Koziolová Eva, Chytil Petr, Etrych Tomáš, Janoušková Olga
Institute of Macromolecular Chemistry, Czech Academy of Sciences, Prague 6, Czech Republic.
Anticancer Drugs. 2017 Nov;28(10):1126-1130. doi: 10.1097/CAD.0000000000000553.
Polymer prodrugs can considerably improve the treatment of tumors with multidrug resistance, often caused by overexpression of P-glycoprotein (P-gp). Here, we present the effect of the N-(2-hydroxypropyl) methacrylamide-based polymer conjugate with P-gp inhibitor ritonavir (RIT) on the increase of free doxorubicin (DOX) and polymer-bound DOX cytotoxicity in the human neuroblastoma 4 cell line and its resistant clones to different cytostatics. The increase in cytotoxicity after polymer-RIT conjugate pretreatment was higher for the lines overexpressing P-gp and less pronounced for those with decreased P-gp levels. Moreover, the effect of polymer conjugate containing inhibitor and DOX on the same polymer chain was lower than that of two individual polymer conjugates used sequentially. In conclusion, the polymer-RIT conjugate can significantly increase the cytotoxicity of free DOX and polymer-DOX conjugates in cells with various multidrug resistance origins and can thus be considered a suitable therapeutic enhancer of polymer prodrugs.
聚合物前药可以显著改善对多药耐药性肿瘤的治疗，这种耐药性通常是由P-糖蛋白（P-gp）过表达引起的。在此，我们展示了基于N-(2-羟丙基)甲基丙烯酰胺的聚合物与P-gp抑制剂利托那韦（RIT）的缀合物对人神经母细胞瘤4细胞系及其对不同细胞抑制剂耐药克隆中游离阿霉素（DOX）增加以及聚合物结合DOX细胞毒性的影响。聚合物-RIT缀合物预处理后细胞毒性的增加在P-gp过表达的细胞系中更高，而在P-gp水平降低的细胞系中则不太明显。此外，含抑制剂和DOX的聚合物缀合物在同一聚合物链上的效果低于依次使用的两种单独聚合物缀合物的效果。总之，聚合物-RIT缀合物可以显著增加游离DOX和聚合物-DOX缀合物在具有各种多药耐药起源的细胞中的细胞毒性，因此可被视为聚合物前药合适的治疗增强剂。
