预激方案HAG及CAG治疗老年初治急性髓性白血病的对比研究

目的:评价含粒细胞集落刺激因子(granulocyte colony-stimulating-factor,G-CSF)的预激HAG及CAG方案治疗老年初治急性髓性白血病(AML)的疗效及不良反应,并对两个方案的疗效及不良反应进行比较。方法:65例老年初治AML分为HAG预激治疗组及CAG预激方案治疗组,31例患者予以HAG预激方案治疗,34例患者予以预激方案CAG方案治疗,所有患者在第1疗程后间歇14d左右进行第2个疗程。结果:HAG预激方案治疗组的完全缓解率为74.2%,总有效率为83.8%;CAG预激治疗组完全缓解(CR)率为67.6%,总有效率达为82.4%。两治疗组的血液系统不良反应及非血液系统毒性不良反应比较无显著性差异。结论:HAG预激方案化疗强度温和、敏感性好、CR率及有效率高、毒副作用小;与CAG预激治疗比较,HAG预激方案可以取的相似的疗效及较少的不良反应,在老年初治AML患者值得推荐应用。     

Synthesis of dual-action parthenolide prodrugs as potent anticancer agents

Cancer stem cells are responsible for the failure of a large number of cancer treatments and the re-emergence of cancer in patients. Parthenolide is a potent anticancer sesquiterpene lactone that is also able to kill cancer stem cells. The main problem with this compound is its poor solubility in water. To solve this problem, medicinal chemists have tried to prepare amino-derivatives of parthenolide, however, most amino-derivatives have less potency than that of parthenolide. In this paper, we proposed a new approach to synthesize parthenolide derivatives with better solubility and higher potency. We prepared novel parthenolide derivatives through the aza-Michael addition of nitrogen-containing anticancer drug molecules (cytarabine and melphalan) to the α-methylene-γ-lactone group of parthenolide. Different types of catalysts were used to catalyze the aza-Michael addition. Among all the used catalysts, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) was found to have the highest catalytic activity. In addition, we examined the effects of parthenolide-anticancer drug hybrids on the growth and proliferation of three cancer cell lines (MCF-7, LNcaP, Hep G2) and CHO. The parthenolide prodrugs showed potent cytotoxic property with IC₅₀ values ranging from 0.2 to 5.2 μM, higher than those of parthenolide and anticancer drugs (cytarabine and melphalan).     

Distribution of 2-chloro-2′-deoxyadenosine, 2-chloro-2′- arabino -fluoro-2′-deoxyadenosine, Fludarabine and Cytarabine in mice: a whole-body autoradiography study

The distribution characteristics of tritiated nucleoside analogs, 2-chloro-2′-deoxyadeonosine (CdA), 2-chloro-2′-arabino-fluoro-2′-deoxyadenosine (CAFdA), 2-fluoroarabinosyladenine (F-ara-A) and cytosine arabinoside (ara-C) were compared in mice using whole-body autoradiography. CdA, CAFdA and F-ara-A have quite similar molecular structures, but they differ substantially in clinical activity as well as the side effects. Eight mice were injected intravenously in couples. One mouse from each pair was killed 20 min postinjection and the other mouse from each pair 4 h after the injection. The distribution, of the label was then analyzed by whole-body autoradiography. The distribution of the nucleoside analogs was rapid and uniform. High concentrations were found in highly perfused organs. After 4 h the overall concentration had decreased but relatively high activities were found in the skin for CdA and CAFdA, in the thymus for ara-C and the bone marrow for CdA. Both CdA and CAFdA were found in the brain, but the concentration, was surprisingly lower after 4 h for CAFdA, a lipophilic and more stable analog as compared to CdA. There was an uptake of CdA, F-ara-A and CAFdA in the skin. There were signs of retention of ara-C in parts of the thymus. The present investigations indicate that the nucleoside analog transport to the brain in mice is not primarily dependent upon passive diffusion over a lipophilic barrier, but suggestive of a specific transport mechanism.     

Facile synthesis of novel mutual derivatives of nucleosides and pyrimidines by regioselectively chemo-enzymatic protocol

We established a facile regioselectively chemo-enzymatic synthesis procedure for the preparation of mutual derivatives of nucleosides and pyrimidines by sequential Markovnikov addition and acylation. Firstly, pyrimidine derivatives containing vinyl ester group were synthesized from pyrimidines and divinyl esters through Markovnikov addition catalyzed by K₂CO₃ in DMSO at 80 °C, and the yields were ranged from 50% to 87%. Then regioselective acylation of ribavirin and cytarabine with pyrimidine vinyl ester was catalyzed by CAL-B (immobilized lipase from Candida antarctica) in anhydrous acetone. Reaction conditions of enzymatic acylation including enzyme resource and solvents were optimized. A series of mutual derivatives of nucleosides and pyrimidines were synthesized successfully and characterized with NMR, IR, and HRMS. This chemo-enzymatic protocol involving sequential Markovnikov addition and acylation provided a novel way of synthesizing complicated functional compounds regioselectively which was hard to be achieved either by chemical or by enzymatic methods.     

大剂量阿糖胞苷治疗儿童急性髓系白血病的耐受性研究

目的:探讨儿童急性髓系白血病对于大剂量阿糖胞苷的耐受性,为临床用药提供指导.方法:从我院2007年1月～2011年1月收治的儿童急性髓系白血病患者中选取40例,将其作为临床研究对象,随机分成A、B两组,每组均20例患者.两组都给予大剂量阿糖胞苷,A组患者给予体表面积3 g/m2用量;B组患者给予体表面积2 g/m2用量.一周后,分别观察两组急性髓系白血病儿童的治疗效果、神经系统毒性和副作用.结果:治疗一周后,A组患者贫血例数2例(10.00％)较B组患者贫血例数8例(40.00％)少,A组患者所表现的神经毒性头疼、嗜睡、淡漠及惊厥方面较B组患者严重,A组患者所表现的副作用眼球震颤、轮替运动障碍、共济失调均较B组患者严重.结论:大剂量阿糖胞苷虽具有更好的疗效,基本耐受但其不良反应相对严重.     

DNA-binding study of anticancer drug cytarabine by spectroscopic and molecular docking techniques

The interaction of anticancer drug cytarabine with calf thymus DNA (CT-DNA) was investigated in vitro under simulated physiological conditions by multispectroscopic techniques and molecular modeling study. The fluorescence spectroscopy and UV absorption spectroscopy indicated drug interacted with CT-DNA in a groove-binding mode, while the binding constant of UV-vis and the number of binding sites were 4.0 ± 0.2 × 10⁴ L mol^?1 and 1.39, respectively. The fluorimetric studies showed that the reaction between the drugs with CT-DNA is exothermic. Circular dichroism spectroscopy was employed to measure the conformational change of DNA in the presence of cytarabine. Furthermore, the drug induces detectable changes in its viscosity for DNA interaction. The molecular modeling results illustrated that cytarabine strongly binds to groove of DNA by relative binding energy of docked structure ?20.61 KJ mol^?1. This combination of multiple spectroscopic techniques and molecular modeling methods can be widely used in the investigation on the interaction of small molecular pollutants and drugs with biomacromolecules for clarifying the molecular mechanism of toxicity or side effect in vivo.     

贞芪扶正颗粒对去甲氧柔红霉素联合阿糖胞苷方案治疗成人急性髓系白血病疗效及毒副反应的影响

目的:研究贞芪扶正颗粒对去甲氧柔红霉素联合阿糖胞苷方案治疗成人急性髓系白血病疗效及毒副反应的影响。方法:选取我院2006年2月~2012年8月期间收治的成人急性髓系白血病患者134例,并将其随机分为对照组与观察组。对照组采用去甲氧柔红霉素+阿糖胞苷方案规范诱导缓解治疗,观察组在对照组治疗方案上加用贞芪扶正颗粒,观察和比较两组的临床疗效及不良反应的发生情况。结果:对照组与观察组的完全缓解率(CR)分别为73.2%(41/56)和79.5%(62/78),中位OS分别为13.9个月和14.6个月,两组比较差异均无统计学意义(P0.05)。观察组III级以上的骨髓抑制现象的发生率显著低于对照组(P0.05),粒细胞最低值显著高于对照组(P0.05),粒细胞缺乏和血小板降低持续的总体时间均明显短于对照组(P0.05);观察组各主要感染部位的发生率及感染总体发生率均显著低于对照组(P0.05);观察组各种主要非血液学毒副反应包括呕吐、腹泻、肝毒性、肾毒性、神经毒性、心率失调、口腔炎症、皮疹及发热等的发生率显著低于对照组(73.1%vs.100%,P0.05)。结论:贞芪扶正颗粒能够有效改善去甲柔红霉素联合阿糖胞苷方案治疗成人急性髓系白血病的毒副反应,且不影响其临床疗效。     

Modulation of Cytarabine Induced Cytotoxicity Using Novel Deoxynucleoside Analogs in the HL60 Cell Line

In order to enhance the cytotoxicity of ara‐C in the HL60 cell line the following deoxynucleoside analogs were used: cladribine, fludarabine and gemcitabine. HL60 cells were co‐incubated with ara‐C and each of the modulators at the ratios of their respective IC50s. Cytotoxicity was determined with the MTT‐assay and drug interactions were evaluated with the combination index (CI) method (Calcusyn; Chou & Talalay). CI < 1, CI ± 1 and > 1 indicate synergism, additive effect and antagonism, respectively. We observed moderate synergism between ara‐C/cladribine and ara‐C/gemcitabine, with CIs of 0.76 ± 0.14 and 0.82 ± 0.04, respectively. The interaction between ara‐C/fludarabine resulted in moderate antagonism (CI = 1.29 ± 0.11). In conclusion, in this in vitro study we showed that the cytotoxicity of ara‐C can be succesfully modulated in the HL60 cell line by cladribine and gemcitabine.     

高三尖杉酯碱联合阿糖胞苷治疗骨髓增生异常综合征的疗效及安全性分析

目的:探讨高三尖杉酯碱联合阿糖胞苷治疗骨髓增生异常综合征的疗效及安全性。方法:选择2015年1月-2019年1月在我院接受治疗的40例骨髓增生异常综合征患者,采用抽签法分为观察组(n=21)和对照组(n=19)。两组均给予地西他滨治疗,对照组在此基础上给予阿糖胞苷治疗,观察组在对照组的基础上给予高三尖杉酯碱治疗。比较两组患者的临床缓解情况、治疗前后血清内皮生长因子(VEGF)、骨髓中原始细胞占比、白细胞介素6(IL-6)、白细胞介素10(IL-10)、肿瘤坏死因子(TNF-α)水平、生存质量评分的变化及并发症的发生情况。结果:治疗后,两组总缓解率分别为71.43%,36.84%,观察组显著高于对照组(P0.05);两组血清VEGF、骨髓中原始细胞占比水平均较治疗前显著降低,且观察组上述指标均明显低于对照组(P0.05);两组血清IL-6、TNF-α水平均较治疗前显著降低,IL-10较治疗前显著升高,且观察组血清IL-6、TNF-α水平均显著低于对照组,IL-10水平明显高于对照组(P0.05);两组生存质量评分水平均较治疗前显著降低,且观察组明显低于对照组(P0.05);两组并发症总发生率为52.38%、84.21%,观察组显著低于对照组(P0.05)。结论:高三尖杉酯碱联合阿糖胞苷治疗骨髓增生异常综合征的效果显著优于单用阿糖胞苷治疗,其可有效改善患者生存质量水平,且安全性更高,可能与其降低血清IL-6、TNF-α水平,升高IL-10水平,减轻炎症反应有关。     

Inhibition of MEK signaling enhances the ability of cytarabine to induce growth arrest and apoptosis of acute myelogenous leukemia cells

The mitogen-activated protein kinase/ERK kinase (MEK)/ERK pathway was shown to be constitutively activated in a large number of acute myelogenous leukemia (AML) cells, suggesting the important roles of this pro-survival signaling in leukemogenesis and proliferation of AML cells. This study explored the impact of the MEK inhibitor AZD6244 on the effect of cytarabien (AraC), one of the most commonly used anti-leukemia agents, to induce growth arrest and apoptosis of AML cells. AZD6244 effectively blocked AraC-induced MEK/ERK activation and enhanced its ability to induce growth arrest and apoptosis of NB4 and HL60 cells in parallel with induction of DNA damage as measured by detection of γ-H2AX by Western Blot analysis, resulting in enhanced expression of p21 ^waf1 and downregulation of c-Myc and Bcl-xl in these cells. Enhanced induction of apoptosis mediated by combination of AZD6244 and AraC was also shown in freshly isolated AML cells (n = 3). Taken together, concomitant administration of AraC and the inhibitor of MEK/ERK signaling may be useful for treatment of individuals with AML.