Nat Commun:新途径定位肿瘤


    近期Nature Communications上发表的一篇研究论文报告了能将药物定位到癌症组织上的一个多用途化学标签。该标签(理论上能被附着到各种现有抗癌药物上,并能被不同类型的与肿瘤相关的酶通过两个步骤除掉)也许能增强抗癌疗法的疗效。


    Nobuhide Ueki及同事报告说,需要两种酶来除掉该标签和释放药物,药物预计主要在癌变组织中出现。组蛋白脱乙酰酶通过将乙酰基从蛋白上除掉来控制基因表达,并且在肿瘤中经常是有活性的;Cathepsin L也已被发现与肿瘤发展和转移相关。通过组蛋白脱乙酰酶将一个乙酰基从这个标签上除掉,会将一个结合点暴露出来,后者允许随后被Cathepsin L劈分。作者将该标签附着到抗癌药物“嘌呤霉素”上,发现带标签的“嘌呤霉素”在一个结肠癌动物模型中在抑制肿瘤生长方面比不带标签的药物更有效。


Selective cancer targeting with prodrugs activated by histone deacetylases and a tumour-associated protease


Nobuhide Ueki,         Siyeon Lee,     Nicole S. Sampson & Michael J. Hayman


Eradication of cancer cells while minimizing damage to healthy cells is a primary goal of cancer therapy. Highly selective drugs are urgently needed. Here we demonstrate a new prodrug strategy for selective cancer therapy that utilizes increased histone deacetylase (HDAC) and tumour-associated protease activities produced in malignant cancer cells. By coupling an acetylated lysine group to puromycin, a masked cytotoxic agent is created, which is serially activated by HDAC and an endogenous protease cathepsin L (CTSL) that remove the acetyl group first and then the unacetylated lysine group liberating puromycin. The agent selectively kills human cancer cell lines with high HDAC and CTSL activities. In vivo studies confirm tumour growth inhibition in prodrug-treated mice bearing human cancer xenografts. This cancer-selective cleavage of the masking group is a promising strategy for the next generation of anticancer drug development that could be applied to many other cytotoxic agents.