Levels of multidrug resistance (MDR1) P-glycoprotein expression by human breast cancer correlate with in vitro resistance to taxol and doxorubicin.
Levels of multidrug resistance (MDR1) P-glycoprotein expression by human breast cancer correlate with in vitro resistance to taxol and doxorubicin.
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发表时间：
1998-02
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通讯作者：
E. Mechetner;A. Kyshtoobayeva;S. Zonis;Hun-Gu Kim;R. Stroup;R. García;R. Parker;J. Fruehauf
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作者：
E. Mechetner;A. Kyshtoobayeva;S. Zonis;Hun-Gu Kim;R. Stroup;R. García;R. Parker;J. Fruehauf
为了确定是否多药耐药（MDR 1）的P-糖蛋白（Pgp）的表达与临床MDR 1相关的耐药，我们建立了一个协议，定量测量Pgp表达和体外耐药阿霉素耐药MCF 7乳腺癌细胞系和359例乳腺癌新鲜切除标本。采用流式细胞术和免疫组织化学（IHC）检测Pgp表达与4 E3，UIC 2和JSB-1单克隆抗体。使用PSC 833在耐药逆转试验和三维琼脂糖极端耐药试验中测定Pgp功能。MCF 7校准细胞系表达Pgp，其是功能性的并且与耐药程度成比例。流式细胞术、UIC 2偏移测定、IHC评分和通过图像分析测定吸光度产物均高度相关（r > 0.9）。总体Pgp表达从未经治疗的患者的11%增加到先前接受化疗的患者的30%。与Pgp阴性肿瘤相比，无论既往是否接受过治疗，表达Pgp的乳腺癌对阿霉素和紫杉醇的耐药性均显著增加。当使用IHC评分或基于图像分析的方法定量Pgp表达时，发现Pgp表达程度与体外对紫杉醇和阿霉素（但不对5-氟尿嘧啶）的耐药性之间存在强相关性（n = 185，P < 0.0001）。Pgp的表达程度与临床标本的耐药程度密切相关。这些数据表明，（a）Pgp有助于临床MDR 1相关的耐药性，（B）乳腺癌中Pgp的内在和获得性表达可能部分导致治疗失败和复发。
To determine whether multidrug resistance (MDR1) P-glycoprotein (Pgp) expression correlated with clinical MDR1-related drug resistance, we established a protocol for quantitative measurement of Pgp expression and in vitro drug resistance in doxorubicin resistant MCF7 breast cancer cell lines and 359 freshly resected specimens of breast carcinoma. Pgp expression was detected with 4E3, UIC2, and JSB-1 monoclonal antibodies using flow cytometry and immunohistochemistry (IHC). Pgp function was determined using PSC833 in a drug resistance-reversal assay and with a three-dimensional agarose-based extreme drug resistance assay. MCF7 calibrator cell lines expressed Pgp, which was functional and in proportion to the degree of drug resistance. Flow cytometry, UIC2 shift assays, IHC scores, and determination of absorbance products by image analysis were all highly correlated (r > 0.9). Overall Pgp expression increased from 11% in untreated patients to 30% in patients who had previously received chemotherapy. Compared with Pgp-negative tumors, a significant increase in doxorubicin and Taxol resistance was seen for breast cancers that expressed Pgp, regardless of prior treatment. A strong correlation between the degree of Pgp expression and in vitro resistance to Taxol and doxorubicin (but not to 5-fluorouracil) was found when either IHC scores or image analysis-based methods were used to quantify Pgp expression (n = 185, P < 0.0001). The degree of Pgp expression strongly correlated with the degree of drug resistance in the clinical specimens studied. These data suggest that (a) Pgp contributes to clinical MDR1-related drug resistance, and (b) both intrinsic and acquired expression of Pgp in breast cancer may contribute in part to therapeutic failure and relapse.