STI571治疗慢性粒细胞白血病相关策略

慢性髓细胞白血病 (CML)是一类造血干细胞克隆增殖紊乱性疾病 ,预后较差 ,蛋白酪氨酸激酶抑制剂STI5 71的出现使其治疗出现转机 ,其能阻断Bcr Abl蛋白激酶的活性 ,选择性抑制白血病细胞增殖。但随着临床应用的深入 ,常出现对STI5 71耐药及治疗后复发病例。因此针对耐药和复发的机制及相关治疗策略的研究也在不断深入 ,现综述STI5 71治疗策略的研究进展。     

ST1571治疗慢性粒细胞白血病相关策略

慢性髓细胞白血病(CML)是一类造血干细胞克隆增殖紊乱性疾病，预后较差，蛋白酪氨酸激酶抑制剂ST1571的出现使其治疗出现转机，其能阻断Bcr-Abl蛋白激酶的活性，选择性抑制白血病细胞增殖。但随着临床应用的深入，常出现对ST1571耐药及治疗后复发病例。因此针对耐药和复发的机制及相关治疗策略的研究也在不断深入，现综述ST1571治疗策略的研究进展。     

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.     

慢性粒细胞白血病的发病机制及治疗现状

慢性粒细胞白血病(CML)是一种发生在骨髓多功能造血干细胞上的恶性增殖性疾病.目前,伊马替尼用于CML的一线治疗,不但对慢性期的患者疗效显著,而且对于加速期和急变期患者也同样能够明显延长其生存时间.随着伊马替尼在临床上的长期应用,逐渐出现了耐药及不耐受现象,因此降低了CML的长期治疗效果.文章就CML的发病机制及治疗现状进行综述.     

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。     

慢性粒细胞白血病靶向治疗研究进展

酪氨酸激酶抑制剂（TKI）的应用革命性地改善了慢性粒细胞白血病（CML）患者的治疗结果和生存。当前治疗CML的新目标是如何获得持续的深度分子生物学反应,以减少耐药复发,甚至实现无治疗的缓解维持和治愈。国际上已有4种TKI获批用于一线治疗初诊的慢性期CML,并且不断有新的药物和治疗方案在研发和临床研究中。文章结合第62届美国血液学会年会相关报道介绍CML靶向治疗研究进展。     

慢性粒细胞白血病治疗进展

第1代酪氨酸激酶抑制剂(TKI)为慢性粒细胞白血病的治疗带来了里程碑式的进步。当前,血液学专家除了关心患者能否获得标准的治疗反应外,更关心如何能快速地降低BCR-ABL转录本水平,因此第2代TKI应运而生。无论第1代还是第2代TKI都有出现耐药的可能,第3代或第4代则着力解决此问题。伊马替尼停药试验强调了数字化聚合酶链反应(PCR)的重要性以及第2次无治疗缓解的可能。     

慢性粒细胞白血病患者血液肿瘤相关基因突变研究进展

慢性粒细胞白血病（CML）是以Ph染色体异位为特征的骨髓增殖性疾病,酪氨酸激酶抑制剂（TKI）的应用显著改善了CML患者的预后。细胞遗传学和分子学监测用于评估TKI疗效并指导疾病管理已成为CML治疗的重要组成部分。然而,在疾病诊断、转化和耐药性方面扩大基因组分析是CML研究中尚未完全探索的领域。文章旨在探讨CML最初诊断和治疗失败转化时的基因突变频率和类别,分析诊治中基因突变与CML患者预后的关系。     

STI571治疗慢性髓系白血病的临床疗效与毒副作用观察

背景与目的:bcr-abl融合基因翻译的蛋白产物P210bcr-abl的酪氨酸激酶(proteintyrosinekinase,PTK)活性异常增高被认为是导致慢性髓系白血病(chronicmyeloidleukmeia,CML)发病的根本原因。STI571能高效特异性抑制P210bcr-abl的PTK活性,在临床应用中获得了显著的疗效,但对急变期患者的治疗效果维持时间短。本研究观察和比较了STI571治疗慢性期与加速/急变期CML患者的临床疗效和所发生的不良反应,并从细胞遗传学的角度对急变期患者STI571耐药机制进行初步的分析。方法:选择接受STI571治疗的CML患者22例,其中慢性期6例,加速/急变期16例。按照血液学缓解和细胞遗传学缓解的标准,结合骨髓细胞形态学分析、骨髓细胞G显带技术分析和间期荧光原位杂交检测结果,对患者STI571治疗前和治疗3个月后的血液学和细胞遗传学缓解情况进行分析,并对3个月内出现耐药复发的患者进行核型演化分析。同时密切观察各系统发生的不良反应及严重程度。结果:6例(100%)慢性期CML患者获血液学完全缓解和细胞遗传学缓解,4例(25%)加速/急变期CML患者获血液学完全缓解,8例(50%)获不同程度的细胞遗传学反应。获血液学完全缓解和细胞遗传学反应的百分率两组比较均有统计学差异(P<0.05)。3例急变期CML患者出现耐药复发,其中2例可见2Ph和其它新     

STI571 as a targeted therapy for CML

Chronic myelogenous leukemia (CML) is a clonal hematopoietic stem cell disorder that progresses through distinct phases as the malignant clone progressively loses the capacity for terminal differentiation. It is characterized by the (9;22) translocation and resultant production of the Bcr-Abl tyrosine kinase. Bcr-Abl functions as a constitutively activated tyrosine kinase, and this kinase activity is absolutely required for the transforming function of the Bcr-Abl protein. In preclinical studies, STI571 (Gleevec, imatinib mesylate), a Bcr-Abl tyrosine kinase inhibitor, specifically inhibited the proliferation of Bcr-Abl-expressing cells in vitro and in vivo. STI571 has shown remarkable results in all phases of CML. Although responses are seen in all phases of the disease, durable responses are most common in earlier stage patients. Thus, STI571 has emerged as a paradigm for gene product targeted therapy, offering expanded treatment options for patients with CML.     

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.     

Trial of IFN or STI571 before proceeding to allografting for CML?

Ten-year survival of IFN-treated low risk CML patients is about 40%, and more in cytogenetic responders. Allografting has a cure rate of up to 75%, but is associated with considerable procedure related morbidity and mortality. One out of three or four is likely not to survive. A comparative quantification of survival after BMT and IFN treatment suggests that a trial of IFN (and possibly STI 571) before proceeding to allografting is a viable, and in low risk patients a probably preferable option.     

STI571: A gene product-targeted therapy for leukemia

Chronic myelogenous leukemia (CML) is a clonal hematopoietic stem-cell disorder characterized by the (9:22) translocation and resultant production of the constitutively activated bcr-abl tyrosine kinase. Characterized clinically by marked myeloid proliferation, it invariably terminates in an acute leukemia. Conventional therapeutic options include interferon-based regimens and stem-cell transplantation, with stem-cell transplantation being the only curative therapy. Through rational drug development, STI571, a bcr-abl tyrosine kinase inhibitor, has emerged as a paradigm for gene product-targeted therapy, offering new hope for expanded treatment options for patients with CML.     

The c-kit tyrosine kinase inhibitor STI571 for colorectal cancer therapy

The c-kit tyrosine kinase inhibitor STI571 exhibits a substantial therapeutic activity in patients with chronic myeloid leukemia and gastrointestinal stromal tumors respectively associated with constitutive activation of the BCR-ABL and c-kit tyrosine kinases. Human colorectal tumors also express the c-kit proto-oncogene. The present study focuses on the anticancer activity of STI571 in human colorectal tumor cells in vitro and in vivo. The c-kit receptor was identified as a M(r) 145,000 immunoreactive band in human colon cancer cells HT29, HCT8/S11, and HCT116. Cellular invasion induced by 10 ng/ml stem cell factor (EC(50) = 3 ng/ml) in HT29 cells was blocked by 1 micro M STI571 (IC(50) = 56 nM) and pharmacological inhibitors of several oncogenic signaling pathways, namely, phosphatidylinositol 3-kinase (LY294002), Rho GTPases (Clostridium botulinum exoenzyme C3 transferase), and Rho-kinase (Y27632). STI571 inhibited HT29 cell proliferation (IC(50) = 6 micro M) and induced apoptosis in vitro. These cellular effects were associated with a decrease in tumor growth. We also demonstrated that stem cell factor is a proangiogenic factor in vivo and in vitro. These encouraging results warrant further preclinical investigations and clinical trials on the use of the c-kit inhibitor STI571 as a chemotherapeutic agent in colon cancer prevention and in treatment of advanced colorectal cancers associated with liver metastases.     

Clinical and prognostic significance of histamine monitoring in patients with CML during treatment with imatinib (STI571).

BACKGROUND: Although imatinib is highly effective in chronic myeloid leukemia (CML), drug-resistance may occur. Therefore, monitoring of minimal residual disease (MRD) during treatment with imatinib is important. However, most MRD-parameters are expensive and require special technology. We determined the value of histamine as MRD-marker in CML. PATIENTS AND METHODS: Histamine levels were measured serially in whole blood samples before and during imatinib therapy in 80 CML patients by radioimmunoassay. RESULTS: Histamine levels were highly upregulated in CML at diagnosis compared to healthy controls, and correlated with the presence of basophils. During treatment with imatinib, histamine levels decreased and returned to normal levels in those achieving a complete cytogenetic response (CCR). Loss of CCR during therapy was invariably accompanied by an increase in histamine. Moreover, a histamine level of >100 ng/ml three or six months after start of imatinib was associated with a significantly reduced probability of survival (p<0.05). Whereas basophils were found to correlate well with histamine during imatinib, no correlations were found between histamine and Ph+ metaphases or histamine and BCR/ABL. CONCLUSION: Histamine-monitoring during treatment with imatinib is of prognostic significance.     

Resistance to daunorubicin-induced apoptosis is not completely reversed in CML blast cells by STI571.

The leukemogenic property of BCR-ABL in chronic myeloid leukemia (CML) is critically dependent on its protein tyrosine kinase activity. STI571 inhibits the BCR-ABL kinase activity, the growth and the viability of BCR-ABL expressing cells. In this study, we report the apoptotic effect of STI571 in combination with daunorubicin (DNR) on peripheral blood mononuclear cells from 11 CML patients and four BCR-ABL-positive cell lines: AR230, LAMA84, K562 and KCL22. Primary blast cells were identified by flow cytometry on the basis of their low CD45 expression. Nucleus fragmentation, exposure of phosphatidylserines and decrease in mitochondrial membrane potential were measured using acridine orange, FITC-annexin V and DiOC6(3), respectively, to evaluate apoptosis. On cell lines, the effect of DNR was negligible, whereas STI571 induced 10 to 35% of apoptosis in 18 h. STI571 sensitized AR230, LAMA84 and K562 cells to DNR when apoptosis was measured at the mitochondrial and membrane but not the nuclear levels. On CML blast cells, phosphatidyl serine exposure was significantly induced by both DNR and STI571 and was higher when these drugs were used in combination (P < 0.0003). However, the effects of this drug combination were only additive and no sensitization of blast cells to DNR by STI571 was observed. Interestingly, sensitization was evidenced in CML but not normal lymphocytes. These results suggest that other mechanisms additional to Bcr-Abl tyrosine kinase activity could be responsible for DNR resistance, and further investigations are needed to understand its origin.