地西他滨治疗骨髓增生异常综合征和急性髓细胞白血病临床观察

目的探讨地西他滨治疗骨髓增生异常综合征（MDS）和急性髓细胞白血病（AML）的临床疗效和安全性。方法收集2011年1月至2013年7月接受地西他滨[15mg／（m2·d）,第1—5天,静脉滴注持续1h以上1单药或联合CAGf阿糖胞苷（Ara-C）、阿克拉霉素（Acla）、粒细胞集落刺激因子（G-CSF）]方案治疗的20例MDS和AML患者的临床资料,评价其疗效和不良反应。结果20例患者中完全缓解（CR）4例,部分缓解（PR）8例,稳定（SD）及进展（PD）8例,总有效率为60．0％（12／20）。其中12例AML患者中CR2例,PR5例,总有效率为58.3％（7／12）,8例MDS患者中CR2例,PR3例,总有效率为62．5％（5／8）。1例MDS．难治性贫血伴环状铁粒幼细胞患者和2例慢性粒一单核细胞性白血病患者输血依赖情况有所改善。14例患者出现Ⅲ－Ⅳ度骨髓受抑,发生率为70．O％（14／20）。总感染率为35．0％（7,20）,其中肺部感染率为20．0％（4／20）,患者经积极抗感染、刺激造血及输血等支持治疗后感染控制。1例患者出现化疗相关死亡。20例患者均未出现严重肝功能损害及出血。结论地西他滨单药或联合CAG方案治疗MDS和AML有一定疗效,可廷缓疾病进展;患者对化疗不良反应均能耐受．且化疗相关病死率低。     

UPLC法同时测定盐酸阿糖胞苷原料药的含量和有关物质

目的:建立同时测定盐酸阿糖胞苷原料药的含量和有关物质的方法。方法:采用超高效液相色谱法。色谱柱为Inertsil ODS-3 C18,流动相为磷酸盐缓冲液-甲醇(梯度洗脱),流速为0.8 ml/min,检测波长为254 nm,柱温为40Ⅴ,进样量为10μl。结果:尿嘧啶、尿苷、阿糖尿苷、盐酸阿糖胞苷检测质量浓度分别在0.100 8²0.16、0.120.16、0.1²0.12、0.095 620.12、0.095 6¹9.12、0.119.12、0.1²0.004μg/ml范围内与各自峰面积积分值呈良好的线性关系(r=0.999 9、0.999 8、0.999 9、0.999 9);精密度、稳定性、重复性试验的RSD≤0.79%;尿嘧啶、尿苷、阿糖尿苷平均加样回收率为103.8%、102.2%、99.7%,RSD分别为2.44%、2.69%、3.16%(n=9)。结论:该方法准确、灵敏度高、专属性强、重复性好,可用于盐酸阿糖胞苷原料药的质量控制。     

Effect of Postremission Therapy before Reduced-Intensity Conditioning Allogeneic Transplantation for Acute Myeloid Leukemia in First Complete Remission

The impact of pretransplant (hematopoietic cell transplantation [HCT]) cytarabine consolidation therapy on post-HCT outcomes has yet to be evaluated after reduced-intensity or nonmyeloablative conditioning. We analyzed 604 adults with acute myeloid leukemia in first complete remission (CR1) reported to the Center for International Blood and Marrow Transplant Research who received a reduced-intensity or nonmyeloablative conditioning HCT from an HLA-identical sibling, HLA-matched unrelated donor, or umbilical cord blood donor from 2000 to 2010. We compared transplant outcomes based on exposure to cytarabine postremission consolidation. Three-year survival rates were 36% (95% confidence interval [CI], 29% to 43%) in the no consolidation arm and 42% (95% CI, 37% to 47%) in the cytarabine consolidation arm (P = .16). Disease-free survival was 34% (95% CI, 27% to 41%) and 41% (95% CI, 35% to 46%; P = .15), respectively. Three-year cumulative incidences of relapse were 37% (95% CI, 30% to 44%) and 38% (95% CI, 33% to 43%), respectively (P = .80). Multivariate regression confirmed no effect of consolidation on relapse, disease-free survival, and survival. Before reduced-intensity or nonmyeloablative conditioning HCT, these data suggest pre-HCT consolidation cytarabine does not significantly alter outcomes and support prompt transition to transplant as soon as morphologic CR1 is attained. If HCT is delayed while identifying a donor, our data suggest that consolidation does not increase transplant treatment-related mortality and is reasonable if required.     

地西他滨联合CHG方案治疗老年急性髓系白血病的疗效分析

目的 分析地西他滨联合CHG方案治疗老年急性髓系白血病的有效率和不良反应.方法 将郑州市第三人民医院2015年1月至2019年1月收治的62例老年急性髓系白血病患者作为观察对象,根据治疗方法不同分为观察组和对照组,每组31例.观察组行地西他滨(20 mg/m2,连续服用5 d)联合CHG治疗(阿糖胞苷,20 mg/m2...     

阿糖胞苷联合冬凌草甲素诱导U937细胞株凋亡的初步研究

目的:探讨阿糖胞苷联合冬凌草甲素诱导白血病细胞株U937凋亡的作用。方法:用阿糖胞苷和冬凌草甲素单药或两药联合处理U937细胞后,采用细胞计数检测细胞增殖,瑞氏染色观察细胞形态,流式细胞术分析细胞磷脂酰丝氨酸外翻情况和线粒体膜电位变化,蛋白印迹法检测凋亡相关分子表达情况。结果:阿糖胞苷和冬凌草甲素单药均能抑制U937细胞增殖,而两药联合抑制作用更加明显,两者能协同诱导U937细胞凋亡,并明显促进细胞磷脂酰丝氨酸外翻和线粒体跨膜电位下降;两药联合较单药组还能明显诱导Caspase-9、Caspase-3活化及PARP的剪切。结论:阿糖胞苷与冬凌草甲素能够协同抑制U937细胞增殖、诱导细胞凋亡,其机制可能是主要通过线粒体途径介导。     

阿糖胞苷联合光动力疗法对人白血病HL-60细胞作用的研究

目的 探讨阿糖胞苷（Ara-c）在癌光啉（PSD-007）介导的光动力疗法（PDT）杀伤人早幼粒白血病HL-60细胞中的联合作用.方法 实验分为空白对照组、PDT单独作用组（PDT l～4组,为光敏剂剂量（5、7.5μg/ml）和激光能量密度（1.2、2.4 J/cm^2）的两两组合）、Ara-c单独作用组（Ara-c A组和Ara-c B组中Ara-c质量浓度分别为0.3 μg/ml和1.2μg/ml）和联合作用组即上述PDT单独作用组和Ara-c单独作用组的两两组合.所有分组分别按3种时序即P24A时序（PDT作用24h后再加入Ara-c共同作用24h）、A24P时序（Ara-c作用24h后进行PDT再共同作用24h）和PA24时序（PDT作用的同时加入Ara-c再共同作用24h）进行处理.采用CCK-8法检测各组细胞活性,用金氏公式分析联合效应,并用流式细胞术检测细胞周期变化.结果 小剂量PSD-007介导的PDT和Ara-c联合时,3种时序的联合作用均表现为协同效应;而大剂量PSD-007介导的PDT和Ara-c联合时,P24A和A24P 2种时序的联合作用效应为协同或相加,PA24时序则主要为相加或拮抗.流式细胞仪检测细胞周期变化结果显示,Ara-c和PSD介导的PDT均能引起细胞周期G0/G1期阻滞.结论 Ara-c与PSD-007介导的PDT联合作用对HL-60细胞的杀伤有协同作用,其协同作用与剂量和作用时序相关,小剂量比大剂量协同效果明显,且Ara-c和PDT间隔24h作用比2者同时作用于该细胞的协同效果明显.     

注射用盐酸阿糖胞苷细菌内毒素检查方法的研究

目的:建立注射用盐酸阿糖胞苷细菌内毒素检查法。方法:按《中国药典》2005年版二部附录ⅪE进行实验和结果判断。结果:注射用盐酸阿糖胞苷最大不干扰浓度为3.85 g·L~(-1)。结论:可建立注射用盐酸阿糖胞苷的细菌内毒素检查方法。     

阿糖胞苷联合粒细胞集落刺激因子动员自体外周血干细胞效果的研究

目的　观察阿糖胞苷 (Ara C)联合重组人粒细胞集落刺激因子 (rhG CSF)对恶性淋巴瘤患者自体外周血造血干细胞 (APBSC)的动员效果 ,并寻找Ara C合适的给药剂量。方法　按照入组的先后顺序 ,将患者分成两组 ,A组Ara C的给药剂量为 6g/m2 静滴 (分 2次 ,间隔 2 4h) ,B组Ara C的给药剂量为 10g/m2 静滴 (分 4次 ,间隔 12h) ,白细胞 (WBC)降至最低点时开始皮下注射rhG CSF 30 0 μg·人 -1·d-1,直至采集结束前 1d ,白细胞恢复到 5 .0× 10 9/L以上时开始连日采集APBSC ,当累计采集的单个核细胞≥ 5× 10 8/kg或CD34+ 细胞≥ 2× 10 6/kg时停止采集。结果　 2 2例患者进入本研究 ,A、B两组各有 11例患者。Ara C给药后 ,患者外周血中白细胞和中性粒细胞绝对值 (ANC)的最低值 ,B组明显低于A组 ,出现的时间B组也明显晚于A组。A、B两组rhG CSF给药的开始时间和持续时间、APBSC采集的开始时间和持续时间均无显著差异 ,在APBSC采集时的循环血量、血流速和采集时间相同的情况下 ,APBSC的采集次数、每次采集的细胞数量和总量亦差异无显著意义 ,B组Ara C引起的某些毒副反应略重于A组 ,但两组间差异无显著意义。结论　Ara C联合rhG CSF是一种安全、高效的APBSC的动员方法 ,6g/m2 的Ara C即可得到满意的动员效果。     

Complementary antineoplastic activity of the cytosine nucleoside analogues troxacitabine (Troxatyl) and cytarabine in human leukemia cells

Purpose Troxacitabine (BCH-4556, l-(–)-OddC, Troxatyl) is a novel -l-nucleoside analogue with potent antineoplastic activity both in vitro and in several tumor models in vivo, and is presently in phase II clinical trials. The combination of the cytosine analogues troxacitabine and araC (1--d-arabinofuranosylcytosine, cytarabine) has shown promising activity in patients with acute myelogenous leukemia. To further examine the interactions between these two analogues, we investigated the in vitro and in vivo effects of their combination against a human leukemia cell line, CCRF-CEM.Methods The in vitro cytotoxic effect of the combination of troxacitabine and araC on the survival of CCRF-CEM cells was measured using a standard MTT assay and combination indices were generated with the CalcuSyn software. For in vivo studies, we evaluated the effect of both drugs, alone and in combination, on survival of CCRF-CEM tumor-bearing animals. Mechanistic studies addressed recovery of DNA synthesis, intracellular levels of araC metabolites, feedback inhibition by triphosphate species and pharmacokinetics of both drugs.Results The combination of troxacitabine and araC in vitro was synergistic with combination indices between 0.1 and 0.7. This appeared to be related to the impact of the combination on DNA synthesis recovery, which was significantly delayed following exposure to the combination of troxacitabine and araC compared to either agent alone. Analysis of the effect of troxacitabine on the intracellular metabolites of araC revealed that troxacitabine did not inhibit araC deamination and caused a slight decrease in the overall intracellular accumulation of araCTP. The lower accumulation of araCTP could not be attributed to feedback inhibition caused by troxacitabine triphosphate on dCK. Furthermore, our in vivo experiments demonstrated that the combination of araC and troxacitabine was better at slowing down the progression of leukemia in SCID mice than either agent used alone without additive toxicities. Injections of 10 mg/kg troxacitabine i.p. daily for 5 days in combination with araC at 10 mg/kg led to an increase in median survival time of 58 days compared to 49.5 and 53.5 days for araC and troxacitabine, respectively, given as single agents. This represents an increase in life span of 17%, respectively when compared to araC alone. A pharmacokinetic study revealed that troxacitabine did not influence the disposition of araC when coadministered.Conclusions Overall, our results show that the antileukemic activity of troxacitabine and araC is complementary when the two nucleoside analogues are combined in vivo. These effects appear to be related to their interaction at the level of DNA repair rather than to pharmacokinetic interactions. These results encourage the use of troxacitabine and araC in combination in patients with acute leukemia.Abbreviations AML Acute myelogenous leukemia - araC 1--d-Arabinofuranosylcytosine, cytarabine - araCMP Cytarabine-5-monophosphate - araCTP Cytarabine-5-triphosphate - araU 1--d-Arabinofuranosyluracil - dCyd Deoxycytidine - CDA Cytidine deaminase - CI Combination index - dCK Deoxycytidine kinase - dCTP Deoxycytidine-5-triphosphate - dFdC Gemcitabine, 2,2-difluorodeoxycytidine - troxacitabineTP Troxacitabine 5-triphosphate