Small molecules targeting histone H4 as potential therapeutics for chronic myelogenous leukemia
Small molecules targeting histone H4 as potential therapeutics for chronic myelogenous leukemia
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DOI：
10.1158/1535-7163.mct-08-0130
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发表时间：
2008-04-01
影响因子：
5.7
通讯作者：
Gottesfeld, Joel M.
中科院分区：
文献类型：
--
作者：
Chou, C. James;Farkas, Michelle E.;Gottesfeld, Joel M.
我们最近鉴定了一种聚酰胺-苯丁酸氮芥缀合物 1R-Chl，它可以烷基化并下调人类组蛋白 H4c 基因的转录，并在体外和小鼠 SW620 异种移植模型中抑制多种癌细胞系的生长，且没有明显的动物毒性。在这项研究中，我们分析了 1R-Chl 在慢性粒细胞白血病细胞系 K562 中的作用，并鉴定了另一种聚酰胺缀合物 6R-Chl，它靶向 H4 基因并引发类似的细胞反应。其他不靶向 H4 基因的聚酰胺缀合物不会引起这种反应。在小鼠模型中，发现 1R-Chl 和 6R-Chl 均能高度有效地阻断 K562 异种移植物的生长，并且具有高剂量耐受性。与传统的和基于偏端霉素的烷化剂不同，在 mg/kg 剂量范围内观察到很少或没有细胞毒性和动物毒性。这些结果表明这些聚酰胺烷基化剂可能是慢性粒细胞白血病的可行治疗替代方案。
We recently identified a polyamide-chlorambucil conjugate, 1R-Chl, which alkylates and down-regulates transcription of the human histone H4c gene and inhibits the growth of several cancer cell lines in vitro and in a murine SW620 xenograft model, without apparent animal toxicity. In this study, we analyzed the effects of 1R-Chl in the chronic myelogenous leukemia cell line K562 and identified another polyamide conjugate, 6R-Chl, which targets H4 genes and elicits a similar cellular response. Other polyamide conjugates that do not target the H4 gene do not elicit this response. In a murine model, both 1R-Chl and 6R-Chl were found to be highly effective in blocking K562 xenograft growth with high-dose tolerance. Unlike conventional and distamycin-based alkylators, little or no cytotoxicities and animal toxicities were observed in mg/kg dosage ranges. These results suggest that these polyamide alkylators may be a viable treatment alternative for chronic myelogenous leukemia.