Prediction of paclitaxel sensitivity by CDK1 and CDK2 activity in human breast cancer cells.
Prediction of paclitaxel sensitivity by CDK1 and CDK2 activity in human breast cancer cells.
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DOI：
10.1186/bcr2231
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发表时间：
2009
期刊：
影响因子：
--
通讯作者：
Ueno NT
中科院分区：
文献类型：
--
作者：
Nakayama S;Torikoshi Y;Takahashi T;Yoshida T;Sudo T;Matsushima T;Kawasaki Y;Katayama A;Gohda K;Hortobagyi GN;Noguchi S;Sakai T;Ishihara H;Ueno NT
紫杉醇广泛用于治疗乳腺癌。然而，并非所有的肿瘤都对这种药物有反应，而且区分耐药肿瘤和敏感肿瘤的特征还没有很好的定义。纺锤体组装检查点的激活是紫杉醇诱导的细胞死亡所必需的。我们假设癌细胞中的细胞周期蛋白依赖性激酶（CDK）1活性和CDK2活性分别反映了纺锤体组装检查点的激活状态和生长状态，可预测对紫杉醇的敏感性。在人乳腺癌细胞系中进行细胞活力测定和DNA和染色质形态学分析，以评价对紫杉醇的敏感性和对紫杉醇的细胞周期反应。然后，我们研究了紫杉醇治疗前后这些细胞系和人乳腺癌异种移植模型中CDK1和CDK2的特异性活性。使用新开发的测定系统分析CDKs和细胞周期蛋白的蛋白表达和激酶活性。在细胞系中，体外对紫杉醇的生物学反应不能准确预测体内对紫杉醇的敏感性。然而，在乳腺癌异种移植肿瘤中，紫杉醇治疗后CDK1比活性显著增加的肿瘤在体内对紫杉醇敏感，而没有这种增加的肿瘤在体内对紫杉醇耐药。对紫杉醇敏感的肿瘤的基线CDK2比活性高于对紫杉醇耐药的肿瘤。紫杉醇治疗后异种移植瘤CDK1比活性的变化和紫杉醇治疗前CDK2比活性的变化均与体内药物敏感性相关。在临床环境中分析细胞周期蛋白依赖性激酶活性可能是预测紫杉醇敏感性的有力方法。
Paclitaxel is used widely in the treatment of breast cancer. Not all tumors respond to this drug, however, and the characteristics that distinguish resistant tumors from sensitive tumors are not well defined. Activation of the spindle assembly checkpoint is required for paclitaxel-induced cell death. We hypothesized that cyclin-dependent kinase (CDK) 1 activity and CDK2 activity in cancer cells, which reflect the activation state of the spindle assembly checkpoint and the growth state, respectively, predict sensitivity to paclitaxel. Cell viability assays and DNA and chromatin morphology analyses were performed in human breast cancer cell lines to evaluate sensitivity to paclitaxel and the cell cycle response to paclitaxel. We then examined the specific activities of CDK1 and CDK2 in these cell lines and in xenograft models of human breast cancer before and after paclitaxel treatment. Protein expression and kinase activity of CDKs and cyclins were analyzed using a newly developed assay system. In the cell lines, biological response to paclitaxel in vitro did not accurately predict sensitivity to paclitaxel in vivo. Among the breast cancer xenograft tumors, however, tumors with significantly increased CDK1 specific activity after paclitaxel treatment were sensitive to paclitaxel in vivo, whereas tumors without such an increase were resistant to paclitaxel in vivo. Baseline CDK2 specific activity was higher in tumors that were sensitive to paclitaxel than in tumors that were resistant to paclitaxel. The change in CDK1 specific activity of xenograft tumors after paclitaxel treatment and the CDK2 specific activity before paclitaxel treatment are both associated with the drug sensitivity in vivo. Analysis of cyclin-dependent kinase activity in the clinical setting could be a powerful approach for predicting paclitaxel sensitivity.
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影响因子：
45.3
作者：
Nabholtz, JM;Gelmon, K;Winograd, B
通讯作者：
Winograd, B
影响因子：
11.5
作者：
Andre, Fabrice;Hatzis, Christos;Pusztai, Lajos
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Pusztai, Lajos
影响因子：
45.3
作者：
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Norton, L
影响因子：
8.4
作者：
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通讯作者：
Escobedo, Agustin P.
影响因子：
45.3
作者：
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Canetta, R