase-2 inhibitor, on the expression of E-cadherin-catenin complexes in gastrointestinal cell lines [J]. J Gastroenterol, 2002,37(11):896-904.
[57] Dohadwala M, Batra RK, LuoJ,et al. Autocrine/paracrine prostaglandin E2 production by non-small cell lung cancer cellsregulates matrix metalloproteinase-2 and CD44 in cyclooxygenase-2-dependent invasion [J]. J Biol Chem, 2002,277(52):50828-50833.
[58] Dohadwala M, Luo J, Zhu L,et al. Non-small cell lung cancer cyclooxygenase- 2-dependent invasion is mediated by CD44 [J]. J Biol Chem, 2001,276(24): 20809-20812.
[59] Masferrer JL, Leahy KM, Koki AT, et al. Antiangiogenic and antitu-mor activities of cyclooxygenase-2 inhibitors [J]. Cancer Res,2000,60(5):1306-1311.
[60] Sonoshita M, Takaku K, Sasaki N,et al. Acceleration of intestinal polyposis through prostaglandin receptor EP2 in Apc (Delta 716) knock out mice [J]. Nat Med, 2001,7(9):1048-1051.
[61] Leval X, Julemont F, Delarge J, Pirotte B, Dogne JM. New trends in dual 5-lox/coxinhibition. Curr Med Chem 2002;9:941-962.
[62] Ikawa H, Kamitani H, Calvo BF, Foley JF, Eling TE. Expression of 15- lipoxygenase-1 in human colorectal cancer. Cancer Res 1999;59:360-366.
[63] Yamamoto S. Mammalian lipoxygenases: molecular structures and functions. Biochim Biophys Acta 1992;1128:117-131.
[64] Matsuyama M, Yoshimura R, Tsuchida K, Takemoto Y, Segawa Y, Shinnka T, Kawahito Y, Sano H, Nakatani T. Lipoxygenase inhibitors prevent urological cancer cell growth. Int J Mol Med 2004; 13: 665-668.
[65] Shureiqi I, Wojno KJ, Poore JA, Reddy RG, Moussalli MJ, Spindler SA, Greenson JK, Normolle D, Hasan AA, Lawrence TS, Brenner DE.Decreased 13-S-hydroxyoctadecadienoic acid levels and 15-lipoxygenase-1 expression in human colon cancers. Carcinogenesis 1999;20:1985-1995.
[66] Heslin MJ, Hawkins A, Boedefeld W, Arnoletti JP, Frolov A, Soong R, Urist MM, Bland KI. Tumor-associated down-regulation of 15-lipoxygenase-1 is reversed by celecoxib in colorectal cancer. Ann Surg 2005;241:941-946; discu- ssion 946-947.
[67] Jack GS, Brash AR, Olson SJ, Manning S, Coffey CS, Smith JA Jr, Shappell SB. Reduced 15-lipoxygenase-2 immunostaining in prostate adenocarcinoma: correlation with grade and expression in high-grade prostatic intraepithelial neoplasia. Hum Pathol 2000;31:1146-1154.
[68] Werz O. 5-lipoxygenase cellular biology and molecular pharmacology.Curr Drug Targets Inflamm Allergy 2002;1:23-44.
[69] Claria J, Romano M. Pharmacological intervention of cyclooxygenase-2 and 5-lipoxygenase pathways impact on inflammation and cancer.Curr Pharm Des 2005;11:3431-3447.
[70] Hoshiko S,Radmark O,Samuelsson B.Characterization of the human 5-lipoxygen- ase gene promoter.Proc Natl Acad Sci USA 1990;87:9073-9077.
[71] Funk CD. Prostaglandins and leukotrienes: advances in eicosanoid biology. Science 2001;294:1871-1875.
[72] Cao Y, Prescott SM. Many actions of cyclooxygenase-2 in cellular dynamics and in cancer. J Cell Physiol 2002;190:279-286.
[73] Werz O, Burkert E, Samuelsson B, Radmark O, Steinhilber D. Activation of 5-lipoxygenase by cell stress is calcium independent in human polymorph- onuclear leukocytes. Blood 2002;99:1044-1052.
[74] Hammarberg T, Reddy KV, Persson B, Radmark O. Calcium binding to 5- lipoxygenase. Adv Exp Med Biol 2002;507:117-121.
[75] Fischer L, Poeckel D, Buerkert E, Steinhilber D, Werz O. Inhibitors of actin polymerisation stimulate arachidonic acid release and 5-lipoxygenase activation by upregulation of Ca2+ mobilisation in polymorphonuclear leukocytes involving Src family kinases.Biochim Biophys Acta 2005;1736:109-119.
[76] Peters-Golden M, Brock TG. 5-lipoxygenase and FLAP. Prostaglandins Leukot Essent Fatty Acids 2003;69:99-109.
[77] Werz O, Steinhilber D. Development of 5-lipoxygenase inhibitors-lessons from cellular enzyme regulation. Biochem Pharmacol 2005;70:327-333.
[78] Hong SH, Avis I, Vos MD, Martinez A, Treston AM, Mulshine JL. Relationship of arachidonic aicd metabolizing enzyme expression in epithelial cancer cell lines to the growth effect of selective biochemical inhibitors. Cancer Res 1999;59: 2223-2228.
[79] Hennig R, Ding XZ, Tong WG, Schneider MB, Standop J, Friess H, Buchler MW, Pour PM, Adrian TE. 5-lipoxygenase and leukotriene B (4) receptor are expr- essed in human pancreatic cancers but not in pancreatic ducts in normal tissue. Am J Pathol 2002;161:421-428.
[80] Hoque A, Lippman SM, Wu TT, Xu Y, Liang ZD, Swisher S, Zhang H, Cao L, Ajani JA, Xu XC, Increased 5-lipoxygenase expression and induction of apoptosis by its inhibitors in esophageal cancer.a potential target for prevention. Carcinogenesis 2005; 26: 785-791.
[81] Chen X, Li N, Wang S, Hong J, Fang M, YousselfsonJ, Yang P, NewmanRA, Lubet RA, Yang CS. Aberrant arachidonic acid metabolism in esophageal adenocarcinogenesis,and the effects of sulindac, nordihydroguaiaretic acid, and alpha-difluoromethylomithine on tumorigenesis in a rat surgicalmodel. Carcino- genesis 2002;23:2095-2102.
[82] Rioux N, Castongvay A. Inhibitors of lipoxygenase: a new class of cancer chemopreventive agents. CarcinoRenesis 1998;19:1393-1400.
[83] Ginning WT, Kramer PM, Steele VE, Pereira MA. Chemoprevention by lipoxygenase and leukotriene pathway inhibitors of vinyl carbamate-induced lung tumors in mice. Cancer Res 2002;62:4199-4201.
[84] Ghosh J, Myers CE. Inhibition of arachidonate 5-1ipoxygenase triggers massive apoptosis in human prostate cancer cells. Proc Natl Acad Sci USA 1998;95:13182 -13187.
[85] Matsuyama M, Yoshimura R, Mitsuhashi M, Tsuchida K, Takemoto Y, Kawahito Y, Sano H, Nakatani T. 5-Lipoxygenase inhibitors attenuate growth of human renal cell carcinoma and induce apoptosis through arachidonic acid pathway. Oncol Rep 2005;14: 73-79.
[86] Schwartz GK, Weitzman A, O'Reilly E, Brail L, de Alwis DP, Cleverly A, Barile-Thiem B, Vinciguerra V, Budman DR Phase I and pharmacokinetic study LY293111, an orally bioavailable LTB4 receptor antagonist, in patients with advanced solid tumors. ] clin Oncol 2005; 23: 5365-5373.
[87] Ding XZ, Talamonri MS, Bell RH Jr, Adrian TE. Anovel anti-pancreatic cancer agent, LY293111. Anti-cancer Drugs 2005;16:467-473.
[88] Ghosh J, Myers CE. Central role of arachidonate 5-lipoxygenase in the regulation of cell growth and apoptosis in human prostate cancer cells. Adv ExpMed Biol 1999:469:577-582.
[89] Steele VE, Holmes CA, Hawk ET, Kopelovich L, Lubet RA, Crowell JA, Sigman CC, Kelloff GJ. Lipoxygenase inhibitors as potential cancer chemopreventives. Cancer Epidemiol Biomarkers Prev 1999; 8:467-483.
[90] Tong WG, Ding XZ, Witt RC, Adrian TE. Lipoxygenase inhibitors attenuate growth ofhuman pancreatic cancer xenografts and induce apoptosis through the mitochondrial pathway. Mol Cancer Ther 2002;1:929-935.
[91] Tong WG, Ding XZ, Adrian TE. The mechanisms of lipoxygenase inhibitor- induced apoptosis in human breast cancer cells. Biochem Biophys Res Commun 2002;296:942-948.
[92] Fan XM, Tu SP, Lam SK, Wang WP, Wu J, Wong WM, Yuen MF, Lin MC, Kung HF, Wong BC. Five-lipoxygenase-activating protein inhibitor MK-886 induces apoptosis in gastric cancer through upregulation of p27kip1 and bax. J Gastroent- erol Hepatol 2004;19:31-37.
[93] Tong WG, Ding XZ, Hennig R, Witt RC, Standop J, Pour PM, Adrian TE. Leukotriene B4 receptor antagonist LY293111 inhibits proliferation and induces apoptosis in human pancreatic cancer cells. Clin Cancer Res 2002;8:3232-3242.
[94] Werz O, Burkert E, Fischer L, Szellas D, Dishart D, Samuelsson B, Radmark O, Steinhilber D. Extracellular signal-regulated kinases phosphorylate 5- lipoxygenase and stimulate 5-lipoxygenase product formation in leukocytes. FASEB J 2002;16:1441-1443.
[95] del Peso L, Gonzalez-Garcia M, Page C, Herrera R,Nunez G. Interleukin-3- induced phosphorylation ofBAD through the protein kinase Akt. Science 1997;278:687-689.
[96] Datta SR, Dudek H, Tao X, Masters S, Fu H, GotohY, Greenberg ME. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 1997;91:231-241.
[97] Kane LP, Mollenauer MN, Xu Z, Turck CW, Weiss A. Akt-dependent phosphorylation specifically regulates Cot induction of NF-kappa B-dependent transcription. Mol Cell Biol 2002;22:5962-5974.
[98] Tyers M, Rachubinski RA, Stewart MI, Varrichio AM, Shorr RG, Haslam RJ, Harley CB. Molecular cloning and expression of the major protein kinase C substrate of platelets. Nature 1988; 333: 470-473.
[99] Szekeres CK, Tang K, Trikha M, Honn KV. Eicosanoid activation of extracellularsignal-regulated kinasel/2 in human epidermoid carcinoma cells. Biol Chem 2000; 275:38831-38841.
[100] Zeng ZZ, Yellaturu CR, Neeli I, Rao GN. 5 (S)-hydroxyeicosatetraenoic acid stimulates DNA synthesis in human microvascular endothelial cells via activation of Jak/STAT and phosphatidylinositol 3-kinase/Akt signaling, leading to induction of expression of basic fibroblast growth factor 2.]Biol Chem 2002;277: 41213-41219.
[101] Romano M, Claria J. Cyclooxygenase-2 and 5-lipoxygenase converging functions on cell proliferation and tumor angiogenesis: implications for cancer therapy. FASEB 2003;17:1986-1995.
[102] Liotta LA, Steeg PS, Stetler-Stevenson WG. Cancer metastasis and angiogenesis: an imbalance of posifive and negative regulation. Cell 1991;64:327 -336.
[103] Wang Y, Zhou B, Li J, Cao YB, Chen XS, Cheng MH, Yin M. Inhibitors of 5-lipoxygenase inhibit expression of intercellular adhesion molecule-1 in human melanoma cells. Acta Pharmacol Sin 2004;25:672-677.
[104]贾旭东,韩弛.生物学标志物在大肠癌化学预防中的应用研究[J].卫生研究, 2000,29(2):109.
[105] Reed JC, Tsujimoto Y, Alpers JD, et al. Regulations of bcl-2 pro-to-oncogene expression during normal human lymphocyte proliferation [J]. Science, 1987,236: 1295.
[106]徐晓丽.大肠癌及腺瘤中细胞凋亡和bcl-2, bax基因的表达[J].中华病理学杂志, 1998,27(2):141.
[107] Wastson AJ, Merritt AJ, Jones LS, et al. Evidence for reciprocity of bcl-2 and p53 expression in human colorectal adenomas and cinomas [J]. Br J Cancer, 1996,73(8):889
[108]侯宝华.热疗联合DDP诱导大肠癌细胞凋亡和bcl-2表达的实验研究[J].湖北医科大学学报, 2000,21(2):133.
[109] Hockenbery D, Nunez G, Milliman C, et al. bcl-2 as inner mito chondrial membrane protein that blocks programmed cell death [J]. Nature,1990,384:334.
[110]孙方利.大肠肿瘤bcl-2和c-myc基因的表达及其意义[J].齐鲁医学杂志, 1999,155:316.
[111]肖小炜. Bcl-2, cmyc和p53致癌蛋白的共同表达对大肠癌预后的评价[J].四川肿瘤防治, 1999,12(4):5.
[112]曹立宇.大肠肿瘤中p53和bcl-2蛋白的表达方式[J].临床与实验病理学杂志, 2000,16(3):214.
[113] Pilotti S, Collini P, Rilke F, et al. Bcl-2 protein expression in carcinomas originating from the follicular epithelium of the thyroidgland [J]. JPathol, 1994,172:337.
[114] Joensun H, Pylkanen L, Toikkqnens. bcl-2 protein expression and long-tern surviral in breast cancer [J]. Am J Pathol, 1994,145(5):1191.
[115] Villuendas R, Riris MA, Orradre JL, et al. Different bcl-2 protein expression in hight grade B-cell lymphomas derived from lymph node of mucosa-associated lymphoid tissue [J]. Am J Pathol,1991,139:989 .
[116]梁智勇,柳凤轩,刘丽梅. p53及bcl-2蛋白在大肠腺瘤及腺癌中的表达[J].第三军医大学学报, 1998,20(6):516.
[117]骆成玉,李世拥.大肠癌bcl-2基因表达和重排的研究[J].中国普外基础与临床杂志, 1999,6(1):4.
[118] Garcia R L, Coltrera M D, Gown A N. Analysis of proliferating grade using anti-PCNA/cyxlin monoclonal antibodies in fixed, embeded tissue: comparison with flow cytometric analysis [J]. Am JPathol, 1989,134:733.
[119] Hsu B, Marin MC, Brisbay S, et al. Expression of bcl-2 gene con-fers multidrug resistance to chemotherapy-induced cell death [J]. Cancer Bull, 1994,46(1):125.
[120] Fisher TC, Milner AE, Gregory CD, et al. Bcl-2 modulation of apoptosis induced by anticancer drugs: resistance to thymidylate stress is independent of classical resistance pathways [J]. Cancer Res,1993,53(15):3321.
[121] Yin XY, Oltval ZN, Korsmeyer SJ. BH1 and BH2 domains of bcl-2 are required for inhibition of apoptosis and heterodimerization with bax [J]. Nature, 1994,369:321.
[122]乔庆,吴金生.凋亡相关基因bcl-2, bax在人类大肠腺癌中的表达意义[J].世界华人消化杂志, 1999,7(11):936.
[123] DuBois RN, Abramson SB, Crofford LRAG, et al. Cyclooxygenase in biology anddisease [J]. FASEB J 1998;12:1063-73.
[124] Samuelsson B, Dahlen SE, Lindgren JA, et al Leukotrienes and lipoxins: structures, biosynthesis, and biological effects [J]. Science 1987;237:1171-6.
[125] Wang D, DuBois RN. Prostaglandins and cancer [J]. Gut 2006;55:115-22.
[126] Shureiqi I, Lippman SM. Lypoxygenase modulation to reverse carcinog- enesis [J]. Cancer Res 2001;61:6307-12.
[127] Gupta RA, DuBois RN. Colorectal cancer prevention and treatment by inhibition of cyclooxygenase-2 [J]. Nat Rev Cancer 2001;1:11-21.
[128] Rikio Yoshimura, Hajime Sano, Chikayosi Masuda, etal. Expression of Cyclooxygenase-2 in prostate carcinoma. Cancer. 2000;89(3):589-596.
[129] Levy GN.Prostaglandin H synthases, nonsteroidal anti-fiammtory drugs, and colon cancer. FASEB J.1997;11(4):234-247.
[130] Lim HY. Joo HJ, etal. Increased expression of cyclooxygenase-2 protein in human gastric cancinoma. Clin cancer Res. 2000;6(2):519-525.
[131] Half E, Tang XM, Gwyn K, et al, Cyclooxygenase-2 expression in human breast cancers and adjacent ductal carcinoma in situ. Cancer Res. 2002;62(6): 1676-1681.
[132] Cao Y, Prescott SM. Many actions of cyclooxygenase-2 in cellular dynamics and in cancer. J Cell Physiol 2002; 190: 279-286.
[133] Ye YN, Liu ES, Shin VY, Wu WK, Cho CH. Contributory role of 5- lipoxygenase and its association with angiogenesis in the promotion of inflammation- associated colonic tumorigenesis by cigarette smoking. Toxicology 2004;203:179-188.
[134] Ikawa H, Kamitani H, Calvo BF, Foley JF, Eling TE. Expression of 15-lipoxygenase-1 in human colorectal cancer. Cancer Res 1999;59:360-366.
[135] Shureiqi I, Wojno KJ, Poore JA, Reddy RG, Moussalli MJ, Spindler SA, Greenson JK, Normolle D, Hasan AA, Lawrence TS, Brenner DE. Decreased 13-S-hydroxyoctadecadienoic acid levels and 15-lipoxygenase-1 expression in human colon cancers. Carcinogenesis 1999;20:1985-1995.
[136] Heslin MJ, Hawkins A, Boedefeld W, Arnoletti JP, Frolov A, Soong R, Urist MM,Bland KI. Tumor-associated down-regulation of 15-lipoxygenase-1 is reversed by celecoxib in colorectal cancer. Ann Surg 2005;241:941-946; discussion 946-947.
[137] Jack GS, Brash AR, Olson SJ, Manning S, Coffey CS, Smith JA Jr, Shappell SB. Reduced 15-lipoxygenase-2 immunostaining in prostate adenocarcinoma: correlation with grade and expression in high-grade prostatic intraepithelial neoplasia. Hum Pathol 2000;31:1146-1154.
[138] Reed JC. Bcl-2 family proteins: regulators of apoptosis and chemoresistance in hematologic malignancies [J]. Sem in Hematol, 1997,34(4):9-19.
[139] Gibson LF, Fortney J, Magro G, et al. Regulation of BAX and Bcl-2 expression in breast cancer cells by chemotherapy [J]. Breast Cancer Res Treat, 1999,55(2):107-17.
[140] Cianchi F, Cortesini C, Magnelli L, et al. Inhibition of 5-lipoxygenase by MK886 augments the antitumor activity of celecoxib in human colon cancer cells Mol Cancer Ther, 2006,5(11):2716-26.
[141]吴在德,吴肇汉.外科学[M].第7版.北京:人民卫生出版社, 2008: 487-92.
[142] WeidnerN. Current pathologic methods formeasuring intratumoral microvessel density within breast carcinoma and other solid tumors [J]. BreastC- ancerResTreat, 1995,36:169.