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Functional regulation and clinical application of the organic anion transporter LST family.

有机阴离子转运蛋白LST家族的功能调控及临床应用。

基本信息

批准号：
16390038
负责人：
ABE Takaaki
金额：
$ 9.54万
依托单位：
TOHOKU UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16390038/
关键词：
gastrointestinal cancers LST organic anion transporter MTX adenovirus 蛍光標識

项目摘要

In the last decade, many transporters have been isolated, characterized their distribution and substrates. Among them, the organic anion transporter OATP family, transport bile acids, hormones as well as eicosanoids and various compounds (BSP, HMG-CoA reductase inhibitor, angiotensin converting enzyme inhibitor, etc.). So far, applicant isolated more than 15 clones of the oatp family firstly in the world and reported. We have isolated the organic anion transporter OATP/LST family which exclusively expressed in various gastrointestinal cancers.Thenm we established LST-2 recombinant adenoviruses, termed AdLST-2. In vivo effects of the combination of MTX with the adenoviruses were estimated in a subcutaneous tumor model using SCID mice. Tumors treated with AdLST-2/MTX grew more slowly than those treated with Adβ-gal/MTX. Whole-body autoradiograph confirmed that incorporation of [^3H]-MTX in tumors of mice treated with AdLST-1/MTX and AdLST2/MTX.Our observations strongly support the possibility that overexpression of influx pumps is a new avenue in the enhancement of cancer chemotherapy. We also raised a ligand-screening method using adenovirus and fluorescent lignd of LST-2. This system unable us to screening various compounds preferable to transported by LST-2.

在过去的十年中，许多转运蛋白已被分离，其分布和底物的特点。其中，有机阴离子转运蛋白OATP家族，转运胆汁酸、激素以及类花生酸和各种化合物（BSP、HMG-CoA还原酶抑制剂、血管紧张素转换酶抑制剂等）。到目前为止，申请人在世界上首次分离并报道了15个以上的oatp家族克隆。我们分离了在多种胃肠道肿瘤中特异表达的有机阴离子转运蛋白OATP/LST家族，构建了LST-2重组腺病毒，命名为AdLST-2。使用SCID小鼠在皮下肿瘤模型中估计MTX与腺病毒组合的体内作用。用AdLST-2/MTX处理的肿瘤比用Adβ-gal/MTX处理的肿瘤生长更慢。全身放射自显影证实AdLST-1/MTX和AdLST-2/MTX治疗的小鼠肿瘤中[^3H]-MTX掺入。我们的观察强烈支持内流泵的过表达是增强癌症化疗的新途径的可能性。我们还提出了一种利用腺病毒和LST-2荧光标记筛选配体的方法。该系统无法筛选出LST-2较易转运的化合物。