The effect of multidrug resistance modulator HZ08 on pharmacodynamics and pharmacokinetics of adriamycin in xenograft-nude mice.
The effect of multidrug resistance modulator HZ08 on pharmacodynamics and pharmacokinetics of adriamycin in xenograft-nude mice.
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DOI：
10.1016/j.ejps.2014.10.011
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发表时间：
2015-01
期刊：
影响因子：
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通讯作者：
Yanyan Zhang;Yi-dong Feng;Kodithuwakku Nandani Darshika;Bo Zhang;Yahui Hu;W. Fang;Yunman Li;Wen-long Huang
中科院分区：
文献类型：
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作者：
Yanyan Zhang;Yi-dong Feng;Kodithuwakku Nandani Darshika;Bo Zhang;Yahui Hu;W. Fang;Yunman Li;Wen-long Huang
克服p -糖蛋白介导的肿瘤多药耐药已成为临床提高肿瘤生存率的关键策略。因此，开发没有副作用或与细胞毒性药物相互作用的先进调节剂势在必行。HZ08作为P-gp抑制剂，在体外表现出明显的逆转作用和较低的细胞毒性。在此基础上，本实验旨在阐明HZ08对荷瘤裸鼠体内阿霉素药效学和药代动力学的影响。采用肿瘤重量、体积、体内显像、western blot、免疫组织化学、atp酶水解等指标和方法评价HZ08对MDR的逆转作用及其机制；此外，荧光检测法测定阿霉素在血液和组织中的分布。本研究发现，HZ08能增强阿霉素的抗肿瘤活性，但对体内P-gp的表达影响不大。HZ08通过抑制ATPase活性增强阿霉素在肿瘤中的蓄积。此外，HZ08没有改变阿霉素在血浆和组织中的药代动力学特征。综上所述，HZ08具有明显的MDR逆转活性，对阿霉素的药代动力学没有影响。
To overcome MDR (multidrug resistance) of cancer mediated by P-gp (P-glycoprotein) has become a key strategy to improve the survival rate in clinic. Therefore, it is imperative to develop advanced modulators that have no side effects or interactions with cytotoxic drugs. HZ08, which acts as a P-gp inhibitor, shows a notable reverse effect with low cytotoxicity in vitro. Based on the previous results, the goal of this experiment is to elucidate the effect of HZ08 on pharmacodynamics and pharmacokinetics of adriamycin in tumor-bearing nude mice. Several criterions and methods, such as tumor weight and volume, in vivo imaging, western blot, immunohistochemistry as well as ATPase hydrolysis assay were selected to evaluate the reversing activity and mechanism of HZ08 on MDR; Furthermore, fluorescence detection assay was applied to determine the distribution of adriamycin in the blood and tissues. This study revealed that HZ08 potentiated the anti-tumor activity of adriamycin but with little effect on the expression of P-gp in vivo. Adriamycin accumulation in tumor was enhanced by HZ08 via ATPase activity inhibition. In addition, HZ08 did not alter the pharmacokinetic characteristic of adriamycin in plasma or tissues. In conclusion, HZ08 showed dramatic MDR reversing activity and had no influence on the pharmacokinetics of adriamycin.