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Development of a novel combined chemotherapy in head and neck cancer-combination of a DNA demethylating agent and an anticancer agent-

开发头颈癌新型联合化疗——DNA去甲基化剂和抗癌剂的组合——

基本信息

批准号：
15390617
负责人：
AZUMA Masayuki
金额：
$ 8.13万
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：
2003
资助国家：
日本
起止时间：
2003 至 2005
项目状态：
已结题

项目摘要

1.Cisplatin treatment affected neither NF-κB activity nor the expression levels of antiapoptotic proteins, including TRAF-1,TRAF-2, and cFLIP, in oral cancer cells. However, two apoptosome molecules, cytochrome c and Apaf-1, were significantly augmented in the cytoplasm by cisplatin treatment. Thus, cisplatin exerts its apoptotic action by the mitochondria-mediated activation of caspases but not by the activation of caspases due to the inhibition of NF-κB activity.2.Introduction into human oral squamous carcinoma cells of a super-repressor form of IκB-α cDNA causes a drastic decrease in tumorigenicity in nude mice due to down-regulation of the expression of IL-1α,IL-6,IL-8,VEGF, and MMP-9.3.Irradiation- and 5-FU-induced production of IL-6 and IL-8 was significantly suppressed in IκB-α cDNA-transfected cell clones, leading to a marked inhibition of the tumorigenic ability in IκB-α cDNA-transfectedcell clones as compared to that in parental cellc or empty vector-transfected cell clones.4.Cepharanthin suppressed the NF-κB activity in oral squamous carcinoma cells and concomitantly enhanced radiosensitization in vitro and in vivo, therefore, leading to the possibility that combination of radiotherapy with cepharanthin could lead to the enhancement of radiosensitization in the treatment of oral cancer.5.Immortalized normal human salivary gland ductal cells, expressing aquaporin (AQP)-3 but not AQP5, acquired the ability to express AQP-5 and secrete fluid in response 5-aza-2'-deoxycytidine. Demethylation at CG sites, both in the second consensus Sp1-binding site and outside of the third consensus Sp1-binding site of the AQP-5 promoter region, directly activated the transcription of the AQP-5 gene in ductal cells.

1.顺铂对口腔癌细胞中抗凋亡蛋白TRAF-1、TRAF-2和CflIP的表达水平及NF-κB活性均无影响。然而，细胞色素c和APAF-1两种凋亡体分子在顺铂处理后胞质中显著增加。2.将超抑制型I-κB-κ基因导入人口腔鳞癌细胞，通过下调IL-1、IL-6、IL-8、α和MMP9的表达，显著降低裸鼠体内的致瘤性。与亲代细胞或空载体转染细胞克隆相比，IκB-α细胞克隆的致瘤能力明显受到抑制。4.头孢菌素抑制口腔鳞癌细胞中的NF-κB活性，并同时增强体内外的放射增敏作用，因此，放射治疗与头孢菌素联合治疗口腔癌可能导致放射增敏的可能性。5.永生化的正常涎腺导管细胞，表达水通道蛋白(AQP)-3，但不表达水通道蛋白(AQP5)，获得表达水通道蛋白-5并分泌5-氮杂-2‘-脱氧胞苷的能力。在AQP-5启动子区域的第二个共识Sp1结合位点和第三个共识Sp1结合位点外的CG位点去甲基化直接激活了AQP-5基因在导管细胞中的转录。