抗肿瘤新药STI571研究新进展

STI571是近年开发的用于治疗慢性髓细胞性白血病(CML)的酪氨酸激酶抑制剂，对bcr-abl激酶有高度特异性的抑制作用。由于该药物是在理解疾病分子机制的基础上，针对CML特异的分子异常进行的一种靶向治疗，因而与传统化疗药物有很大的不同，从而引起了人们的普遍关注。现介绍其作用机制、体内外抗瘤作用、临床试验结果及耐药性等的最新进展。     

抗肿瘤新药STI571研究新进展

STI571是近年开发的用于治疗慢性髓细胞性白血病（CML）的酪氨酸激酶抑制剂，对bcr-abl激酶有高度特异性的抑制作用。由于该药物是在理解疾病分子机制的基础上，针对CML特异的分子异常进行的一种靶向治疗，因而与传统化疗药物有很大的不同，从而引起人们的普遍关注。现介绍其作用机制、体内外抗瘤作用、临床试验结果及耐药性等的最新进展。     

酪氨酸激酶抑制剂耐药的分子机制及耐药后治疗策略

酪氨酸激酶抑制剂(TKI)治疗慢性粒细胞性白血病(CML)的效果虽然显著,但治疗过程中产生的耐药问题仍无法避免.因此,TKI耐药是CML治疗失败的主要原因之一.据报道,约5%的患者对TKI存在原发性耐药,20%~30%的患者对TKI产生继发性耐药.目前已知的TKI耐药分子机制有bcr-abl过表达、基因突变、DNA修复机制缺陷、ATP-binding cassette(ABC)转运蛋白介导的药物外排、异常信号通路及骨髓微环境等.同时,针对各种耐药机制开发的药物多处于临床前或临床研究阶段,这些药物的研究为克服TKI耐药提供了可能.本文拟对TKI耐药的分子机制及耐药后治疗策略的进展进行综述.     

酪氨酸激酶抑制剂致慢性髓系白血病患者乙肝再激活1例并文献复习

0引言酪氨酸激酶抑制剂(tyrosine kinase inhibitor,TKI)作为一类针对酪氨酸激酶的分子靶向治疗药物,已成为慢性髓系白血病(chronic myelogenous leukemia,CML)患者药物治疗的首选。近年来出现了合并慢性HBV感染的CML患者接受TKI治疗后发生乙肝再激活的报道,引起医疗工作者对该药物靶向外不良反应的关注。基于此,本文通过报道1例CML患者在服用第一代TKI伊马替尼的过     

慢性粒细胞白血病的治疗进展

Bcr/Abl酪氨酸激酶抑制剂作为分子靶向治疗药物用于慢性粒细胞白血病(CML)的治疗,大大提高了血液学缓解率和遗传学缓解率,且在聚乙二醇干扰素(IFN)、非清髓造血干细胞移植(HSCT)、树突状细胞疫苗等治疗方面也取得了新进展.临床研究表明,以酪氨酸激酶抑制剂为基础的联合治疗更加有效.     

尼洛替尼一线治疗慢性髓系白血病的进展

慢性髓系白血病(CML)是一类骨髓增殖性肿瘤,其发病机制与BCR/ABL融合基因相关。酪氨酸激酶抑制剂(TKI)可显著改善CML患者的生存及预后。尼洛替尼一线治疗CML患者疗效显著、治疗反应快、缓解程度深并且安全性高。在获得持续深层分子反应后,实现停止尼洛替尼用药并达到无治疗缓解是CML治疗的新目标。此外,由于疾病耐药及突变的产生,尼洛替尼治疗失败后如何开始新的治疗值得进一步研究。     

慢性粒细胞白血病靶向治疗和靶向鸡尾酒疗法研究进展

酪氨酸激酶抑制剂（TKI）的应用显著改善了慢性粒细胞白血病（CML）患者的预后,但目前单用 TKI 仍难以根治 CML。除更有效 TKI 类药物的研发及现有药物的精确使用外,CML 其他分子靶点的开发、针对 CML 肿瘤干细胞的治疗研究和联合用药为改进治疗和治愈 CML 带来新的希望。文章就相关研究进展进行综述。     

抑制Hedgehog信号通路可以阻止CML的进展

染色体易位是大多数慢性粒细胞白血病（CML）的主要发病机制，染色体易位导致断裂点簇集区（breakpoint cluster region。BCR）和酪氨酸激酶ABL1形成融合蛋白。酪氨酸激酶抑制剂伊马替尼（imatinib）可控制CML患者的病程，但是BCR—ABL1 T3151点突变的CML患者对伊马替尼等酪氨酸激酶抑制剂表现出耐药性。     

慢性粒细胞白血病的治疗新进展

慢性粒细胞白血病(chronicmyelogenousleukemia,CML)是以粒系增生为主要表现的恶性克隆性疾病。以往CML的常规治疗包括羟基脲、马利兰、靛玉红及甲异靛、干扰素、联合化疗及造血干细胞移植等。近年来,CML的治疗在以往的基础上有了长足的进展,其中以bcr-ab融合基因及其具有酪氨酸激酶活性的蛋白产物为靶向的酪氨酸激酶抑制剂Imatinib是近年来CML治疗最重要的进展,此外在干扰素及干细胞移植治疗方面亦有了新的认识。CML的治疗已发展为一个复杂而有序的系统。本文就近年来CML治疗方面的进展进行综述。     

Iressa治疗非小细胞肺癌的进展

分子靶向药物,如表皮生长因子受体酪氨酸激酶抑制剂,是近年来在血液和实体肿瘤治疗中涌现出的新治疗手段。现就表皮生长因子受体酪氨酸激酶抑制剂Iressa在非小细胞肺癌治疗中的进展作一综述。     

Detection of tyrosine protein kinase substrates in fresh leukemia cells and normal blood cells using an immunoblotting technique

Kinases which phosphorylate proteins on tyrosine residues are of importance in the control of both normal and malignant cell proliferation. The receptors for a number of growth factors have intracellular domains with tyrosine protein kinase activity and several viral oncogenes code for tyrosine protein kinases. An abnormal tyrosine protein kinase has been implicated in the pathogenesis of chronic granulocytic leukemia. Using an immunoblot method and an antiphosphotyrosine antibody, we have detected substrates of tyrosine protein kinases in fresh human leukemia cells and normal blood and bone marrow cells. These substrates were present in all types of cells examined. Cells from patients with acute lymphoblastic leukemia, acute myeloid leukemia, and chronic lymphocytic leukemia contain prominent phosphotyrosine-containing protein bands with molecular weights in excess of 95 kDa. By contrast, chronic granulocytic leukemia cells, as well as normal bone marrow cells, lymphocytes, and monocytes, contain predominantly low molecular weight (less than 95 kDa) tyrosine kinase substrates. When lymphocytes were stimulated to enter cell cycle, however, high molecular weight substrates of similar molecular weights to those detected in acute lymphoblastic leukemia, acute myeloid leukemia, and chronic lymphocytic leukemia became prominent. The implications of these findings in the control of normal and malignant cell proliferation and differentiation are discussed.     

Managing side effects of tyrosine kinase inhibitor therapy to optimize adherence in patients with chronic myeloid leukemia: the role of the midlevel practitioner

In the last decade, the development of imatinib, a tyrosine kinase inhibitor, has brought about unprecedented change in the way newly diagnosed, chronic-phase chronic myeloid leukemia patients are treated. Two next-generation tyrosine kinase inhibitors, nilotinib and dasatinib, were initially indicated for imatinib-resistant or imatinib-intolerant chronic myeloid leukemia patients and recently received approval from the Food and Drug Administration for treatment of newly diagnosed, chronic-phase chronic myeloid leukemia patients. In comparison with the previous standards of care, benefits with these three tyrosine kinase inhibitors have included more rapid response rates, increased survival, and fewer side effects. The improved long-term outcomes have altered the approach to management of chronic myeloid leukemia from a progressive fatal disease with a poor prognosis to a chronic condition similar to diabetes or hypertension. Prolonged survival increases the need for patient education, support, monitoring, and assistance with adverse event management. Even low-grade side effects can adversely affect patients' quality of life and, therefore, require prompt attention to prevent long-term complications or suboptimal outcomes. New evidence has indicated that patient adherence to tyrosine kinase inhibitor therapy is essential to successful treatment. Midlevel practitioners can help to optimize outcomes by educating patients regarding the importance of adherence, performing regular monitoring, helping patients to understand their test results, and aggressively managing treatment-related side effects.     

Imatinib mesylate (STI571) for myeloid malignancies other than CML

Imatinib mesylate, a small molecule tyrosine kinase inhibitor, has had a major impact on the treatment of Philadelphia chromosome positive chronic myelogenous leukemia. This review will explore its potential in the treatment of other myeloid neoplasms, based on its ability to inhibit Kit and PDGFR kinases in addition to Bcr-Abl. Imatinib's potential role in the treatment of Philadelphia chromosome negative chronic myelogenous leukemia, systemic mastocytosis with associated hematologic neoplasms, chronic myelomonocytic leukemia, specific subtypes of acute myelogenous leukemia, myelofibrosis/myeloid metaplasia, and polycythemia vera is discussed.     

Chronic myeloid leukemia: mechanisms of resistance and treatment

Imatinib mesylate has revolutionized the treatment landscape for patients with newly diagnosed chronic myeloid leukemia. Follow-up has shown excellent response rates, progression-free survival, and overall survival after 8 years. However, some patients develop resistance to imatinib treatment because of a multitude of reasons. Strategies to overcome resistance include dose escalation of imatinib or switching to a second-generation tyrosine kinase inhibitor or to one of the newer non-tyrosine kinase inhibitors. This article guides the treating physician with a rational approach in the management of patients with chronic myeloid leukemia who fail initial treatment with imatinib or lose response while on therapy with imatinib.     

Protein kinase D2 mediates activation of nuclear factor kappaB by Bcr-Abl in Bcr-Abl+ human myeloid leukemia cells

The Bcr-Abl tyrosine kinase activates various signaling pathways including nuclear factor kappaB that mediate proliferation, transformation, and apoptosis resistance in Bcr-Abl(+) myeloid leukemia cells. Here we report that protein kinase (PK) D2, a serine threonine kinase of the PKD family, is a novel substrate of Bcr-Abl. PKD2 was found to be the major isoform of the PKD family expressed in chronic myeloid leukemia cells and is tyrosine phosphorylated by Bcr-Abl in its pleckstrin homology domain. A mutant that mimicks tyrosine phosphorylation of PKD2 in the pleckstrin homology domain activates nuclear factor kappaB independently of its catalytic activity. Furthermore, our data show that Bcr-Abl-induced activation of the nuclear factor kappaB cascade in LAMA84 cells is largely mediated by tyrosine-phosphorylated PKD2. These data present a novel mechanism of Bcr-Abl-induced nuclear factor kappaB activation in myeloid leukemia. Targeting PKD2 tyrosine phosphorylation, not its kinase activity, could be a novel therapeutic approach for the treatment of Bcr-Abl(+) myeloid leukemia.     

Implications of BCR-ABL1 kinase domain-mediated resistance in chronic myeloid leukemia

Patients with chronic myeloid leukemia develop resistance to both first-generation and second-generation tyrosine kinase inhibitors (TKIs) as a result of mutations in the kinase domain (KD) of BCR-ABL1. A wide range of BCR-ABL1 KD mutations that confer resistance to TKIs have been identified, and the T315I mutant has proven particularly difficult to target. This review summarizes the prevalence, impact, and prognostic implications of BCR-ABL1 KD mutations in patients with chronic myeloid leukemia who are treated with current TKIs and provides an overview of recent treatment guidelines and future trends for the detection of mutations.     

Genetic Mechanisms of Chronic Myeloid Leukemia Blastic Transformation

The BCR-ABL1 oncogenic tyrosine kinase can transform pluripotent hematopoietic stem cells and initiate chronic myeloid leukemia in chronic phase (CML-CP), a myeloproliferative disorder characterized by excessive accumulation of mature myeloid cells. Patients in CML-CP usually respond to treatment with ABL1 tyrosine kinase inhibitors (TKIs) such as imatinib, though some patients who respond initially may become resistant later. CML-CP leukemia stem cells (LSCs) are intrinsically insensitive to TKIs and thus survive in the long term. These LSCs or their progeny may at some stage acquire additional genetic changes that cause the leukemia to transform further, from CML-CP to a more advanced phase, which has been subclassified as either accelerated phase (CML-AP) or blastic phase (CML-BP). CML-BP is characterized by a major clonal expansion of immature progenitors, which have either myeloid or lymphoid features. CML-BP responds poorly to treatment and is usually fatal. This review discusses the role of genomic instability leading to blastic transformation of CML and proposes some novel therapeutic approaches.     

Current perspectives on the treatment of patients with chronic myeloid leukemia: an individualized approach to treatment

PURPOSE: The BCR-ABL tyrosine kinase inhibitor imatinib has dramatically improved the prognosis for most patients with chronic myeloid leukemia (CML). Efforts to optimize therapy in CML have resulted in new and revised treatment guidelines or algorithms, which are reviewed here. METHODS: Data were identified by searches of MEDLINE, PubMed, and references from relevant articles using the terms "chronic myeloid leukemia," "imatinib," and "tyrosine kinase inhibitors." Articles published in English between 1996 and 2006 were included. RESULTS: In this article we review consensus criteria for a therapeutic response and current expectations for CML therapy with imatinib, as well as the evidence supporting these recommendations. In addition, novel approaches to CML treatment are considered in light of the availability of second-generation tyrosine kinase inhibitors. CONCLUSION: With the advent of novel agents capable of treating imatinib-resistant or imatinib-intolerant CML, it should be possible in the future to further refine treatment algorithms.     

The role of allogeneic stem cell transplantation for CML in the tyrosine kinase inhibitor era

Allogeneic stem cell transplantation is an accepted standard therapy for chronic myeloid leukemia (CML). In recent years, however, the use of transplantation has diminished, largely because of the introduction of the novel tyrosine kinase inhibitor, imatinib mesylate. Despite the introduction of imatinib and the other new tyrosine kinase inhibitors, a rational role for transplantation remains. This review focuses on the indications for transplantation in the tyrosine kinase inhibitor era.     

The role of allogeneic stem cell transplantation for CML in the tyrosine kinase inhibitor era

Allogeneic stem cell transplantation is an accepted standard therapy for chronic myeloid leukemia (CML). In recent years, however, the use of transplantation has diminished, largely because of the introduction of the novel tyrosine kinase inhibitor, imatinib mesylate. Despite the introduction of imatinib and the other new tyrosine kinase inhibitors, a rational role for transplantation remains. This review focuses on the indications for transplantation in the tyrosine kinase inhibitor era.