P-glycoprotein-mediated acquired multidrug resistance of human lung cancer cells in vivo.
P-glycoprotein-mediated acquired multidrug resistance of human lung cancer cells in vivo.
复制标题
P-糖蛋白介导的人体肺癌细胞的获得性多药耐药性。
DOI：
10.1038/bjc.1996.655
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发表时间：
1996-12
影响因子：
8.8
通讯作者：
Nakamura, M
中科院分区：
文献类型：
--
作者：
Abe, Y;Ohnishi, Y;Yoshimura, M;Ota, E;Ozeki, Y;Oshika, Y;Tokunaga, T;Yamazaki, H;Ueyema, Y;Ogata, T;Tamaoki, N;Nakamura, M
我们研究了人类多药耐药基因MDR1编码的P-糖蛋白（P-gp）表达增加是否与体内肺癌的获得性多药耐药有关。我们根据 Mann-Whitney U 检验确定的统计显着性（P < 0.01，单侧），通过计算体内相对肿瘤生长（T/C%，治疗/对照）来估计肺癌异种移植物（LC-6，腺癌；Lu-24，小细胞癌）的化疗敏感性。通过逆转录聚合酶链反应（RT-PCR）测定评估MDR1基因表达水平。分别通过蛋白质印迹和免疫组织化学分析检查 P-gp 产生和 P-gp 定位。 LC-6和Lu-24最初在体内对长春新碱（VCR，1.6 mg kg-1：LC-6，45％；Lu-24，39％）和阿霉素（DOX，12 mg kg-1：LC-6，26％；Lu-24，27％）敏感。用 VCR (0.4 mg kg-1, x 9) 选择的 VCR 抗性变体（LC-6R，66% 和 Lu-24R，68%）显着获得了对 DOX 的交叉耐药性（分别为 LC-6R，55% 和 Lu-24R，55%）。 RT-PCR 检测显示 LC-6R 和 Lu-24R 中 MDR1 表达水平升高，且 MDR1 表达水平稳定。 LC-6R 和 Lu-24R 中 P-gp 表达水平升高，P-gp 阳性肿瘤细胞的百分比增加。这些结果表明P-gp/MDR1过表达与肺癌体内获得性多药耐药性有关。
We examined whether the increased expression of P-glycoprotein (P-gp) encoded by the human multidrug resistance gene MDR1 is related to the acquired multidrug resistance of lung cancer in vivo. We estimated the chemosensitivity of lung cancer xenografts (LC-6, adenocarcinoma; Lu-24, small-cell cancer) by calculation of relative tumour growth (T/C%, treated/control) in vivo, based on statistical significance determined by the Mann-Whitney U test (P < 0.01, one-sided). MDR1 gene expression levels were evaluated by reverse transcription-polymerase chain reaction (RT-PCR) assay. P-gp production and P-gp localisation were examined by Western blotting and by immunohistochemical analysis respectively. LC-6 and Lu-24 were initially sensitive to both vincristine (VCR, 1.6 mg kg-1: LC-6, 45%; Lu-24, 39%) and doxorubicin (DOX, 12 mg kg-1: LC-6, 26%; Lu-24, 27%) in vivo. VCR-resistant variants (LC-6R, 66% and Lu-24R, 68%) selected with VCR (0.4 mg kg-1, x 9) significantly acquired cross-resistance to DOX (LC-6R, 55% and Lu-24R, 55% respectively). RT-PCR assay showed increased levels of MDR1 expression in LC-6R and Lu-24R with stable MDR1 expression levels. P-gp expression levels were elevated, and the percentage of P-gp-positive tumour cells increased in both LC-6R and Lu-24R. These results suggest that P-gp/MDR1 overexpression is related to acquired multidrug resistance in lung cancer in vivo.