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Toll-like receptor 4 signaling : Enhancement of therapeutic effect of anti-cancer drugs and radiation in oral Cancer

Toll样受体4信号传导：增强口腔癌的抗癌药物和放射治疗效果

基本信息

批准号：
14207090
负责人：
SATO Mitsunobu
金额：
$ 32.28万
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 (A)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14207090/
关键词：
Oral cancer Toll-like receptor 4 MD-2 OK-432 UFT Radiation Lipoteichoic acid-related molecule NF-κB Toll-like receptor4 抗腫瘍免疫療法剤OK-432 リポタイコ酸関連分子OK-PSA Toll様受容体4 テガフール樹状細胞(DC)DC局所療法リポタイコ酸 NF-kB

项目摘要

Of 67 oral cancer patients who received OK-432,UFT in combination with radiation therapy (RT), complete remission (CR) was observed in 38 cases (56.7%), partial response in 29 cases (43.3%). Response rate was 100%. Of 14 patients received RT+UFT without OK-432,CR was observed only in 2 cases (14,3%). Therapeutic effect of this protocol was almost completely dependent on the expression of Toll-like receptor (TLR) 4 and MD-2 genes on peripheral blood mononuclear cells derived from the patients. We have isolated an active component from the OK-432, a lipoteichoic acid-related molecule designated OK-PSA. OK-PSA induced the maturation of human dendritic cells (DCs), and OK-PSA-treated DCs stimulated allogeneic T cells to produce IFN-γ, and to induce allo-antigen specific cytotoxic T cells. These activities of OK-PSA were also dependent on the gene expression of TLR4 and MD-2. Next, we encapsulated OK-PSA with poly (lactide-co-glycolide) micro-particles, and designated PLG-OK-PSA. In tumor-bearing mice, PLG-OK-PSA augmented the anti-cancer effect of RT and UFT far better than OK-PSA as well as OK-432,and CR was observed in most of the animals bearing tumors. Th1-type cytokines and nitric oxide were detected in the sera derived from the mice administered PLG-OK-PSA. The increased cytotoxic activities of the lymphocytes were also observed. These effects of OK-432,OK-PSA as well as PLG-OK-PSA were not observed in TLR4-mutant and in TLR4-deficient mice. It was greatly suggested that RT+UFT+OK-432 therapy is effective for the regulation of oral cancer, that TLR4 signaling is involved in anti-cancer effect of this therapy, and that PLG-OK-PSA may be useful tool for treating human cancer.

67例接受OK-432、UFT联合放疗的口腔癌患者中，完全缓解（CR）38例（56.7%），部分缓解（PR）29例（43.3%）。应答率为100%。在14例接受RT+UFT而未使用OK-432的患者中，仅2例（14.3%）观察到CR。该方案的治疗效果几乎完全依赖于患者外周血单个核细胞Toll样受体（TLR）4和MD-2基因的表达。我们已经从OK-432中分离出一种活性成分，这是一种脂磷壁酸相关分子，命名为OK-PSA。OK-PSA诱导人树突状细胞（DCs）成熟，OK-PSA处理的DCs刺激同种异体T细胞产生IFN-γ，诱导同种异体抗原特异性细胞毒性T细胞。OK-PSA的这些活性也依赖于TLR 4和MD-2的基因表达。接下来，我们用聚（丙交酯-共-乙交酯）微粒包封OK-PSA，并命名为PLG-OK-PSA。在荷瘤小鼠中，PLG-OK-PSA增强RT和UFT的抗癌作用远优于OK-PSA和OK-432，并且在大多数荷瘤动物中观察到CR。在来自给予PLG-OK-PSA的小鼠的血清中检测到Th 1型细胞因子和一氧化氮。淋巴细胞的细胞毒活性也有所增加。OK-432、OK-PSA以及PLG-OK-PSA的这些作用在TLR 4突变体和TLR 4缺陷小鼠中未观察到。提示RT+UFT+OK-432对口腔癌的治疗有一定的调节作用，TLR 4信号通路参与了该治疗的抗癌作用，PLG-OK-PSA可能成为治疗人类癌症的有效工具。