Identification of organic anion transporter LST-2 which expressed in the gastrointestinal cancers: clinical implication for anticancer drug delivery.
胃肠道癌症中表达的有机阴离子转运蛋白LST-2的鉴定:抗癌药物递送的临床意义。
基本信息
- 批准号:13557218
- 负责人:
- 金额:$ 7.49万
- 依托单位:
- 依托单位国家:日本
- 项目类别:Grant-in-Aid for Scientific Research (B)
- 财政年份:2001
- 资助国家:日本
- 起止时间:2001 至 2002
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Background & Aims: One approach to the development of targeted cancer chemotherapy exploits increased uptake of the agent into neoplastic cells. In this scenario, higher concentrations of the agent in cancer cells are responsible for differential killing while the low concentration in normal human cells decreases side effects. The aim of this study is to isolate an organic anion transporter which in weakly in normal, but abundantly expressed in cancer cells, to deliver the anti-cancer drugs to the cells.Methods: A human liver cDNA library was screened with LST-1 cDNA as a probe, Northern blot analyses were performed using the isolated cDNA (termed LST-2). A LST-2 specific antibody was raised and immunohistochemical analyses including immuno-electron microscopy were performed. Xenopus oocyte expression system was used for functional analysis. We also established a permanent cell line which consistently expresses LST-2 to examine the relationship between MTX uptake and sensitivity.Results: The isolated cDNA, LST-2 has 79,7 % of overall homology wish human LST-1. LST-2 exclusively expressed in the liver under normal conditions and immunoreactivity was highest at the basolateral membrane of the hepatocytes around the central vein. Although its weak expression in the liver, LST-2 is abundantly expressed in the gastric, colon and pancreatic cancers, On she other hand, she LST-1 was only detected in a hepatic cell line, LST-2 transports methotrexate in a saturable and dose dependent manner Furthermore, introduction of the LST-2 gene into mammalian cells potentiates sensitivity to methotrexate.Conclusion: LST-2 is one of the prime candidate molecule for determining methotrexate sensitivity and may be a good target on deliver anti-cancer drugs to the gastrointestinal cancers.
背景与目的:发展靶向癌症化疗的一种方法是增加肿瘤细胞对药物的摄取。在这种情况下,癌细胞中较高浓度的药剂负责差异杀伤,而正常人类细胞中的低浓度则降低了副作用。本研究的目的是分离一种在正常细胞中表达较弱,但在癌细胞中大量表达的有机阴离子转运蛋白(LST-2),为肿瘤细胞的药物转运提供分子基础。提出了LST-2特异性抗体,并进行免疫组织化学分析,包括免疫电镜。利用非洲爪蟾卵母细胞表达系统进行功能分析。我们还建立了持续表达LST-2的永久细胞系,以检测MTX摄取和敏感性之间的关系。LST-2在正常情况下仅在肝脏中表达,并且在中央静脉周围的肝细胞的基底外侧膜处免疫反应性最高。LST-2基因在肝脏中表达较弱,但在胃癌、结肠癌和胰腺癌中大量表达,LST-1基因仅在肝细胞系中表达,LST-2基因以饱和和剂量依赖的方式转运甲氨蝶呤。此外,LST-2基因导入哺乳动物细胞可增强对甲氨蝶呤的敏感性。LST-2是测定甲氨蝶呤敏感性的主要候选分子之一,可能成为胃肠道肿瘤抗肿瘤药物的良好靶点。
项目成果
期刊论文数量(67)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Sasaki M., Suzuki H., Ito K., Abe T., Sugiyama Y.: "Transcellular transport of organic anions across a double-transfected Madin-Darby Canine Kidney II cell monolayer expressing both human organic anion-transporting polypeptide(OATP2/SLC21A6)and multidrug
Sasaki M.、Suzuki H.、Ito K.、Abe T.、Sugiyama Y.:“有机阴离子跨双转染的 Madin-Darby 犬肾 II 细胞单层的跨细胞转运,表达人类有机阴离子转运多肽(OATP2/
- DOI:
- 发表时间:
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- 影响因子:0
- 作者:
- 通讯作者:
Kodawara T, Masuda S, Abe T et al.: "Organic anion transporter oatp2-mediated interaction between digoxin and amiodarone in the rat liver"Pharmaceutical Res.. 19. 738-743 (2002)
Kodawara T、Masuda S、Abe T 等人:“有机阴离子转运蛋白 oatp2 介导的大鼠肝脏中地高辛和胺碘酮之间的相互作用”Pharmaceutical Res.. 19. 738-743 (2002)
- DOI:
- 发表时间:
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- 影响因子:0
- 作者:
- 通讯作者:
Takeuchi A., Masuda S., Saito H., Abe T.and Inui K.: "Multispecific substrate recognition of kidney-specific organic anion transporers OAT-K1 and OAT-k2."J Pharmacol Exp Ther. 299. 1-7 (2001)
Takeuchi A.、Masuda S.、Saito H.、Abe T. 和 Inui K.:“肾脏特异性有机阴离子转运蛋白 OAT-K1 和 OAT-k2 的多特异性底物识别。”J Pharmacol Exp Ther。
- DOI:
- 发表时间:
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- 影响因子:0
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- 通讯作者:
Abe T, Suzuki T, Unno M et. Al.: "Thyroid hormone transporters: recent advances"Trends in Endocrinol. Metab.. Vol.13. 215-220 (2002)
Abe T、铃木 T、Unno M 等。
- DOI:
- 发表时间:
- 期刊:
- 影响因子:0
- 作者:
- 通讯作者:
Abe T., Michiaki U., Tokui T., et al.: "LST-2, a human liver-specificorganic anion transporter detemines methotrexate sensitivity in the gastrointestinal cancers."Gastroenterology. 120. 1689-1699 (2001)
Abe T.、Michiaki U.、Tokui T. 等人:“LST-2,一种人类肝脏特异性有机阴离子转运蛋白,决定胃肠癌中甲氨蝶呤的敏感性。”胃肠病学。
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- 影响因子:0
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ABE Takaaki其他文献
ABE Takaaki的其他文献
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{{ truncateString('ABE Takaaki', 18)}}的其他基金
Drug discovery for Diabetic Nephropathy through altering gut microbiota community
通过改变肠道菌群来发现糖尿病肾病的药物
- 批准号:
20K20604 - 财政年份:2020
- 资助金额:
$ 7.49万 - 项目类别:
Grant-in-Aid for Challenging Research (Pioneering)
Development of novel drugs for CKD
CKD新药开发
- 批准号:
26293031 - 财政年份:2014
- 资助金额:
$ 7.49万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Relation between 1-metyl adenosinea and rheumatoid arthritis
1-甲基腺苷与类风湿性关节炎的关系
- 批准号:
26305007 - 财政年份:2014
- 资助金额:
$ 7.49万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Indole analog mitochonic acid-5 (MA-5) has novel therapeutic effects on kidney injury
吲哚类似物线粒体酸5(MA-5)对肾损伤具有新的治疗作用
- 批准号:
26670070 - 财政年份:2014
- 资助金额:
$ 7.49万 - 项目类别:
Grant-in-Aid for Challenging Exploratory Research
Biomarkers for ischemia and renal faiure
缺血和肾衰竭的生物标志物
- 批准号:
24659062 - 财政年份:2012
- 资助金额:
$ 7.49万 - 项目类别:
Grant-in-Aid for Challenging Exploratory Research
Blockade of renal malignant cycle by transcriptional regulation of SLCO transporter
通过 SLCO 转运蛋白的转录调节阻断肾恶性循环
- 批准号:
23390033 - 财政年份:2011
- 资助金额:
$ 7.49万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Development of in vivo evaluation system of human organic anion transpoter
人体有机阴离子转运蛋白体内评价系统的研制
- 批准号:
20390043 - 财政年份:2008
- 资助金额:
$ 7.49万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Clinical application of the origanic anion transporter family
有机阴离子转运蛋白家族的临床应用
- 批准号:
18390045 - 财政年份:2006
- 资助金额:
$ 7.49万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
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。
- 批准号:
16390038 - 财政年份:2004
- 资助金额:
$ 7.49万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Molecular characterization of the organic anion transporter family
有机阴离子转运蛋白家族的分子表征
- 批准号:
14370777 - 财政年份:2002
- 资助金额:
$ 7.49万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
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