Development of the therapy for oral cancer by transduction of iNOS gene in combination with radiotherapy

iNOS基因转导联合放疗治疗口腔癌的进展

基本信息

批准号：
12557176
负责人：
SATO Mitsunobu
金额：
$ 6.66万
依托单位：
The University of Tokushima
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-12557176/
关键词：
oral cancer iNOS gene NO radiotherapy OK-432 lipoteichoic acid-related molecule Th1-type cytokine anti-tumor effect iNos遺伝子口腔扁平上皮癌口腔小唾液腺癌 iNOS IFN-γ TIL NK

项目摘要

1. Transfection of human oral squamous cell carcinoma cells (B88) with the gene encoding inducible nitric oxide synthase (INOS) resulted in the suppression of cell growth and NO production in vitro or in nude mice. The effect of overexpression of iNOS gene on B88 cells was augmented by irradiation, while down-regulation of iNOS gene in B88 cells caused significantly the enhancement of cell growth.2. In transfection of iNOS gene to B88 cells, bystander effect on the tumor cells without expression of iNOS gene was detected.3. We have already reported the high effectiveness of the therapy for oral squamous cell carcinoma by UFT and OK-432 in combination with radiotherapy. When we examined immunohistochemically the expression of iNOS in the biopsy materials taken at the first visit to our clinic, group with complete remission showed the strong expression of iNOS in the inflammatory cells infiltrating into the subepithellal region.4. We found that a lipoteichoic acid-related molecule (OK-PSA) prepared from streptococcal agent, OK-432 is a potent inducer of Th1-type cytokines.5. When human salivary cancer (HSG) ?bearing nude mice were administered OK-PSA peritumorally, production of Th1 type cytokines such as IFN-γ, , TNF-α, IL-2, IL-12 or IL-18 as well as of nitrite/nitrate was detected in the blood, in which radiotherapy augmented production of the cytokines and NO.6. Treatment with OK-PSA of human peripheral blood mononuclear cells, U937 cells, human gingival fibroblasts or human oral squamous carcinoma cells (BHY) resulted in production of N0_2^-.7. Cultivation of B88 cells under the presence of NO donor (NOC18 ; 0.01-1mg/ml) caused potent induction of apoptosis.

1. 用编码诱导型一氧化氮合酶（INOS）的基因转染人口腔鳞状细胞癌细胞（B88），导致体外或裸鼠体内细胞生长和NO产生受到抑制。 iNOS基因过表达对B88的影响。辐射使细胞增殖增强，而B88细胞中iNOS基因的下调则导致细胞生长显着增强。 2． 3．我们已经报道了UFT和OK-432联合放疗治疗口腔鳞状细胞癌的高效性。首次就诊时采集的活检材料中iNOS的含量，完全缓解组的iNOS在浸润上皮下区域的炎症细胞中呈强表达。4．由链球菌制剂制备的脂磷壁酸相关分子(OK-PSA)，OK-432是Th1型细胞因子的有效诱导剂。 5．人唾液腺癌(HSG)荷瘤裸鼠瘤周注射OK-PSA后，产生了Th1型细胞因子。 Th1 型细胞因子如 IFN-γ、TNF-α、IL-2、IL-12 或 IL-18 以及亚硝酸盐/硝酸盐在血液中，放射治疗增加了细胞因子和 NO.6 的产生，用 OK-PSA 处理人外周血单核细胞、U937 细胞、人牙龈成纤维细胞或人口腔鳞状细胞癌细胞 (BHY) 导致 N0_2^- 的产生。 7.在NO供体(NOC18；0.01-1mg/ml)存在下培养B88细胞引起细胞凋亡的有效诱导。