A validated UPLC–MS/MS method for simultaneous determination of imatinib, dasatinib and nilotinib in human plasma

A sensitive, rapid, simple and economical ultra-performance liquid chromatography-tandem mass spectrometric method （UPLC-MS/MS） was developed and validated for simultaneous determination of imatinib, dasatinib and nilotinib in human plasma using gliquidone as internal standard （IS）. Liquid-liquid extraction method with ethyl acetate was used for sample pre-treatment. The separation was performed on an Xtimate Phenyl column using isocratic mobile phase consisting of A （aqueous phase： 0.15% formic acid and 0.05% ammonium acetate） and B （organic phase： aeetonitrile） （A：B=40：60, v/v）. The flow rate was 0.25 mL/min and the total run time was 6 min. The multiple reaction monitoring （MRM） transitions, m/z 494.5-394.5 for imatinib, 488.7-401.5 for dasatinib, 530.7-289.5 for nilotinib and 528.5-403.4 for IS, were chosen to achieve high selectivity in the simultaneous analyses. The method exhibited great improvement in sensitivity and good linearity over the concentration range of 2.6-5250.0 ng/mL for imatinib, 2.0-490.0 ng/mL for dasatinib, and 2.4-4700.0 ng/mL for nilotinib. The method showed acceptable results on sensitivity, specificity, recovery, precision, accuracy and stability tests. This UPLC-MS/MS assay was successfully used for human plasma samples analysis and no significant differences were found in imatinib steady-state trough concentrations among the SLC22A5 -1889T 〉 C or SLCOIB3 699G 〉 A genotypes （P 〉 0.05）. This validated method can provide support for clinical therapeutic drug monitoring and pharmacokinetic investigations of these three tyrosine kinase inhibitors （TKIs）.

Efficacy of Nilotinib versus Imatinib in Philadelphia Positive Patients with Chronic Myeloid Leukemia in Early Chronic Phase Who Have a Warning Molecular Response to Imatinib

Background and Objectives: Chronic myeloid leukemia (CML) accounts for approximately 15% of newly diagnosed cases of leukemia in adults. In this study, the efficacy of nilotinib at 400 mg BID is compared with imatinib at 400 mg BID in CML patients with suboptimal molecular response after at least 12 months of daily dose 400 mg of imatinib therapy. Patients and Methods: This study included a total number of 50 patients, divided into two groups (25 patients each). The first group (Group I): Patients received imatinib at 400 mg BID, second group (Group II): Patients had a suboptimal molecular response to imatinib and received nilotinib at 400 mg BID in early chronic phase. During the two years period of data collection, the primary end included median survival. The secondary end included response rate, type of response, duration of response and progression free survival. Also side effects were recorded. Patients were followed up every month by complete and differential blood counts, liver function test, renal function test and (PCR) every three months for two year. Results: Nilotinib group had significantly higher frequency of major molecular response (MMR) where 23 (92%) patients achieved it while only 16 (64%) patients in Imatinib group achieved MMR (P = 0.01). Nilotinib had better toxicities profile than Imatinib. Conclusion: Both Nilotinib and high dose Imatinib achieved response in CML patients with suboptimal response with rapid and deeper molecular response, better survival outcomes and less side effects in nilotinib.

Is dose modification or discontinuation of nilotinib necessary in nilotinib-induced hyperbilirubinemia?

Nilotinib is a specific breakpoint cluster region-Abelson leukemia virus-tyrosine kinase inhibitor that is used as an effective first-or second-line treatment in imatinib-resistant chronic myelogenous leukemia(CML)patients.Hepatotoxicity due to nilotinib is a commonly reported side effect;however,abnormal liver function test(LFT)results have been reported in asymptomatic cases.When alanine aminotransferase(ALT)and aspartate aminotransferase(AST)levels are more than five-fold the upper limit of the normal(ULN)or when the serum total bilirubin level is more than three-fold the ULN,dose modification or discontinuation of nilotinib is recommended,resulting in decreased levels of hematological indicators in certain patients with CML.Nilotinib-induced hyperbilirubinemia typically manifests as indirect bilirubinemia without elevated ALT or AST levels.Such abnormal liver functioning is thus not attributed to the presence of a true histologic lesion of the liver.The underlying mechanism may be related to the inhibition of uridine diphosphate glucuronosyltransferase activity.Therefore,nilotinib dose adjustment is not recommended for this type of hyperbilirubinemia,and in the absence of elevated liver enzyme levels or presence of abnormal LFT findings,physicians should consider maintaining nilotinib dose intensity without modifications.

Clinical Effect of Imatinib,Nilotinib,and Dasatinib on Chronic Myeloid Leukemia in Chronic Phase

The study was conducted to explore the effect of imatinib,nilotinib,and dasatinib in the treatment of chronic myeloid leukemia(CML)patients.Around 66 patients with CML in chronic phase were selected,subsequently the patients were subdivided into 3 groups with 22 patients in each group:Group A were treated with imatinib;Group B were treated with nilotinib;and Group C were treated with dasatinib.The study showed that,at 18 months of treatment,compared with group A,the molecular biology remission rates of group B and group C were significantly higher,p<0.05;at 6 months and 18 months of treatment,compared with group A,the complete cytogenetic remission rates of group B and group C were significantly higher,p<0.05;and compared with group A,the incidences of vomiting,headache and edema in groups B and C were significantly lower,p<0.05.However,no significant different p>0.05 were observed in the complete hematologic remission rates,and the incidences of neutropenia and thrombocytopenia among the three groups.In summary,nilotinib and dasatinib are effective in the treatment of patients with CML in the chronic phase,which is significantly better than imatinib treatment.

Remodeling of the liver fibrosis microenvironment based on nilotinib-loaded multicatalytic nanozymes with boosted antifibrogenic activity

Liver fibrosis is a reversible pathological process caused by chronic liver damage and a major risk factor for hepatocellular carcinoma(HCC).Hepatic stellate cell(HSC)activation is considered the main target for liver fibrosis therapy.However,the efficiency of this strategy is limited due to the complex microenvironment of liver fibrosis,including excessive extracellular matrix(ECM)deposition and hypoxia-induced imbalanced ECM metabolism.Herein,nilotinib(NIL)-loaded hyaluronic acid(HA)-coated Ag@Pt nanotriangular nanozymes(APNH NTs)were developed to inhibit HSCs activation and remodel the microenvironment of liver fibrosis.APNH NTs efficiently eliminated intrahepatic reactive oxygen species(ROS)due to their inherent superoxide dismutase(SOD)and catalase(CAT)activities,thereby downregulating the expression of NADPH oxidase-4(NOX-4)and inhibiting HSCs activation.Simultaneously,the oxygen produced by the APNH NTs further alleviated the hypoxic microenvironment.Importantly,the released NIL promoted collagen depletion by suppressing the expression of tissue inhibitor of metalloproteinase-1(TIMP-1),thus synergistically remodeling the microenvironment of liver fibrosis.Notably,an in vivo study in CCl_(4)-induced mice revealed that APNH NTs exhibited significant antifibrogenic effects without obvious long-term toxicity.Taken together,the data from this work suggest that treatment with the synthesized APNH NTs provides an enlightening strategy for remodeling the microenvironment of liver fibrosis with boosted antifibrogenic activity.

尼洛替尼与达沙替尼二线治疗慢性髓性白血病的成本效用分析

目的评估费城染色体阳性慢性髓性白血病慢性期(Ph+CML-CP)患者中对伊马替尼耐药或不耐受的二线尼洛替尼与达沙替尼的成本效果。方法建立状态转移马尔可夫(Markov)模型进行成本效用分析,模型包括4种健康状态:慢性期(CP),加速期(AP),急变期(BP)和死亡。尼洛替尼与达沙替尼治疗的无进展生存率,疾病进展发生率,总生存率等有关临床参数来源于既往发表的研究和专家意见,健康状态效用值来源于文献。通过Treeage软件以增量成本效果比(ICER)作为评价指标,对尼洛替尼和达沙替尼2个方案的总产出和总成本进行评价,并通过单变量、概率敏感性分析评估模型稳定性。结果与选用达沙替尼治疗相比,选用尼洛替尼治疗的ICER为182487.71元·QALY^(-1),低于3倍2021年全国人均GDP。敏感性分析显示主要的影响参数有贴现率,达沙替尼价格和尼洛替尼价格,模型结果稳定。结论选用尼洛替尼相对达沙替尼用于对伊马替尼耐药或不耐受的Ph+CML-CP患者治疗具有成本效用优势。

Superiority of allogeneic hematopoietic stem cell transplantation to nilotinib and dasatinib for adult patients with chronic myelogenous leukemia in the accelerated phase

In the tyrosine kinase inhibitor （TKI） era, imatinib is the first-line therapy for patients with chronic myeloid leukemia （CML） in chronic or accelerated phase. Although second-generation TKIs （TKI2）, including dasatinib and nilotinib, are appropriate treatment regimens for patients with disease that progressed to accelerated phase following imatinib therapy, allogeneic hematopoietic stem cell transplantation （allo-HSCT） is the only curative therapy. This study retrospectively analyzed the efficacy of TKI2 and HSCT for treatment of CML in accelerated phase. Ninety-three patients with CML registered in the Chinese CML alliance database from February 2001 to February 2014 were enrolled and divided into the TKI2 （n = 33） and allo-HSCT （n = 60） groups. In the TKI2 group, 26 and 7 patients received nilotinib and dasatinib, respectively, as initial TKI2 and 11 patients transferred to the alternative TKI2 after failure to one TKI2. In the allo-HSCT group, 22 （36.7%）, 35 （58.3%）, and 3 （10%） patients underwent aHo-HSCT from an HLA-matched sibling donor, HLA mismatched/haploidentical donor, and unrelated donor, respectively. All patients in the HSCT group were engrafted. Overall, 69.7%, 48.5%, and 45.5% of patients presented hematological, cytogenetic, and major molecular responses, respectively, to at least one of TKI2. All 60 patients （100%） achieved CHR and cytogenetic response in the HSCT group. Patients in the TKI2 group exhibited lower 5-year overall survival rate （42.9% vs. 86.4%, P = 0.002）, 5-year event-free survival rate （14.3% vs. 76.1%, P 〈 0.001）, and 5-year progression-free survival （28.6% vs. 78.1%, P 〈 0.001） than those in the alIo-HSCT group. Multivariate analysis showed that male sex and TKI2 therapy were predictors of poor overall survival, whereas hemoglobin 〈 100 g/L and TKI2 therapy were predictors of poor event-free survival and progression-free survival. These results indicated that allo-HSCT may be superior to nilotinib and dasatinib for adult patients with CML in accelerated phase.

基于FAERS数据库对尼洛替尼ADE信号的挖掘与分析

目的 为临床安全使用尼洛替尼提供参考。方法 从美国FDA不良事件报告系统(FAERS)数据库提取2007年第1季度至2022年第4季度尼洛替尼的药品不良事件(ADE)报告,使用比例失衡测量法中的报告比值比(ROR)法和比例报告比值比(PRR)法挖掘潜在的ADE信号,同时与药品说明书和相关个案文献进行比对,并结合欧洲药品管理局制定的指定医疗事件(DME)清单来筛选和分析。结果 获得以尼洛替尼为首要怀疑药物的ADE报告23 332份,检出阳性信号359个,共涉及24个系统器官分类(SOC),主要为各类检查、心脏器官疾病、血管与淋巴管类疾病、各类神经系统疾病等;椎动脉狭窄、冠状动脉狭窄、动脉性疾病、肝脏感染及第二种原发恶性肿瘤等ADE未在其药品说明书中提及。检出了7个DME,其中骨髓功能衰竭、肺动脉高压及耳聋未在其药品说明书中提及。结论 所挖掘出的常见ADE信号与尼洛替尼的药品说明书一致;临床使用中应特别关注骨髓功能衰竭、肺动脉高压及耳聋等其药品说明书中未提及的DME,并密切监测患者心脏功能和血糖、血脂指标,以降低用药风险。

达沙替尼、尼洛替尼及伊马替尼治疗新诊断慢性髓系白血病慢性期3年临床观察

目的:评估第二代酪氨酸激酶抑制剂(TKI)达沙替尼、尼洛替尼与伊马替尼的疗效差异,探讨最佳临床选择。方法:对近3年在我院接受治疗的163例新诊断慢性髓系白血病(CML)慢性期患者(47例接受达沙替尼,43例接受尼洛替尼,73例接受伊马替尼治疗)的临床资料及随访结果进行分析,评价各时间节点治疗反应及疗效,评估不良事件。结果:达沙替尼组、尼洛替尼组、伊马替尼组治疗3个月完全血液学缓解(CHR)率分别为77%、79%和67%,12个月分别为92%、91%和90%。3组治疗3个月完全细胞遗传学缓解(CCyR)率分别为55%、53%和33%,而12个月分别为86%、88%和69%。3个月主要分子生物学缓解(MMR)率分别为11%、9%和1%,而12个月分别为49%、50%和28%。达沙替尼组2例(4%),尼洛替尼组2例(5%)出现疾病进展,而伊马替尼组6例(8%)出现疾病进展。达沙替尼、尼洛替尼及伊马替尼药物安全性未表现出显著差异。结论:第二代TKI达沙替尼及尼洛替尼可带来更快更深的缓解,从而获得更好的远期预后。

伊马替尼耐药慢性粒细胞白血病的药物治疗

伊马替尼(imatinib)是一种酪氨酸激酶抑制剂。通过占据BCR-ABL融合蛋白的ATP结合位点抑制BCR-ABL蛋白的自身磷酸化和底物磷酸化,使BCR-ABL阳性细胞的增生受抑制或者凋亡。伊马替尼是治疗CML的临床一线用药,随着其耐药的出现,不断研发的新药是CML患者新的希望。

尼洛替尼治疗伊马替尼耐药或不耐受慢性髓系白血病患者的临床研究

本研究目的旨在评价尼洛替尼治疗伊马替尼耐药或不耐受的慢性髓系白血病(CML)患者的疗效及安全性。23例伊马替尼耐药或不耐受的CML患者纳入本研究。患者每日口服尼洛替尼600-800 mg,对他们的疗效、总体生存和耐受情况进行评估。结果表明,23例接受尼洛替尼治疗的患者中,全部获得完全血液学缓解(CHR),19例(82.6%)获得完全细胞遗传学缓解(CCyR),13例(56.5%)获得完全分子学缓解(CM R),中位尼洛替尼治疗时间13.5(1-44)个月,中位随访时间40(12-102)个月。尼洛替尼治疗后的不良反应大半为轻微的,而且可以逆转。结论:尼洛替尼治疗伊马替尼耐药的CML患者疗效佳,患者耐受性好。

尼洛替尼治疗伊马替尼耐药或不耐受的慢性粒细胞白血病的长期随访研究

目的评价对伊马替尼耐药或不耐受的慢性粒细胞白血病(CML)患者接受尼洛替尼治疗的远期疗效和安全性。方法 26例对伊马替尼耐药或不耐受CML患者接受尼洛替尼400～800 mg/d治疗,随访观察近5年,定期监测血液学、细胞遗传学及分子生物学指标,记录用药后患者临床表现及各项生化指标,评价其疗效、不良反应。结果 26例对伊马替尼耐药或不耐受的CML患者,尼洛替尼中位治疗时间17个月,中位随访时间51个月。累计获得完全血液学缓解(CHR)16例(61.5%),获得主要细胞遗传学缓解(MCyR)13例(50.0%),获得完全细胞遗传学缓解(CCyR)9例(34.6%),获得主要分子生物学缓解(MMR)7例(26.9%)。尼洛替尼治疗相关的非血液学不良反应多为l～2级,主要为胆红素升高(69.2%)和皮疹(57.7%)。3～4级血液学不良反应包括血小板减少(53.8%)、中性粒细胞减少和贫血(分别为26.9%和19.2%)。相比进展期患者,尼洛替尼对慢性期和缓解期的患者疗效更佳、血液学副作用更少。结论尼洛替尼为对伊马替尼耐药和不耐受的CML患者提供了一个有效并安全的治疗选择,尤其对非进展期CML患者更为安全和有效。

尼洛替尼与伊马替尼治疗慢性粒细胞白血病早期临床疗效比较

目的比较尼洛替尼与伊马替尼治疗慢性粒细胞白血病(CML)的早期(3个月时)疗效以及安全性。方法选取2007年1月至2017年12月安徽省立医院确诊CML的患者129例,采用随机数字表法按照1∶7分为尼洛替尼组(18例)和伊马替尼组(111例)。两组患者服药3个月后门诊复查骨髓形态学、BCR-ABL融合基因国际标准值(BCR-ABLIS),比较两组患者的BCR-ABLIS结果,评价两组患者的疗效(主要指标为BCR-ABLIS≤10%的达标率、BCR-ABLIS≤0.0032%的比例)以及药物的安全性(白细胞减少、血小板减少、贫血等血液学毒性;Q-T间期延长,以及肝功能损害、骨骼肌肉疼痛、水肿、皮疹、消化道症状等不良反应发生情况)。结果尼洛替尼组患者治疗3个月时达到BCR-ABLIS≤10%、BCR-ABLIS≤0.0032%的比例均高于伊马替尼组(94.44%vs 69.37%;55.55%vs 27.92%),差异均有统计学意义(P<0.05);两组患者药物安全性比较,差异无统计学意义(P>0.05)。结论尼洛替尼治疗CML的早期分子学反应达标率以及患者分子学反应的深度均高于伊马替尼组,两种药物不良反应发生情况无显著差异。

BCR-ABL蛋白激酶抑制剂的研究进展

伊马替尼是首个上市的BCR-ABL蛋白激酶抑制剂,在靶向治疗慢性粒细胞白血病上取得了很大成功。随着临床应用的增加,部分患者产生了耐药性。伊马替尼耐药性的产生与BCR-ABL激酶的突变有关,第二代激酶抑制剂达沙替尼和尼罗替尼能克服大部分突变产生的耐药性,但不能有效克服T315I突变。AP245234、达努塞替等针对T315I突变的BCR-ABL蛋白激酶抑制剂相继出现,展现出较好的临床应用前景。

早期应用尼洛替尼治疗慢性髓性白血病的疗效观察

目的观察早期应用尼洛替尼治疗慢性髓性白血病(CML)的疗效及不良反应。方法观察我院2013年11月至2015年8月收治的10例CML患者,使用高杉尖三酯碱和/或羟基脲将白细胞降至20×10~9/L以下后口服尼洛替尼治疗。其中慢性期8例,每日口服尼洛替尼600 mg;加速期2例,每日口服尼洛替尼800 mg。监测患者治疗前后的血液学、细胞遗传学、分子生物学、血液生化学等指标,评价其疗效及不良反应。结果所有患者治疗满3个月时均达到CHR。8例慢性期患者中,7例达到CCyR,1例达到PCyR。2例BCR-ABLIS转录水平<1%,6例>1%而<10%。2例加速期的患者中,1例达到CCyR,1例无细胞遗传学缓解。2例BCR-ABLIS转录水平>1%而<10%。在治疗满6个月的9例患者中,7例慢性期患者均达到CCyR。3例达到MMR,3例BCRABLIS转录水平>0.1%而<1%,1例BCR-ABLIS转录水平>1%而<10%。2例加速期患者中,1例维持CCyR,另外1例细胞遗传学依旧未发生缓解。2例分子生物学均达到MMR。1例慢性期患者在治疗第8个月时发生急髓变。在治疗满12个月的6例患者中,4例慢性期患者均为CCyR。3例为MMR,1例BCR-ABLIS转录水平<1%。2例加速期患者中,1例为CCyR,1例细胞遗传学依旧未发生缓解。2例均为MMR。10例患者均未发生严重的不良反应。常见的不良反应为1~2级的血红蛋白减少、皮疹、关节及肌肉酸痛等。结论早期应用尼洛替尼治疗慢性髓性白血病安全有效。

尼洛替尼的合成研究

3-乙酰基吡啶与N,N-二甲基甲酰胺二甲缩醛反应制得(E)-3-二甲胺基-1-(3-吡啶基)-2-丙烯-1-酮,接下来与硝酸胍环合得4-(3-吡啶基)-2-胺基嘧啶,然后与3-溴-4-甲基苯甲酸乙酯缩合再经水解反应制得关键中间体4-甲基-3-[[4-(3-吡啶基)-2-嘧啶基]胺基]苯甲酸。此关键中间体直接与3-三氟甲基-5-(4-甲基-1H-1-咪唑基)苯胺进行酰胺化反应,最终制得高选择性酪氨酸激酶抑制剂尼洛替尼,总收率约39.4%。

尼罗替尼的合成

5-溴-3-三氟甲基苯胺和4-甲基-1H-咪唑在碳酸铯和碘化亚铜作用下缩合,得到3-三氟甲基-5-(4-甲基-1H-咪唑-1-基)苯胺(4)。另用3-氨基-4-甲基苯甲酸乙酯(5)与氨腈成胍6,6与3-二甲胺基-1-(3-吡啶基)-2-丙烯-1-酮环合得4-甲基-3-[[4-(3-吡啶基)-2-嘧啶基]氨基]苯甲酸乙酯(8),8经叔丁氧羰基保护、水解,再与4经酰胺化、脱保护后得到尼罗替尼,总收率40%(以5计)。

尼洛替尼和伊马替尼一线治疗慢性髓性白血病的疗效及安全性观察

目的 ：比较尼洛替尼和伊马替尼一线治疗初诊慢性髓性白血病（chronic myeloid leukemia,CML）慢性期（chronic phase,CP）患者的疗效和安全性。方法：65例新诊断的CML-CP患者,接受口服尼洛替尼300~400 mg,每日2次（尼洛替尼组）或口服伊马替尼400 mg,每日1次（伊马替尼组）治疗,比较两组患者的疗效及安全性。结果：65例初发CML-CP患者,确诊CML的中位时间均为19.5（5~39）个月。尼洛替尼组26例,伊马替尼组39例,治疗后3、6、12个月时尼洛替尼组主要分子学反应（major mdecular response,MMR）获得率高于伊马替尼组,分别为23.1%vs.7.6%、45.5%vs.21.2%、66.7%vs.54.8%,且在6个月时有显著差异。Sokal积分低、中和高危组患者12个月MMR的获得率在尼洛替尼组和伊马替尼组分别为81.3%vs.42.8%、42.8%vs.57.1%、66.7%vs.50.0%。3个月获得Bcr-Abl≤10%的发生率在尼洛替尼组为80.8%,显著高于伊马替尼组的41.0%;6个月达Bcr-Abl〈1%的比例在尼洛替尼组为77.3%,高于伊马替尼组的48.5%,均有显著差异。12个月Bcr-Abl〈0.1%的比例在尼洛替尼组为66.7%,高于伊马替尼组的54.8%,尼洛替尼组达MMR的中位时间短于伊马替尼组（14 vs.34个月）。尼洛替尼组和伊马替尼组3、6和12个月获得细胞遗传学缓解（complete cytogenetic rewsponse,CCy R）的比例分别为76.9%vs.52.9%、89.5%vs.70.0%、78.5%vs.77.3%,达CCy R的中位时间分别为3个月和6个月。尼洛替尼和伊马替尼组治疗相关的不良反应多为1~2级,患者大多可耐受。结论：尼洛替尼治疗初诊CML-CP较伊马替尼更早达到分子学缓解,安全有效,有可能作为一线用药。

伊马替尼耐药或不耐受的CML患者更换二代TKI治疗的疗效观察及相关因素分析

目的观察伊马替尼耐药或不耐受的慢性髓性白血病(CML)患者更换二代酪氨酸激酶抑制剂(TKI)后的疗效,分析相关因素对疗效的影响。方法随机选取伊马替尼耐药或不耐受而转用二代TKI(达沙替尼和尼洛替尼)的患者各25例,监测患者3个月或6个月时BCR/ABL融合基因定量结果,分析患者在6个月达到BCR/ABL≤10%这一"最佳"疗效与换药原因、换药时分期、换药时血液学缓解状态、换药后依从性之间的关系。结果因耐药或不耐受而换用二代TKI的患者6个月达到BCR/ABL≤10%分别有16例(41.0%)和9例(81.8%);转用二代TKI时处于慢性期和进展期的患者6个月达到BCR/ABL≤10%分别有23例(76.7%)和2例(10.0%);转用二代TKI时未丧失完全血液学缓解(CHR)和丧失CHR的患者6个月达到BCR/ABL≤10%分别有16例(72.7%)和9例(32.1%);转用二代TKI后依从性好和依从性差的患者6个月达到BCR/ABL≤10%分别有23例(74.2%)和2例10.5%)。结论伊马替尼耐药或不耐受的CML患者改用二代TKI药物可取得一定的疗效,且两种二代TKI药物(达沙替尼、尼洛替尼)疗效差异无统计学意义。因不耐受而换药的患者的疗效要优于因耐药而换药的患者;换药时处于慢性期的患者的疗效要优于换药时处于进展期的患者;换药时未丧失CHR的患者的疗效要优于丧失CHR的患者;服用二代TKI药物依从性好的患者的疗效要优于依从性差的患者。

尼洛替尼和伊马替尼对慢性粒细胞白血病表达谱的影响

目的探索尼洛替尼和伊马替尼对慢性粒细胞白血病(CML)细胞基因表达谱的影响,阐明酪氨酸激酶抑制剂(TKI)抑制白血病的分子机制。方法从在线基因表达数据库中下载表达谱数据集GSE19567,利用BRB-Array Tools软件进行质量控制并筛选差异表达基因(DEGs),然后分别对差异基因进行GO功能富集分析、KEGG通路富集分析、pathway互作网络和基因互作网络分析。结果共筛选出差异基因519个,其中177个上调表达,342个下调表达。GO富集分析发现DEGs主要涉及小分子代谢、血液凝固、转录调控、细胞增殖与凋亡调控等生物过程,发挥的分子功能集中在蛋白结合、蛋白二聚化、序列特异性DNA结合和ATP结合等。KEGG富集分析发现代谢通路、PI3K-Akt信号通路、Jak-STAT信号通路和HIF-1信号通路等pathway显著富集。网络分析挖掘出的核心基因有SHMT2、CBS、CTH、HK2,核心pathway包括MAPK信号通路、细胞周期和细胞凋亡等。结论酪氨酸激酶抑制剂影响了CML细胞代谢通路和信号转导通路的相关基因,通过细胞周期阻滞和诱导凋亡等机制抑制白血病,为白血病的靶向治疗提供了基础。