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Lipoteichoic acid : Augmentation of the therapeutic effect of radiation and 5-fluorouracil in head and neck cancer

脂磷壁酸：增强放射线和5-氟尿嘧啶对头颈癌的治疗效果

基本信息

批准号：
09557170
负责人：
SATO Mitsunobu
金额：
$ 7.55万
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：
1997
资助国家：
日本
起止时间：
1997 至 1999
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09557170/
关键词：
lipoteichoic acid OK-432 radiation 5-fluorouracil head and neck cancer cytokine liposome killer cells 頭頚部癌キラー活性分化誘導アポトーシス

项目摘要

1. Interferon (IFN-γ-inducing molecule (OK-LTA) has been purified from the streptococcal agent OK-432, by an affinity chromatography on CNBr-activated Sepharose 4B bound the TS-2 monoclonal antibody which neutralizes IFN-γ-inducing activity of OK-432. The OK-LTA is a glyco-conjugate with a certain structure of lipoteichoic acids. OK-LTA carried striking antitumor activity in vivo and in vitro.2. OK-LTA induced several cytokines such as IFN-α,-β,-γ, tumor necrosis factor(TNF)-α,-β, interleukin(IL)-2, IL-6, IL-12, IL-18, as well as natural killer(NK) and lymphokine-activated killer(LAK) activities on human peripheral blood mononuclear cells(PBMC).3. Nude mice bearing human head and neck cancer cells were treated with X-ray(10Gy), 5-FU(40mg/Kg), and/or OK-LTA. It was sugested that the anti-tumor effect of 5-FU were enhanced by OK-LTA.4. The negative liposome kit (egg lecithin : dicethyphosphate : cholesterol = 7 : 2 : 1, molar ratio) was used to improve the delivery of the agent (OK-LTA) to effector cells and to increase its therapeutic effect. The significantly lesser amounts of OK-LTA encapsulated into liposomes (Lipo-OK-LTA) than OK-LTA alone (1/100 or less amounts of OK-LTA alone) were required to induce IFN-γ, TNF-α,-β, IL-1β, NK, and LAK activities by human PBMC as well as by mouse spleen cells (MSC). Furthermore, higher levels of these activities were detected in PBMC and MSC treated with Lipo-OK-LTA than with OK-LTA alone.5. All of these activities induced by Lipo-OK-LTA were almost completely neutralized by anti-asialo-GM1 antibody and complement (P<0.001). In in vivo experiments, it was clearly indicated that Lipo-OK-LTA significantly accelerated anti-tumor ability of X-ray and 5-FU.

1. 从链球菌制剂OK-432中纯化干扰素(IFN-γ诱导分子（OK-LTA），通过cnbr激活的Sepharose 4B结合TS-2单克隆抗体进行亲和层析，从而中和了OK-432诱导IFN-γ的活性。OK-LTA是具有一定结构的脂质胆酸的糖缀合物。2. OK-LTA在体内外均具有显著的抗肿瘤活性。OK-LTA诱导多种细胞因子如IFN-α，-β,-γ，肿瘤坏死因子(TNF)-α,-β，白细胞介素(IL)-2, IL-6, IL-12, IL-18，以及自然杀伤（NK）和淋巴因子活化杀伤（LAK）对人外周血单核细胞（PBMC）的活性。用x射线（10Gy）、5-FU（40mg/Kg）和/或OK-LTA治疗携带人头颈部癌细胞的裸鼠。结果表明，ok - lta可增强5-FU的抗肿瘤作用。阴性脂质体试剂盒（卵磷脂：二磷酸酯：胆固醇= 7:2:1，摩尔比）用于改善药物（OK-LTA）对效应细胞的递送，提高其治疗效果。通过人PBMC和小鼠脾细胞（MSC）诱导IFN-γ、TNF-α、-β、IL-1β、NK和LAK活性所需的OK-LTA包被脂质体（lipoo -OK-LTA）的量明显少于单独的OK-LTA（1/100或更少的单独OK-LTA量）。此外，lipoo -OK-LTA处理的PBMC和MSC中检测到的这些活性水平高于单独使用OK-LTA处理的PBMC和MSC。Lipo-OK-LTA诱导的这些活性几乎完全被抗asialo- gm1抗体和补体所中和（P<0.001）。体内实验明确表明，Lipo-OK-LTA能显著加速x射线和5-FU的抗肿瘤能力。