Increase in chemo-and radiotherapy and cancer gene therapy by means of suppression of DNA repair genes

通过抑制 DNA 修复基因来增加化疗、放疗以及癌症基因治疗

• 批准号: 14570540
• 负责人: TAKIGUCHI Yuichi
• 金额: $ 2.5万
• 依托单位: Chiba University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570540/
• 关键词: DNA repair gene; Ku70; antisense oligonucleotide; radiosensitivity; chemosensitivity; gene therapy; lung cancer

Ku70 protein, cooperating with Ku80 and DNA-dependent protein kinase (DNA-PK) catalytic subunits (DNA-PKcs), is involved in DNA double-strand break (DNA DSB) repair and V(D)J recombination. Recent studies have revealed increased ionizing radiosensitivity in Ku70-deficient cells. The presented study, using a human squamous cell lung carcinoma cell line, demonstrated that introduction of an antisense Ku70 nucleic acid made the cells more radio-and chemosensitive than the parental cells. Ku70 protein expression was suppressed in the cells with antisense Ku70 construct when compared to the wild type cells : A relatively small but statistically significant increase in radiosensitivity of the cells was achieved by the introduction of the antisense Ku70. The increased radiosensitivity in vitro was accompanied by an approximately two-fold increase in a and alb values in a linear-quadratic model. The antisense Ku70 increased the chemosensitivity of the cells to some DNA-damaging agents such as bleomycin and methyl methanesulfonate, but not to cisplatin, mitomycin C, and paclitaxel. This system provides us with partial suppression of Ku70, and will be a useful experimental model for investigating the physiological roles of the DNA DSB repair gene.

Ku 70蛋白与Ku 80和DNA依赖性蛋白激酶（DNA-PK）催化亚基（DNA-PKcs）协同作用，参与DNA双链断裂（DNA DSB）修复和V（D）J重组。最近的研究表明Ku 70缺陷细胞的电离辐射敏感性增加。目前的研究，使用人鳞状细胞肺癌细胞系，证明了导入反义Ku 70核酸使细胞比亲本细胞更放射和化学敏感。与野生型细胞相比，在具有反义Ku 70构建体的细胞中Ku 70蛋白表达被抑制：通过引入反义Ku 70实现了细胞的放射敏感性的相对较小但统计学显著的增加。在线性二次模型中，体外放射敏感性的增加伴随着a和alb值的约2倍增加。反义Ku 70增加了细胞对一些DNA损伤剂如博来霉素和甲磺酸甲酯的化学敏感性，但对顺铂、丝裂霉素C和紫杉醇没有影响。该系统为我们提供了Ku 70的部分抑制，并将为研究DNA DSB修复基因的生理作用提供一个有用的实验模型。

项目成果

Shingyoji M., Takiguchi Y.et al.: "Detection of tumor specific gene expression in bone marrow and peripheral blood from patients with small cell lung carcinoma."Cancer. 97・4. 1057-1062 (2003)

Shingyoji M.、Takiguchi Y. 等：“小细胞肺癌患者骨髓和外周血中肿瘤特异性基因表达的检测”。癌症 97・4 (2003)。

Tada Y., JO.Wang, Wada A., Takiguchi Y.et al.: "Fas ligand-expressing tumors induce tumor-specific protective immunity in the inoculated hosts but vaccination with the apoptotic tumors suppresses antitumor immunity."Cancer Gene Therapy. 10・2. 134-140 (200

Tada Y.、JO.Wang、Wada A.、Takiguchi Y.等人：“表达 Fas 配体的肿瘤在接种的宿主中诱导肿瘤特异性保护性免疫，但接种凋亡肿瘤会抑制抗肿瘤免疫。”癌症基因治疗。 10・2.134-140（200）

Tada Y., J O.Wang, Wada A., Takiguchi Y.et al.: "Fas ligand-expressing tumors induce tumor-specific protective immunity in the inoculated hosts but vaccination with the apoptotic tumors suppresses antitumor immunity."Cancer Gene Therapy. 10・2. 134-140 (20

Tada Y.、J O.Wang、Wada A.、Takiguchi Y.等人：“表达 Fas 配体的肿瘤在接种的宿主中诱导肿瘤特异性保护性免疫，但接种凋亡肿瘤会抑制抗肿瘤免疫。”癌症基因治疗10・2.134-140（20）

Takiguchi Y.: "Hiccups as an adverse reaction to cancer chemotherapy."Journal of the National Cancer Institute. 94・10. 772-772 (2002)

Takiguchi Y.：“打嗝是癌症化疗的不良反应。”国立癌症研究所杂志 94・10 (2002)。

Watanabe R., Takiguchi Y.et al.: "Feasibility of combination chemotherapy with cisplatin and etoposide for haemodialysis patients with lung cancer."British Journal of Cancer. 88. 25-30 (2003)

Watanabe R.、Takiguchi Y.等人：“顺铂和依托泊苷联合化疗治疗肺癌血液透析患者的可行性。”英国癌症杂志。