THE ROLE OF REACTIVE OXYGEN INTERMEDIATES AND THEIR SCAVENGERS ON APOPTOSIS INDUCTION OF SQUAMOUS CELL CARClNOMA CELLS

活性氧中间体及其清除剂对鳞状细胞癌细胞凋亡诱导的作用

• 批准号: 10671769
• 负责人: YONEDA Kazunori
• 金额: $ 2.3万
• 依托单位: Kochi Medical School
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10671769/
• 关键词: squamous cell carcinoma cells; apoptosis; reactive oxygen intermediates; HィイD22ィエD2OィイD22ィエD2; Mn-SOD; LAK cells

To induce apoptosis sufficient for cancer control, we investigated the role of reactive oxygen intermediates (ROI) and their scavengers in induction of apoptosis of squamous cell carcinoma (SCC) cells. The results obtained are as follows ;1, The SCC lines, which were established from oral SCCs, revealed almost same activities of catalase, gluthatione peroxidase, and Cu, Zn-superoxide dismutase (SOD). However, Mn-SOD activities differed largely among the cell lines.2, SCC lines with a high Mn-SOD activity were more resistant to 5-FU and γ-rays than those with a low Mn-SOD activity, and the Mn-SOD activities were inversely correlated with apoptosis by 5-FU and γ-rays.3, Apoptosis was closely correlated with the intracellular and intra-mitochondrial ROI (HィイD22ィエD2OィイD22ィエD2) levels, which were parallel with the decrease of mitochondrial membrane potential, release of cytochrome c, caspase-3 activation, and DNA fragmentation.4, By treatment with 5-FU and γ-rays, Mn-SOD-mRNA expression and Mn-SOD activities were increased in all SCC lines.5, Mn-SOD-antisense-transfected SCC cells were more strongly induced to apoptosis after treatment with 5-FU and γ -rays compared with wild SCC cells.6, Subcutaneous tumors in nu/nu mice, in which Mn-SOD-antisense-transfected SCC cells were transplanted, were more sensitive to γ-rays and 5-FU than tumors of non-transfected SCC cells.These results indicate that ROI play an important role in apoptosis induced by 5-FU and γ-rays and that among the ROI scavengers, Mn-SOD is the strongest inhibitor of apoptosis. Therefore, as the effective SCC therapy, inactivation of ROI scavengers, especially, Mn-SOD, is proposed.

为了诱导细胞凋亡足以控制癌症，我们研究了活性氧中间体（ROI）及其清除剂在诱导鳞状细胞癌（SCC）细胞凋亡中的作用。结果表明：1、口腔SCC细胞系的过氧化氢酶、谷胱甘肽过氧化物酶和铜锌超氧化物歧化酶（SOD）活性基本相同。Mn-SOD活性高的SCC细胞对5-FU和γ-射线的耐受性强于Mn-SOD活性低的SCC细胞，且Mn-SOD活性与5-FU和γ-射线诱导的细胞凋亡呈负相关5-FU和γ-射线处理后，各SCC细胞株Mn-SOD-mRNA表达和Mn-SOD活性均升高。Mn-SOD反义转染的SCC细胞经5-FU和γ射线处理后，较野生型SCC细胞有更强的凋亡诱导作用。6、nu/nu小鼠皮下肿瘤，其中移植Mn-SOD反义转染的SCC细胞，结果表明，ROI在5-FU和γ-射线诱导的细胞凋亡中起重要作用，而在ROI清除剂中，Mn-SOD对细胞凋亡的抑制作用最强。因此，作为有效的SCC治疗，建议灭活ROI清除剂，特别是Mn-SOD。

项目成果

Kazunori Yoneda: "The inhibitory action of BOF-A2,a 5-fluorouracil derivative,on squamous cell carcinoma"Cancer Letters. 137・1. 17-25 (1999)

Kazunori Yoneda：“5-氟尿嘧啶衍生物BOF-A2对鳞状细胞癌的抑制作用”Cancer Letters 137・1（1999）。

Eisaku Ueta: "Manganese superoxide dismutase negatively regulates the induction apoptosis by 5-fluorouracil, peplomycin and γ-rays in squamous cell carcinoma cells"Japanese Journal of Cancer Research. 90(5). 555-564 (1999)

Eisaku Ueta：“锰超氧化物歧化酶对鳞状细胞癌细胞中 5-氟尿嘧啶、培洛霉素和 γ 射线的诱导细胞凋亡负调节”，日本癌症研究杂志 90(5) (1999)。

Tokio Osaki: "Diffuse mode of tumor cell invasion and expression of p53 ptotein but not of p21 protein are correlated with control failure in oral carcinoma and their metastasis foci"Oncology. (in press). (2000)

Tokio Osaki：“肿瘤细胞侵袭的弥散模式和 p53 蛋白的表达（而非 p21 蛋白的表达）与口腔癌及其转移灶的控制失败相关”肿瘤学。

Eisaku Ueta: "Manganese superoxide dismutase negatively regulates the induction of apoptosis by 5-fluorouracil,peplomycin and γ-rays in squamous cell carcinoma cells"Japanese Journal of Cancer Research. 90・5. 555-564 (1999)

Eisaku Ueta：“锰超氧化物歧化酶负调节鳞状细胞癌细胞中 5-氟尿嘧啶、培洛霉素和 γ 射线诱导的细胞凋亡”，日本癌症研究杂志 90·5 (1999)。

Tokio Osaki: "Diffuse mode of tumor cell invasion and expression of p53 protein but not of p2 1 protein are correlated with control failure in oral carcinoma and their metastasis foci."Oncology. in press. (2000)

Tokio Osaki：“肿瘤细胞侵袭的弥散模式和 p53 蛋白的表达（而非 p2 1 蛋白）与口腔癌及其转移灶的控制失败相关。”肿瘤学。