白血病多靶点联合治疗的基础和临床研究

Basic and clinical studies of the combined multi-targeting therapy of leukemia

作为靶向诱导肿瘤细胞分化和凋亡的代表性模式，全反式维甲酸（ATRA）和三氧化二砷（ATO）治疗急性早幼粒细胞白血病（APL）取得了巨大的成功。ATRA与ATO均作用于异常转录因子PML—RARα，通过不同的途径降解PML—RARα致病蛋白，导致APL细胞分化和凋亡。临床试验证实了两药的协同作用，两药联合治疗初发APL获得了迄今急性白血病治疗的最好疗效。体外实验证实ANLL—M2b型白血病存在c—kif突变和过度表达，提示异常c—kif可以作为靶向治疗该类型白血病的候选靶点。冬凌草甲素（Oridonin）可以特异性地降解AML1-ETO，有可能成为治疗该类白血病的候选药物。酪氨酸激酶抑制剂在慢性粒细胞白血病（CML）治疗中获得了成功，该药联合砷剂治疗CML已在体外实验中初步证实其有效性。

The success of ATRA and ATO in APL treatment furnishes the first model of molecular target-based induction of differentiation and apoptosis. Two drugs all target PML-RARα oncoprotein through different moieties and induce APL cells differentiation and apoptosis. In acute myeloid leukemia M2b, we reveal that gain-of-function of C-kit coexists with persistent AML1-ETO, suggesting that abnormal C-kit may serve as a therapeutic target in AML L-M2b. Oridonin becomes a potential candidate target drug which specifically degrades AML1-ETO protein. Experiment in vitro proves the combinatorial effectiveness of imatinib and cytarabin in the treatment of chronic myelogenous leukemia （CML）. Imatinib is an inhibitor of abnormal protein tyrosine kinases activity. While arsenic agent triggers the degradation of ber-abl, and combination of the two drugs in treating CML leads to a better outcome.