Development of anti-cancer therapy combined with cyclooxygenase-2 inhibitors

环加氧酶2抑制剂联合抗癌疗法的开发

• 批准号: 17590639
• 负责人: TSUJII Masahiko
• 金额: $ 1.98万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590639/
• 关键词: cyclooxygenase; colon cancer; tumon angiogenesis; chemotherapy; interferon-γ; cyclooxgenase; 5FU; celecoxib; 併用療法; cyclooxygenase-2阻害剤; 5-FU; VEGF

Background ＆ Aims : Cyclooxygenase-2 (COX-2) inhibitors are effective chemopreventive agents against colorectal cancers. For treatment of advanced cancers, combination of COX-2 inhibitors and chemotherapy has been attempted, but the results are still controversial. In the present study, the effects of the COX-2 inhibitor celecoxib on the anticancer potential of chemotherapy, and its mechanisms of action were investigated in point of the angiogenesis and the immune response using an advanced cancer model in mice.Methods : BALB/c mice or BALB/c IFN-γ null mice were inoculated with colon 26 cells. After the allograft grew up to 5mm in diameter, the animals received celecoxib (3mg/kg), 5FU (20mg/kg), or a combination of 5FU and celecoxib (5FU/celecoxib). After 21-days of the treatment, tumors were harvested and used for analyzing angiogenesis (expression of CD31) or leukocyte infiltration (CD45 expression) by immunohistochemistry and for measuring VEGF, IFN-γ concentration by ELISA. The fr … More equency of infiltrating immune cells in the tumors was also analyzed by flow cytometric analyses.Result s: 5FU/celecoxib significantly inhibited the tumor growth and the tumor vessel density compared with the other groups. Celecoxib, 5FU or 5FU/celecoxib significantly suppressed the VEGF content in tumor tissues. 5FU/celecoxib also enhanced IFN-γ levels in tumor tissue, which could be involved in the potent antitumor effects of 5FU/celecoxib. This hypothesis was proven, because in IFN-γ null mice, the inhibitory effects of 5FU/celecoxib on angiogenesis and tumor growth were significantly impaired compared with that in wild type mice. 5FU decreased leukocyte infiltration and increased CD4+CD25^<high> T cell frequency, but the addition of celecoxib reversed these 5FU treatment related effects. 5FU and 5FU/celecoxib increased frequency of matured dendritic cells in the tumors compared with control.Conclusion : These results suggest that celecoxib enhances the antitumor effect of 5FU against an advanced colon cancer model by suppressing angiogenesis and enhancing the immune response against the tumor. In addition to VEGF, IFN-γ has pivotal roles in tumor suppression induced by a COX-2 inhibitor. Less

背景与目的：环加氧酶-2 (COX-2) 抑制剂是结直肠癌的有效化学预防剂，对于晚期癌症的治疗，已尝试将 COX-2 抑制剂与化疗联合使用，但目前的研究结果仍存在争议。 ，COX-2抑制剂塞来昔布对化疗抗癌潜力的影响及其作用机制，使用先进的癌症模型从血管生成和免疫反应的角度进行了研究。方法：给BALB/c小鼠或BALB/c IFN-γ无效小鼠接种结肠26细胞，待同种异体移植物直径长至5mm后，给予塞来昔布(3mg/kg)、5FU(20mg/kg)。 ，或5FU和塞来昔布的组合（5FU/塞来昔布）治疗21天后，收获肿瘤并用于分析。通过免疫组织化学检测血管生成（CD31 表达）或白细胞浸润（CD45 表达），并通过 ELISA 测量 VEGF、IFN-γ 浓度。还通过流式细胞术分析了肿瘤中浸润免疫细胞的频率。结果：与其他组相比，5FU/塞来昔布显着抑制肿瘤生长和肿瘤血管密度。 5FU/塞来昔布显着抑制肿瘤组织中的VEGF含量，还增强了肿瘤组织中的IFN-γ水平，这可能参与了5FU/塞来昔布的强效抗肿瘤作用，因为IFN-γ无效。在小鼠中，与野生型小鼠相比，5FU/塞来昔布对血管生成和肿瘤生长的抑制作用显着受损，白细胞浸润减少并增加。 CD4+CD25^<高> T 细胞频率，但添加塞来昔布逆转了这些 5FU 治疗相关效应，与对照相比，5FU/塞来昔布增加了肿瘤中成熟树突细胞的频率。结论：这些结果表明塞来昔布增强了 T 细胞频率。 5FU 通过抑制血管生成和增强针对肿瘤的免疫反应对晚期结肠癌模型产生抗肿瘤作用。 COX-2 抑制剂在肿瘤抑制中发挥关键作用。

项目成果

Combination of enprostil and cimetidine is more effective than cimetidine alone in treating gastric ulcer : prospective multicenter randomized controlled trial.

恩前列素和西咪替丁联合治疗胃溃疡比单独使用西咪替丁更有效：前瞻性多中心随机对照试验。

• 发表时间: 2005
• 期刊: Hepatogastroenterology 52
• 作者: Murata H;Kawano S;Tsuji S;Tsujii M;Hori M;Kamada T;Matsuzawa Y;Katsu K;Inoue K;Kobayashi K;Mitsufuji S;Bamba T;Kawasaki H;Kajiyama G;Umegaki E;Inoue M;Saito I
• 通讯作者: Saito I

Synergistic antitumor effects of celecoxib with 5-fluorouracil depend on IFN-γ

• DOI: 10.1002/ijc.22720
• 发表时间: 2007-08-15
• 期刊: INTERNATIONAL JOURNAL OF CANCER
• 影响因子: 6.4
• 作者: Irie, Takanobu;Tsujii, Masahiko;Hayashi, Norio
• 通讯作者: Hayashi, Norio

Geranylgeranylacetone induces cyclooxygenase-2 expression in cultured rat gastric epithelial cells through NF-kappaB.

香叶基香叶基丙酮通过 NF-kappaB 诱导培养的大鼠胃上皮细胞中环氧合酶 2 的表达。

• 发表时间: 2007
• 期刊: Dig Dis Sci. 52
• 作者: Nishida T;Yabe Y;Fu HY;Hayashi Y;Asahi K;Eguchi H;Tsuji S;Tsujii M;Hayashi N;Kawano S.
• 通讯作者: Kawano S.

(2E,6Z,10E)-7-hydxoxymethyl-3,11,15-trimethyl-2,6,10,14-hex adecatetraen-1-ol (Plaunotol) increases cyclooxygenase-2 expression via nuclear factor kappaB and cyclic AMP response element in rat gastric epithelial cells.

(2E,6Z,10E)-7-hydxoxymethyl-3,11,15-trimethyl-2,6,10,14-hex adecatetraen-1-ol (Plaunotol) 通过核因子 kappaB 和环 AMP 反应增加 cyclooxygenase-2 表达

• 发表时间: 2005
• 期刊: Eur J Pharmacol. 7;524
• 作者: Fu H;Yabe Y;Asahi K;Hayashi Y;Murata H;Eguchi H;Tsujii M;Tsuji S;kawano S
• 通讯作者: kawano S

Helicobacter pylori eradication to prevent gastric cancer : underlying molecular and cellular mechanisms.

根除幽门螺杆菌预防胃癌：潜在的分子和细胞机制。

• 发表时间: 2006
• 期刊: World J Gastroenterol. 12
• 作者: Tsuji S;Tsujii M;Murata H;Nishida T;Komori M;Yasumaru M;et al.
• 通讯作者: et al.