In vivo synergy between topoisomerase II and histone deacetylase inhibitors:: predictive correlates
In vivo synergy between topoisomerase II and histone deacetylase inhibitors:: predictive correlates
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DOI：
10.1158/1535-7163.mct-05-0194
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发表时间：
2005-12-01
影响因子：
5.7
通讯作者：
Munster, PN
中科院分区：
文献类型：
--
作者：
Marchion, DC;Bicaku, E;Munster, PN
组蛋白去乙酰化酶抑制剂（HDACi）是一类有前途的抗癌剂，但导致细胞死亡的特定生物学效应仍然知之甚少，并且临床相关的反应标志物也没有充分定义。抗惊厥药丙戊酸最近作为HDACi出现，体外研究表明丙戊酸可能增强细胞毒性药物。我们评估了丙戊酸对乳腺癌小鼠组蛋白乙酰化、染色质结构和拓扑异构酶II抑制剂诱导的DNA损伤的药理学和生物学作用，并开发了一种使用彗星试验进行反应预测的体外方法。当丙戊酸以足以进行组蛋白超乙酰化、异染色质维持蛋白下调和染色质解凝聚的浓度给药48小时时，小鼠在暴露于表柔比星之前暴露于丙戊酸，导致肿瘤消退。通过离体彗星矩准确预测肿瘤反应。丙戊酸未加重表柔比星相关毒性。尽管丙戊酸浓度具有生物活性，但单独使用丙戊酸时未观察到抗肿瘤作用。这些结果表明，暴露于丙戊酸荷瘤小鼠增强拓扑异构酶II抑制剂的抗肿瘤作用，而不增加毒性。HDACi诱导的组蛋白乙酰化和异染色质的调节与表阿霉素介导的DNA损伤的增强相关。然而，当单独使用HDACi时，这些作用不会导致抗肿瘤活性，因此不应被视为替代标志物。当肿瘤细胞有限且难以获得连续活检时，体外彗星试验可用作预测工具。
Histone deacetylase inhibitors (HDACi) are a promising class of anticancer agents, yet the specific biological effects resulting in cell death are still poorly understood and clinically relevant markers of response are not adequately defined. The anticonvulsant valproic acid has recently emerged as an HDACi, and in vitro studies suggested that valproic acid may potentiate cytotoxic agents. We evaluated the pharmacologic and biological effects of valproic acid on histone acetylation, chromatin structure, and DNA damage induced by topoisomerase II inhibitors in mice bearing breast cancer tumors and developed an ex vivo methodology for response prediction using comet assays. The exposure of mice to valproic acid before exposure to epirubicin led to tumor regression when valproic acid was given for 48 hours at concentrations sufficient for histone hyperacetylation, down-regulation of heterochromatin maintenance proteins, and chromatin decondensation. Tumor response was accurately predicted by ex vivo comet moments. Valproic acid did not exacerbate epirubicin-related toxicity. Antitumor effects were not observed with valproic acid alone despite biologically active valproic acid concentrations. These findings suggest that exposure of tumor-bearing mice to valproic acid potentiated the antitumor effects of topoisomerase II inhibitors without enhancing toxicity. The HDACi-induced histone acetylation and modulation of heterochromatin correlated with potentiation of epirubicinmediated DNA damage. However, these effects did not result in antitumor activity when using a HDACi alone and hence should not be considered a surrogate marker. Ex vivo comet assays may be useful as a predictive tool when tumor cells are limited and serial biopsies are difficult to obtain.