标题:
慢性髓细胞白血病对伊马替尼产生耐药性的机制
Imatinib Resistance Mechanism on Chronic Myeloid Leukemia
作者:
夏君燕, 朱平
关键字:
酪氨酸激酶抑制剂, 伊马替尼, 耐药, 激酶区突变, BCR-ABL1Tyrosine Kinase Inhibitor; Imatinib; Drug Resistance; Kinase Domain Mutation; BCR-ABL1
期刊名称:
《World Journal of Cancer Research》, Vol.2 No.3, 2012-07-26
摘要:
慢性髓细胞白血病(Chronic Myeloid Leukemia, CML)是克隆性造血细胞骨髓增殖性疾病。这种疾病是由特殊染色体易位引起的，即Ph染色体。Ph染色体由22号染色体的长臂和9号染色体的长臂断裂融合而成，大约在95%的CML患者、5%的儿童急性淋巴细胞白血病(Acute Lymphoblastic Leukemia, ALL)、15%~30%的成人ALL、2%新诊断的AML(Acute Myeloid Leukemia)中能检测到Ph。由该基因编码后翻译出具有持续活化的酪氨酸激酶活性(PTK)的BCR-ABL1融合蛋白，能够活化下游多条信号通路，抑制细胞凋亡，刺激细胞无限增殖，增强细胞的侵袭力，诱导对细胞毒药物和辐射治疗的抵抗。伊马替尼(Imatinib, IM)是人工设计的一种酪氨酸激酶抑制剂(Tyrosine kinase inhibitor, TKI)，作为一种靶向药物自2001年FDA批准上市以来，对治疗CML具有显著疗效。伊马替尼的作用是结合ABL1激酶催化结构域，使该结构域的构象处于非活动性的状态，不能再与ATP结合，从而抑制了白血病细胞的生长活性。不幸的是，许多患者服用不久后会出现耐药现象，已有相关报道称在接受伊马替尼治疗5年后的CML患者中，有24%出现继发耐药。80%的耐药原因是由于BCR-ABL1激酶区的点突变(KDM, Kinase Domain Mutation)，造成伊马替尼不能与其结合。
Chronic myeloid leukemia is a clonal myeloproliferative disease of hematopoietic cells, induced by specific chromosome translocation. The Ph chromosome is a shortened chromosome 22 resulting from a reciprocal translocation, t(9; 22) - (q34; q11), between the long arms of chromosomes 9 and 22. It is the hallmark of CML and is found in up to 95 percent of patients. It is also found in 5 percent of children and in 15 to 30 percent of adults with acute lymphoid leukemia and in 2 percent of patients with newly diagnosed acute myeloblastic leukemia. This translocation generates a fusion protein, BCR-ABL which has constitutively tyrosine kinases activity. Leading to activation of downstream signal transduction pathways in cells responsible for protection apoptosis, stimulation proliferation, enhance the invasion abil- ity and induction of resistance to genotoxic drugs and radiation therapy. Imatinib is an artificial design targeted drug of tyrosine kinase inhibitor. Since it comes to the market at 2001 authorized by FDA, it gets a significant progress in the treatment of CML. The role of imatinib is bind the kinase catalytic domain of ABL1, then the non-activity domain can not bind the ATP, inhibiting the activity of the proliferate of CML cells. Unfortunately many patients get efficacy shortly before the emergence of drug resistance. It have been reported that CML patients get 5 years treatment by Imatinib. 24% have secondary resistance, 80% of drug-resistant is the BCR-ABL1 kinase domain mutation, resulting in Imatinib can not bind the key domain.