[乳腺癌耐药蛋白表达与5-氟尿嘧啶耐药关系的研究]

[Study on the relationship between breast cancer resistance protein expression and 5-fluorouracil resistance].

作者信息

Yuan Jian-Hui, Cheng Jin-Quan, Ke Yue-Bin, Ji Na-Na, Zhou Jian-Meng, Zhou Li, Huang Hai-Yan, Yang Lin-Qing, Liu Jian-Jun, Xu Xin-Yun, Zhuang Zhi-Xiong

机构信息

Toxicology Laboratory, Shenzhen Center for Disease Control and Prevention, Shenzhen 518020, China.

出版信息

Zhonghua Yu Fang Yi Xue Za Zhi. 2008 Jul;42(7):506-10.

PMID:19035187

Abstract

OBJECTIVE

To screen breast cancer resistance protein BCRP-mediated resistance agents and to investigate the relations between BCRP expression and drug resistance.

METHODS

MT assay was performed to screen BCRP-mediated resistant agents with established BCRP expression cell model. While, the high performance liquid chromatography (HPLC) assay was administrated to measure the related dosage of intracellular retention resistant agents. The BCRP expression was investigated by both real-time RT-PCR and immunohistochemistry (IHC) assay in 140 clinical breast cancer tissue specimens. Chemosensitivity to resistant agents for clinical breast cancer tissue specimens was analyzed by MT assay. The Nonparametric variance statistics method was used to analyze the correlations between clinical breast cancer tissue of BCRP expression and drug resistance.

RESULTS

MT assay showed that increasing resistance of 5-fluorouracil (5-Fu) climbed with the increases of the BCRP expressions by 10.58 times (P < 0.05, n = 3) in cell model. HPLC assay also proved that a significant negative correlation between the intracellular retention dose of 5-Fu with different expression of BCRP (r = -0.897, P < 0.05, n = 3). Forty-seven tissue specimens of BCRP-positive expression were rapidly determined by using both real-time RT-PCR and IHC in 140 clinical breast cancer tissue specimens. Subsequently, the resistance index (RI) for 47 BCRP-positive clinical breast cancer tissues to 5-Fu was shown from 7 to 12 times compared with normal cancer-side tissues through MT assay. The statistical correlation between BCRP expression and 5-Fu resistance was observed in clinical breast cancer tissue specimens (R2 = 0.8124, P < 0.01).

CONCLUSION

This study results showed that there is a significant relationship between BCRP expression and 5-Fu resistance. Moreover, the results suggest that the chemotherapy scheme could be optimized on BCRP-positive expression breast cancer patients.

摘要

目的

筛选乳腺癌耐药蛋白BCRP介导的耐药相关药物，并研究BCRP表达与耐药性之间的关系。

方法

采用MT法，利用已建立的BCRP表达细胞模型筛选BCRP介导的耐药相关药物。同时，采用高效液相色谱（HPLC）法测定细胞内滞留的耐药相关药物的相关剂量。通过实时逆转录聚合酶链反应（RT-PCR）和免疫组织化学（IHC）法检测140例临床乳腺癌组织标本中的BCRP表达。采用MT法分析临床乳腺癌组织标本对耐药相关药物的化疗敏感性。采用非参数方差统计方法分析临床乳腺癌组织中BCRP表达与耐药性之间的相关性。

结果

MT法显示，在细胞模型中，随着BCRP表达增加10.58倍，5-氟尿嘧啶（5-Fu）的耐药性增加（P < 0.05，n = 3）。HPLC法也证明，5-Fu在细胞内的滞留剂量与不同表达水平的BCRP之间存在显著负相关（r = -0.897，P < 0.05，n = 3）。在140例临床乳腺癌组织标本中，通过实时RT-PCR和IHC法快速检测出47例BCRP阳性表达的组织标本。随后，通过MT法检测，47例BCRP阳性的临床乳腺癌组织对5-Fu的耐药指数（RI）是正常癌旁组织的7至12倍。在临床乳腺癌组织标本中观察到BCRP表达与5-Fu耐药性之间存在统计学相关性（R2 = 0.8124，P < 0.01）。