Department of Experimental Medicine and Biochemical Sciences, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy.
Recent Pat Anticancer Drug Discov. 2010 Jan;5(1):58-68. doi: 10.2174/157489210789702163.
Chronic myelogenous leukemia (CML) is a myeloproliferative disorder characterized by unregulated growth of myeloid leukemia cells in the bone marrow and accumulation of these cells in the blood. CML represents approximately 15-20% of all adult leukemia and the disease development is clearly linked to the constitutively active tyrosine kinase of the chimeric protein BCR-ABL. It is encoded by the Bcr-Abl fusion gene sequence as the result of chromosome 9/22 translocation (Philadelphia chromosome) or other aberrant cytogenetic events. The development of targeted agents that specifically inhibit the tyrosine kinase (TK) activity of BCR-ABL has revolutionized the treatment of CML. Imatinib is now the first-line treatment for chronic phase CML, and several newer tyrosine kinase inhibitors (TKIs) such as dasatinib and nilotinib have been added to the pharmacologic compendium. Despite the proven efficacy of TKIs to induce hematological and cytogenetic remission, the large majority of patients still have molecularly detectable disease. Therefore, new options are needed to improve therapeutic success in the treatment of leukemia. Pyrrolo[1,2-b][1,2,5]benzothiadiazepine 5,5-dioxides (PBTDs) induced apoptosis in human BCR-ABL expressing leukemia cells. The apoptotic activity was also observed in primary leukemic blasts, obtained from CML patients at onset or from patients in blast crisis and who were imatinib- dasatinib- and nilotinib resistant. These results suggests that these compounds are promising agent for the treatment of leukemia. Due to the fact that the phenomenon of resistance to TKIs remains a major issue in the treatment of patients with CML, the identification of new drugs may be of clinical relevance. This review summarises patents and papers dealing with the present understanding of mechanism of action and the most relevant data concerning TKs inhibition.
慢性髓性白血病（CML）是一种骨髓增生性疾病，其特征是髓性白血病细胞的不受调节的生长和这些细胞在血液中的积累。CML 约占所有成人白血病的 15-20%，疾病的发展显然与嵌合蛋白 BCR-ABL 的组成性激活的酪氨酸激酶有关。它是由 Bcr-Abl 融合基因序列编码的，作为染色体 9/22 易位（费城染色体）或其他异常细胞遗传学事件的结果。靶向药物的开发，这些药物专门抑制 BCR-ABL 的酪氨酸激酶（TK）活性，彻底改变了 CML 的治疗方法。伊马替尼现在是慢性期 CML 的一线治疗药物，几种新型酪氨酸激酶抑制剂（TKIs），如达沙替尼和尼洛替尼，已被添加到药理学概要中。尽管 TKIs 已被证明能诱导血液学和细胞遗传学缓解，但绝大多数患者仍存在分子上可检测到的疾病。因此，需要新的选择来提高白血病治疗的治疗成功率。吡咯并[1,2-b][1,2,5]苯并噻二嗪 5,5-二氧化物（PBTDs）诱导表达 BCR-ABL 的人白血病细胞凋亡。在初发的白血病细胞中也观察到了这种凋亡活性，这些细胞是从 CML 患者初发或从处于爆发危机且对伊马替尼、达沙替尼和尼洛替尼耐药的患者中获得的。这些结果表明，这些化合物是治疗白血病的有前途的药物。由于对 TKI 耐药的现象仍然是 CML 患者治疗的一个主要问题，因此，寻找新的药物可能具有临床意义。本综述总结了涉及目前对作用机制的理解以及与 TKIs 抑制最相关的数据的专利和论文。
