Alteration of genomic responses to doxorubicin and prevention of MDR in breast cancer cells by a polymer excipient: Pluronic P85
Alteration of genomic responses to doxorubicin and prevention of MDR in breast cancer cells by a polymer excipient: Pluronic P85
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DOI：
10.1021/mp050050g
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发表时间：
2006-03-01
影响因子：
4.9
通讯作者：
Kabanov, Alexander V.
中科院分区：
文献类型：
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作者：
Batrakova, Elena V.;Kelly, David L.;Kabanov, Alexander V.
聚合物疗法已成为治疗人类疾病的新的临床选择。然而，人们对用聚合物配制的药物的药物遗传学反应知之甚少。在这项研究中，我们证明含有嵌段共聚物 Pluronic P85 和抗肿瘤药物阿霉素 (Dox) 的制剂可防止人乳腺癌细胞系 MCF7 产生多药耐药性。具体而言，在存在 Pluronic 的情况下培养的 MCF7 细胞在 Dox 浓度超过 10 ng Dox/mL 培养基时无法稳定生长。与此形成鲜明对比的是，在没有嵌段共聚物的情况下培养的 MCF7 细胞导致细胞的选择和稳定生长，这些细胞耐受高出 1000 倍的药物浓度（10 000 ng Dox/mL 培养基）。分离的亚系的详细表征表明，在聚合物药物制剂中选择的那些细胞没有表现出 MDR1 基因的扩增，这可能导致它们对药物高度敏感。相反，单独使用 Dox 选择的细胞显示出 MDR1 基因表达水平升高，同时药物外流转运蛋白 Pgp 表达水平相应增加，这可能导致细胞对 Dox 的高耐药性。通过 DNA 微阵列对 20K 基因的表达谱进行整体分析表明，Pluronic 与 Dox 联合使用极大地改变了肿瘤细胞对 Dox 的遗传反应的方向和程度，并可能增强治疗效果。总体而言，这项研究强调了对聚合物疗法的药物基因组效应进行彻底评估的必要性。
Polymer therapeutics has emerged as a new clinical option for the treatment of human diseases. However, little is known about pharmacogenetic responses to drugs formulated with polymers. In this study, we demonstrate that a formulation containing the block copolymer Pluronic P85 and antineoplastic drug doxorubicin (Dox) prevents the development of multidrug resistance in the human breast carcinoma cell line, MCF7. Specifically, MCF7 cells cultured in the presence of Pluronic were unable to stably grow in concentrations of Dox that exceeded 10 ng of Dox/mL of culture medium. In sharp contrast, MCF7 cells cultured in the absence of the block copolymer resulted in the selection and stable growth of cells that tolerated a 1000 times higher concentration of the drug (10 000 ng of Dox/mL of culture medium). Detailed characterization of the isolated sublines demonstrated that those cells selected in the polymer-drug formulation did not show amplification of the MDR1 gene, likely resulting in their high sensitivity to the drug. Conversely, cells selected with Dox alone showed an elevated level in the expression of the MDR1 gene along with a corresponding increase in the expression level of the drug efflux transporter, Pgp, and likely contributing to the high resistance of the cells to Dox. Global analysis of the expression profiles of 20K genes by DNA microarray revealed that the use of Pluronic in combination with Dox drastically changed the direction and magnitude of the genetic response of the tumor cells to Dox and may potentially enhance therapeutic outcomes. Overall, this study reinforces the need for a thorough assessment of pharmacogenomic effects of polymer therapeutics.