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Drug Resistance which ABCG2/BCRP contributes

ABCG2/BCRP 导致的耐药性

基本信息

批准号：
17590139
负责人：
IKEGAMI Yoji
金额：
$ 2.3万
依托单位：
Meiji Pharmaceutical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590139/
关键词：
Pharmacy Cancer Drug resistance

项目摘要

1. Change of substrate specificity, according to single nucleotide polymorphisms (SNPs) of ABCG2/BCRPIt is thought that 141st amino acid mutation influences the translation as one of the causes of the relative resistance decreases seen with PC6/Q141K, and the protein expression decreased. However, the protein expression was expected and some factors were expected to exist to about 65% of PC-6/WT from about 35% it as for the decrease in the resistance degree. The 141st amino acid mutation appears especially at high frequency in the Japanese, and it is necessary to pursue this result further. Whether the 141st amino acid is an amino acid that exists in the ATP binding site, and the localization of the mutation might influences the function of ABCG2. Then, the mutation that exists in the ATP binding site and/or outside of cell, in the transmembrane domain was examined.2. Expression of ABCG2/BCRP in clinical specimenThe amount of expression of ABCG2mRNA was observed among 12 samples examin … More ed by a real-time PCR analysis and an example that was remarkably higher in the cancer organization than the normal tissue and lower in the cancer organization than the normal tissue was observed. It was guessed that normal organization excretion of anti-cancer drug to protect itself by high expression of ABCG2 in the normal tissue. Moreover, examples were seen expression whose one of this level is almost higher than that of the normal tissue in three examples and the cancer organizations in the normal tissue and the cancer organization were two examples. A state and malignancy of cancer, stage classifications, and the lymph node metastasis were various in each patient, so that the correlation of expression amount of ABCG2mRNA and the malignancy of cancer were not detected.3. Inhibition mechanism of ABCG2/BCRP inhibitor and examination of specificityWe showed that quercetin, nobobioshin, and ZD1839 inhibit the transport activity of ABCG2 strongly, and to overcome various anti-cancer drug resistance in the ABCG2 expression cell line. Then, the inhibition effect of the transport activity was examined by using the ABCG2 gene transfection membrane to examine these three kinds of drugs inhibit the transport activity of the CPT derivatives that showed the resistance to ABCG2 excessive expression cell, and whether overcome the resistance. As a result, three kinds of inhibitors strongly inhibit transport activity of each CPT derivatives. It was suggested that the CPT derivatives shows the resistance to ABCG2 excessive expression cell overcome the drug resistance by using these inhibitors together. Less

1.根据ABCG 2/BCRP的单核苷酸多态性（SNP），底物特异性的变化被认为第141个氨基酸突变影响翻译，是PC 6/Q141 K相对耐药性下降的原因之一，并且蛋白质表达下降。然而，蛋白质表达是预期的，并且预期一些因素从PC-6/WT的约35%存在到约65%，关于抗性程度的降低。第141位氨基酸突变在日本人中出现的频率特别高，有必要进一步研究这一结果。第141位氨基酸是否为ATP结合位点的氨基酸，以及突变的位置可能影响ABCG 2的功能。然后，检测存在于ATP结合位点和/或细胞外、跨膜区的突变. ABCG 2/BCRP在临床肿瘤中的表达 ...更多信息艾德通过实时PCR分析，观察到癌组织中显著高于正常组织且癌组织中低于正常组织的实例。推测正常组织通过ABCG 2的高表达，分泌抗癌药物保护自身。此外，在3例中观察到其表达水平几乎高于正常组织的例子，在正常组织和癌组织中观察到2例表达水平高于正常组织的例子。各患者的肿瘤状态、恶性程度、分期、淋巴结转移情况各不相同，未检测到ABCG 2 mRNA表达量与肿瘤恶性程度的相关性. ABCG 2/BCRP抑制剂的抑制机制及特异性检测我们发现槲皮素、信生素和ZD 1839强烈抑制ABCG 2的转运活性，并克服ABCG 2表达细胞系中的各种抗癌药物耐药性。然后，通过使用ABCG 2基因转染膜检测转运活性的抑制效果，以检测这三种药物抑制对ABCG 2过度表达细胞显示抗性的CPT衍生物的转运活性，以及是否克服抗性。结果，三种抑制剂强烈抑制每种CPT衍生物的转运活性。提示CPT衍生物对ABCG 2过度表达细胞表现出耐药性，联合使用这些抑制剂可克服耐药性。少