Expression of cyclooxygenase (COX)-2 in head and neck cancer and inhibitory effect of COX-2 inhibitors on tumor growth

环氧合酶(COX)-2在头颈癌中的表达及COX-2抑制剂对肿瘤生长的抑制作用

• 批准号: 12470453
• 负责人: URADE Masahiro
• 金额: $ 6.78万
• 依托单位: Hyogo Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12470453/
• 关键词: head and neck cancer; cyclooxygenase (COX)-2; tumor growth and metastasis; COX-2 inhibitors; anticancer drugs; apoptosis; 転移; 腫瘍増殖抑制; 扁平上皮癌; 前癌病変; 唾液腺癌

This study was designed to examine the immunohistochemical expression of cyclooxygenase (COX)-2 in head and neck cancer, and the inhibitory effect of COX-2 inhibitors on head and neck cancer cell growth. Based on the above experimental data, the chemopreventive potential of COX-2 inhibitors against DMBA-induced hamster cheek pouch carcinogenesis as animal model and synergistic effect of COX-2 inhibitors with anticancer agents as therapeutic strategy are also investigated. The results obtained were as follows.1) The immunohistchemical examination showed the expression of COX-2 protein n both squamous cell carcinoma (SCC) of the head and neck and salivary gland carcinoma (SGC). The expression rate was higher in SGC than SCC. In SCC, COX-2 expression became higher as the degree of tumor differentiation was lower, and undifferentiated carcinomas all showed high expression. In addition, metastatic lesions demonstrated significantly higher expression than primary lesions.2) The COX-2 express … More ion was shown not only in SCC but also in epithelial hyperplasia, epithelial dysplasia and carcinoma in situ. The extent of the expression was increased toward carcinogenesis. There was a close correlation between COX-2 expression and topoisomerase II α expression, and a tendency of poor prognosis in SCC patients with high expression of these enzymes.3) The COX-2 inhibitors inhibited the growth of head and neck cancer cell lines in a dose-dependent manner via apoptosis induction. These effects were more prominent in celecoxib than sulindac and etodolac. Celecoxib inhibited PGE_2 production and COX-2 expression efficiently.4) The non-cytotoxic or less cytotoxic concentrations of celecoxib augmented the growth inhibitory effect of anticancer agents such as adriamycin, vincristine and bleomycin by 2 to 10-fold via increased apoptosis induction.5) Oral administration of celecoxib retarded the onset of carcinoma formation, tumor growth and death in DMBA-induced hamster cheek pouch carcinogenesis model, although all hamsters developed SCC by DMBA application. Less

本研究通过免疫组织化学方法检测环氧合酶（考克斯）-2在头颈部肿瘤中的表达，并观察考克斯-2抑制剂对头颈部肿瘤细胞生长的抑制作用。基于上述实验数据，还研究了考克斯-2抑制剂对DMBA诱导的仓鼠颊囊癌变的化学预防潜力作为动物模型，以及考克斯-2抑制剂与抗癌药物的协同作用作为治疗策略。结果表明：1）免疫组化显示考克斯-2蛋白在头颈部鳞癌和涎腺癌中均有表达。胃癌中的表达率高于鳞癌。在鳞癌中，考克斯-2表达随肿瘤分化程度的降低而增高，未分化癌均呈高表达。此外，转移灶的表达明显高于原发灶。2）考克斯-2表达 ...更多信息 不仅在鳞状细胞癌中，而且在上皮增生、上皮不典型增生和原位癌中均有表达。表达的程度随着癌变的进展而增加。考克斯-2和拓扑异构酶II α的表达密切相关，高表达者预后差; 3）考克斯-2抑制剂通过诱导细胞凋亡抑制头颈癌细胞株的生长，呈剂量依赖性。塞来昔布的这些作用比舒林酸和依托度酸更显著。塞来昔布可有效抑制PGE_2的产生和考克斯-2的表达。4）塞来昔布的非细胞毒性或较小的细胞毒性浓度通过增加细胞凋亡诱导作用使抗癌药物如阿霉素、长春新碱和博来霉素的生长抑制作用增强2至10倍。5）塞来昔布口服给药可延缓肿瘤形成。在DMBA诱导的仓鼠颊囊癌发生模型中的肿瘤生长和死亡，尽管所有仓鼠通过DMBA应用发展了SCC。少

项目成果

Sakurai K., Urade M., Noguchi K., Kishimoto H., Ishibashi M., Yasoshima H., Yamamoto T., Kubota A.: "Increased expression of cyclooxygenase-2 in human salivary gland tumors"Pathology International. 51. 762-769 (2001)

Sakurai K.、Urade M.、Noguchi K.、Kishimoto H.、Ishibashi M.、Yasoshima H.、Yamamoto T.、Kubota A.：“人类唾液腺肿瘤中环氧合酶 2 的表达增加”国际病理学。

Hashitani S., Urade M., Nishimura N., Maeda T., Takaoka K., Noguchi K., Sakurai K.: "Apoptosis induction and enhancement of cytotoxicity of anticancer drugs by celecoxib, a selective cyclooxygenase-2 inhibitor, in human head and neck carcinoma cell lines"

Hashitani S.、Urade M.、Nishimura N.、Maeda T.、Takaoka K.、Noguchi K.、Sakurai K.：“塞来昔布（一种选择性环氧合酶 2 抑制剂）在人体中诱导细胞凋亡并增强抗癌药物的细胞毒性

Hashitani S., Urade M., Nishimura N., Maeda T., Takaoka K., Noguchi K. and Sakurai K.: "Apoptosis induction and enhancement of cytotoxicity of anticancer drugs by celecoxib, a selective cyclooxygenase-2 inhibitor, in human head and neck carcinoma cell lin

Hashitani S.、Urade M.、Nishimura N.、Maeda T.、Takaoka K.、Noguchi K. 和 Sakurai K.：“塞来昔布（一种选择性环氧合酶 2 抑制剂）在人体中诱导细胞凋亡并增强抗癌药物的细胞毒性

櫻井一成, 黒田純子, 橋谷 進, 西村則彦, 野口一馬, 岸本裕充, 浦出雅裕: "口腔扁平上皮癌の原発、転移巣におけるCyclooxygenase(COX)-2蛋白発現の比較検討"日本口腔科学会雑誌. 51巻6号. 366-373 (2002)

Kazunari Sakurai、Junko Kuroda、Susumu Hashitani、Norihiko Nishimura、Kazuma Noguchi、Hiromitsu Kishimoto、Masahiro Urade：“口腔鳞状细胞癌原发性和转移性病变中环氧合酶 (COX)-2 蛋白表达的比较研究”日本口腔医学会杂志。第 51 卷，第 6 期。366-373 (2002)

櫻井一成, 黒田純子, 橋谷進, 西村則彦, 野口一馬, 岸本裕充, 浦出雅裕: "口腔扁平上皮癌の原発,転移巣におけるCyclooxygenase(COX)-2蛍日発現の比較検討"日本口腔科学会雑誌. 51巻6号. 366-373 (2002)

Kazunari Sakurai、Junko Kuroda、Susumu Hashitani、Norihiko Nishimura、Kazuma Noguchi、Hiromitsu Kishimoto、Masahiro Urade：“口腔鳞状细胞癌原发性和转移性病变中环氧合酶 (COX)-2 表达的比较研究”日本口腔学会科学杂志学会。第 51 卷，第 6 期。366-373 (2002)