The hematopoietic-specific β1-tubulin is naturally resistant to 2-methoxyestradiol and protects patients from drug-induced myelosuppression
The hematopoietic-specific β1-tubulin is naturally resistant to 2-methoxyestradiol and protects patients from drug-induced myelosuppression
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DOI：
10.4161/cc.8.23.10105
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发表时间：
2009-12-01
期刊：
影响因子：
4.3
通讯作者：
Giannakakou, Paraskevi
中科院分区：
文献类型：
--
作者：
Escuin, Daniel;Burke, Patricia A.;Giannakakou, Paraskevi
紫杉烷和其他微管靶向药物（MTDs）是最有效的癌症化疗药物之一。然而，由于药物诱导的骨髓抑制，它们的效用最终受到限制。在这里，我们发现2-甲氧基雌二醇（2ME2）是第一个能够特异性靶向肿瘤细胞的MTD，同时使骨髓免受剂量限制，危及生命的毒性。在2ME2药物选择后，上皮癌细胞在V β 236I上获得了一个微管蛋白突变，破坏了2ME2-微管蛋白的相互作用，使细胞对2ME2产生抗性。我们进一步表明，造血特异性H β 1微管蛋白同型自然编码I β 236，对2ME2不敏感。与紫杉烷或长春花生物碱诱导的毒性相比，C57BL6小鼠全身给予2ME2对骨髓微管没有影响。在对人骨髓和cd34阳性干细胞/祖细胞进行药物治疗时，也获得了类似的结果。在此，我们描述了第一个同型靶向化疗，为整个MTDs类别设置了一个新的范例，并提供了一个模型，可以允许设计新的无骨髓抑制的微管蛋白抑制剂。设计一种副作用最小的药物的能力将大大增加临床成功的机会，因为它允许使用真正的治疗剂量，而不是最大限度的耐受剂量。
Taxanes and other microtubule-targeting drugs (MTDs) represent one of the most effective classes of cancer chemotherapeutics. However, ultimately their utility is limited due to drug-induced myelosuppression. Here we identify 2-Methoxyestradiol (2ME2) as the first MTD able to specifically target tumor cells while sparing the bone marrow from dose-limiting, life-threatening toxicities. Following drug selection with 2ME2, epithelial cancer cells acquired a tubulin mutation at V beta 236I that impaired the 2ME2-tubulin interaction and rendered cells resistant to 2ME2. We further show that the hematopoietic-specific H beta 1 tubulin isotype naturally encodes I beta 236 and is insensitive to 2ME2. Systemic administration of 2ME2 in C57BL6 mice revealed that there was no effect on bone marrow microtubules, in contrast to the taxane or Vinca alkaloid induced toxicities. Similar results were obtained upon drug treatment of human bone marrow and CD34-positive stem/progenitor cells. Herein, we describe the first isotype-targeted chemotherapeutic, setting a new paradigm for the entire class of MTDs, and providing a model that could allow the design of new tubulin inhibitors devoid of myelosuppression. The ability to design a drug with minimal side-effects would significantly augment the chances of clinical success by allowing the use of a truly therapeutic dose rather than the maximally tolerated.