反应停联合三氧化二砷及维生素C治疗多发性骨髓瘤8例分析

目的观察反应停联合三氧化二砷及维生素C治疗多发性骨髓瘤的疗效及不良反应。方法确诊的多发性骨髓瘤患者8例，使用反应停联合三氧化二砷及维生素C的方案：持续口服小剂量反应停（100mg／d），第1周（d1—5）将As2O3 10mg加入液体静滴，后再以维生素C1000mg加入液体静滴；第2—12周，每周两次As2O3 10mg及维生素C1000mg如前使用。结果部分缓解6例（75％），进步1例（12．5％），总有效率87．5％（7／8）。不良反应有乏力，便秘，恶心、呕吐，肝功能受损，浮肿等。结论反应停联合三氧化二砷及维生素c治疗多发性骨髓瘤疗效明显，患者耐受性可，特另Ⅱ适用于有多种并发症的老年患者。     

三氧化二砷对肝细胞肝癌抗肿瘤作用的实验研究

近年来，砷剂（主要成分三氧化二砷，As2O3）治疗白血病取得明显疗效，并已证实砷剂可通过诱导肿瘤细胞凋亡达到治疗的目的。有报道砷剂可诱导人肝癌细胞株凋亡，抑制肝癌细胞增殖。为进一步研究其搞肿瘤效应及其机制，以期为临床上使用As2O3治疗肝细胞肝癌的可行性提供理论依据，我们的研究设计用As2O3治疗实验性肝癌大鼠，研究As2O3及复方苦参对体内肝癌的治疗作用及其作用机制。     

亚细胞毒性剂量As2O3增加胃癌细胞对rhTRAIL的敏感性及其机制

目的:研究亚细胞毒性剂量As2O3对rhTRAIL诱导胃癌细胞凋亡的影响及其机制．方法:人胃腺癌细胞株SGC 7901以As2O3(1μmol／L),rhTRAIL(500μg／L)及两者联用处理:采用AnnexinV-FITC和PI双染色流式细胞仪检测细胞凋亡:用间接免疫荧光染色结合流式细胞技术检测细胞表面TRAIL R1／DR4和TRAIL R2／DR5分子表达;RT-PCR方法检测TRAIL R1／DR4和TRAIL R2／DR5 mRNA表达．结果:rhTRAIL在单用或与As2O3联用时均可以诱导胃癌SGC7901细胞凋亡,并且随着作用时间延长(12-72 h),细胞凋亡率逐渐增高．As2O3与rhTRAIL联用24,48,72 h后,SGC7901细胞凋亡率分别显著高于单用rhTRAIL处理相同时间细胞(36．49％±7．12％,47．13％±3．44％,55．63％±7．16％vs 29．78％±3.18％、38．56％±1．89％,43．12％±6．23％,P<0．05); As2O3单用或联用rhTRAIL处理SGC7901细胞24 h后,细胞表面TRAIL R1／DR4和TRAIL R2／DR5分子的平均荧光密度(MFI)较对照组细胞显著增加(R1／DR4:29．44±4．29,26．14±3．40 vs13．45±3．81,P<0．05或P<0．01;R2／DR5:28．04±0．79．3 1．47±4．56vs16．45±5．07,P<0．05或P<0．01);与此同时,TRAIL R1／DR4和TRAIL R2／DR5mRNA表达水平增高．结论:亚细胞毒性剂量As2O3可能通过增加TRAIL R1／DR4和TRAIL R2／DR5基因表达、上调细胞表面TRAIL死亡受体从而增加胃癌细胞SGC7901对rhTRAIL的敏感性,两药可能联合用于治疗胃癌．     

砷剂对神经母细胞瘤MYCN mRNA表达的影响

选取生长良好的神经母细胞瘤LA-N-5细胞,分别按三氧化二砷(As2 O3)终浓度为0.75、1.5、3.0、6.0 ìmol/L加药,作用24.48及72 h.RT-PCR法检测MYCN mRNA的表达.发现不同浓度的As2O3均可使MYCNmRNA的表达减少,以3.0ìmol/L组减少最明显;砷剂的抑制作用出现在用药48 h后,延长时间仍能保持抑制作用.认为砷剂能够抑制神经母细胞瘤细胞MYCN mRNA的表达.     

小剂量化疗联合三氧化二砷治疗急性早幼粒细胞白血病

近年来应用砷剂治疗急性早幼粒细胞白血病(APL),获得了较高的缓解率[1],但三氧化二砷(As2O3)治疗中由于其诱导分化作用,部分患者会出现白细胞过多综合征(HLS)[2].对此,我们在As2O3诱导治疗APL过程中出现高白细胞现象的患者加用小剂量化疗,取得了较好效果,现报告如下.     

三氧化二砷吸入治疗中心型肺癌的临床研究

目的探讨经支气管雾化吸入三氧化二砷（As2O3）治疗中心型肺癌的疗效及副作用。方法中心型肺癌患者41例。治疗前常规行肺CT、血常规、心肌酶、肝、肾功能检查。将病人按本人及家属意愿分为两组。两组年龄、性别、身体状况、伴有的并存疾病相当，具有可比性。试验组以高流量氧喷射雾化吸入方法吸入As2O3，对照组以同样方法吸入顺铂，疗程28d。疗程结束后1W。重复治疗前各项检查。按WHO标准评定疗效和毒性反应.结果As2O3对三种病理类型的肺癌都有作用，总有效率CR＋PR试验组61．90％明显高于对照组55．00％（P〈0．05），其中对腺癌的作用更突出。试验组3例均达到了部分缓解，而顺铂对照组3例中只有2例保持无变化，1例进展。不良反应比较：试验组有2人产生咽喉部刺激，而对照组有8人产生。且程度超过试验组。试验组中两例咽喉都有轻度刺激的患者行支气管镜检查。未发现支气管黏膜有明显的充血和水肿。两组患者均未发现治疗后肝功、心肌酶改变及WBC下降。结论经支气管雾化吸入As2O3治疗中心型肺癌的疗效肯定，毒副作用小，是治疗老年人中、晚期中心型肺癌的较理想方法。     

As2O3与NaAsO2抑制HeLa细胞生长的研究

目的探讨As2O3和NaAsO2两种砷剂对HeLa细胞的抑制作用.方法培养HeLa细胞,使细胞悬液浓度为105个/mL,用四甲基偶氮唑蓝还原反应(MTT法),倒置显微镜观察两种砷剂对HeLa细胞的作用后细胞形态的变化.结果两种砷剂As2O3和NaAsO2对HeLa细胞均有抑制作用,随着药物浓度的增加,HeLa细胞存活率逐渐下降并存在剂量反应关系,显微镜下观察,三角形的活细胞逐渐减少而圆形的死亡细胞逐渐增加,As2O3的作用比NaAsO2作用强,对照组均未见上述变化. 结论两种砷剂对HeLa细胞均有抑制作用,As2O3的作用比NaAsO2作用强.     

三氧化二砷诱导肿瘤细胞凋亡分子机制的研究进展

三氧化二砷（As2O3）俗称砒霜，是传统中药毒药，中国古代曾用来治疗牛皮癣、梅毒、风湿病及一些恶性肿瘤，但由于毒性较大。限制了它的广泛应用。自20世纪70年代初，哈尔滨医科大学第一附属医院使用砷剂（As2O3）治疗急性早幼粒白血病（APL）获得满意疗效，且未出现严重不良反应，使人们重新重视As2O3的抗恶性肿瘤作用，拉开了世界范围内的大量相关系列研究。众多的研究表明，     

砷对人胶质瘤细胞周期调控相关基因表达的影响

目的比较三氧化二砷（As2O3）对两种不同p53表型胶质瘤细胞U87MG、T98G细胞周期调控相关基因表达的影响。方法应用功能分类细胞周期基因芯片技术，筛选出As2O3作用于两种胶质瘤细胞U87MG、T98G后与细胞周期调控表达有差异的基因，并对3条有共性表达的基因进行Western印迹分析；四甲基偶氮唑蓝（MTT）法检测细胞生长抑制率；流式细胞仪分析细胞周期改变。结果MTT分析表明：As2O2对2个细胞系的生长有抑制作用，且抑制率具有浓度和时间的依赖性，砷作用72h后，U87MG和T98G细胞系的生长抑制率为50％（IC50）时，其浓度分别为1．78、3．55μmol／L。As2O3可以将U87MG和T98G细胞周期阻滞于G0／G1和G2／M期。U87MG细胞在加入As2O3后，差异表达2倍以上的基因共11条，表达上调的有5条，下调的有6条。T98G细胞在加入As2O3后，差异表达的基因共13条，表达上调的有9条，下调的有4条。Western分析显示，As2O3能上调2个胶质瘤细胞系的P53蛋白水平，同时降低细胞周期蛋白B1、D1表达。结论As2O3通过将细胞周期阻滞于G0／G1和G2／M期来抑制U87MG和T98G细胞的增殖；p53、CyclinB、CylinD等基因表达与As2O3诱导胶质瘤细胞周期阻滞的发生有关。     

全反式维甲酸与三氧化二砷治疗急性早幼粒细胞白血病临床分析

目的:观察全反式维甲酸(ATRA)与三氧化二砷(As2O3 )联合治疗初发急性早幼粒细胞白血病(APL)的疗效和不良反应。方法:As2O3 联合ATRA治疗初治APL患者16 例,As2O3 0.1%注射液10 ml加入5%葡萄糖溶液500 ml静脉点滴,持续4~5 h,1 次/d;ATRA 25 mg·m-2·d-1,分3 次口服,观察CR率、获得CR所需时间、不良反应。结果:15例患者获得完全缓解(CR),CR率93.8%,获得缓解时间(27.3±3.6) d,没有发现明显的不良反应。结论:As2O3 联合ATRA治疗初发APL患者疗效好,能缩短CR的时间,长期CR时间需要进一步观察。     

Thallium and arsenic poisoning in a small midwestern town

Thallium and arsenic have been used as a means of criminal poisoning. Although both manifest characteristically with peripheral neuropathies, thallium is associated with alopecia and arsenic with gastrointestinal symptoms. We describe the symptoms, physical findings, diagnostic test results, and outcomes in a group of men poisoned with thallium and arsenic. Seven patients had evidence of elevated thallium levels, and 2 patients had elevated arsenic and thallium levels. The most commonly reported symptoms included myalgias, arthralgias, paresthesias, and dysesthesias. Five patients developed alopecia. All patients with symptoms and peripheral neuropathies had characteristic blackening of their hair roots. Initially treated with dimercaptosuccinic acid, patients were switched to multiple-dose activated charcoal after testing revealed thallium poisoning. By 6 months, all patients' symptoms and peripheral neuropathies improved, but 5 patients had ongoing psychiatric problems. Thallium remains a means of criminal poisoning and should be considered in any patient with a rapidly progressing peripheral neuropathy with or without alopecia.     

急性早幼粒细胞白血病患者口服多剂量四硫化四砷复方胶囊的临床研究

目的了解多剂量口服四硫化四砷(As4S4)在体内的药代动力学过程及毒副作用。方法用氢化物发生原子吸收分光光度法对7例急性早幼粒细胞白血病(APL)患者进行了药代动力学研究,测定血砷含量,同时检测尿砷排泄及发砷蓄积情况。结果口服As4S4复方胶囊20mg/kg,3次/d,持续14d,服药10~14d血砷浓度平稳,平均谷浓度和峰浓度分别为(53·3±9·0)μg/L和(70·7±10·8)μg/L,波动系数为0·28,消除缓慢,全血清除半衰期为(70·0±31·7)h,曲线下面积为(448·9±71·8)μg·h-1·L-1。中位达峰时间为1(0·5~8)h。维持治疗期间尿砷排泄量(6170·8±3141·8)μg/d,约为日服药量的(0·152±0·082)%,停药后逐渐下降,至28d降至(645·0±288·2)μg/d。服药后末梢组织砷含量明显增高,为用药前的10倍。结论多剂量口服As4S4复方胶囊是治疗APL患者的一种安全可靠,不良反应轻微的有效药物,但应注意长期服药的蓄积倾向。     

Delayed recovery of normal hematopoiesis in arsenic trioxide treatment of acute promyelocytic leukemia: a comparison to all-trans retinoic acid treatment

OBJECTIVE: To examine laboratory data including total blood cell count, leukocyte morphology and coagulation parameters during treatment for acute promyelocytic leukemia (APL) at a single institute, and compare the precise differences between all-trans retinoic acid (ATRA) and arsenic trioxide (As2O3) treatment. PATIENTS AND METHODS: Sixteen patients with APL who were treated with ATRA or As2O3 alone and achieved complete remission (CR) were analyzed. ATRA 45 mg/m2/day was given orally until CR. As2O3 0.15 mg/kg/day was given intravenously until leukemic blasts and promyelocytes were eliminated from the bone marrow. RESULTS: All 7 patients in the ATRA-treated group were primary cases and all 9 patients in the As2O3-treated group were relapsed cases after the achievement of CR with the ATRA. There was no difference in the data before treatment between these two groups. The duration of leukocytopenia and neutropenia during As2O3 treatment was significantly longer than those of ATRA treatment. The nadir of leukocyte and neutrophil counts was observed later in the As2O3-treated group. Terminal neutrophil differentiation was observed more obviously in the ATRA-treated group. The red blood cell count and hemoglobin concentration decreased significantly at the end of As2O3 treatment and were lower than those of ATRA treatment. Platelets recovered earlier in the ATRA-treated group. Coagulation parameters were not significantly changed between the two groups. CONCLUSION: In comparison with ATRA treatment, the recovery of several components in the peripheral blood cells was delayed in As2O3 treatment. Therefore we should pay more and longer attention in As2O3 treatment.     

Bone marrow necrosis in a patient with acute promyelocytic leukemia during re-induction therapy with arsenic trioxide

Arsenic trioxide (As2O3) therapy at a daily dose of 0.15 mg/kg was given to a 60-yr-old Japanese male with refractory acute promyelocytic leukemia. White blood cell (WBC) of 6.6 x 10(3)/microl increased to 134 x 10(3)/microl following the administration of As2O3. Daily hydroxyurea (HU), and 6-mercaptopurine (6-MP) were added on days 7 and 19, respectively. Both HU and 6-MP were discontinued on day 28, when WBC declined to 54.0 x 10(3)/microl. He developed unexplained fever and profound cytopenia requiring multiple blood products transfusions. Bone marrow examination on day 42 revealed massive necrosis. Pharmacokinetics confirmed a mean maximum plasma arsenic concentration (Cpmax) and a half-life time (t1/2) of 6.9 microm and 3.2 h, respectively, in the therapeutic range. This is the first case of bone marrow necrosis after standard-dose As2O3 therapy.     

全反式维甲酸联合三氧化二砷治疗初发急性早幼粒细胞白血病的疗效观察

目的观察全反式维甲酸(ATRA)联合三氧化二砷(As2O3)治疗急性早幼粒细胞白血病(APL)的完全缓解(CR)率和不良反应。方法ATRA25mg.m-2.d-1,As2O3(0.1%溶液)10mL/d联合治疗初发APL直至CR。根据外周血白细胞计数、维甲酸综合征,以及肝功能变化调整ATRA和As2O3的剂量。结果29例初发APL患者,早期死亡2例,27例获得CR,CR率93.1%。获得CR的平均时间为(25.2±3.5)d。没有发现严重不良反应。结论ATRA联合As2O3治疗初发APL疗效好,不良反应患者能耐受。     

Arsenic-induced bone marrow toxicity: ultrastructural and electron-probe analysis.

A patient with severe arsenic poisoning that resulted in marked peripheral blood and bone marrow abnormalities, including megaloblastic erythropoiesis experienced many of the previously reported hematologic complications of arsenic poisoning: leukopenia, granulocytopenia, absolute eosinophilia, and profound anemia. In this study we report an ultrastructural and electron-probe analysis of the bone marrow. Although megaloblastic anemia associated with arsenic poisoning has been described rarely, the presence of arsenic in the local bone marrow milieu has not been demonstrated previously. The ultrastructural features of arsenic-induced bone marrow toxicity are similar to those described in other dyserythropoietic states and include marked nuclear aberrations involving shape, chromatin distribution, and nuclear envelope. Using the technique of energy-dispersive x-ray analysis (electron probe) we demonstrated arsenic in bone marrow spicules; this supports the contention that arsenic can cause megaloblastic anemia. We suggest that this technique may be a useful tool in further studies that attempt to explore the mechanism of arsenic-induced hematologic toxicity. Finally, we suggest that arsenic has a direct toxic effect on DNA synthesis that results in marked disturbances of nuclear division. We recommend that the most appropriate screening procedure to evaluate possible arsenic poisoning is tissue arsenic measurements (hair and nails) rather than 24-hr urinary measurements.     

Effect of arsenic trioxide on human hepatocarcinoma in nude mice

AIM: To study the effect of arsenic trioxide (As(2)0(3)) on human hepatoma cell line BEL-7402 in vivo. METHODS: Human hepatoma cell line BEL-7402 cultured in vitro was inoculated into nude mice and arsenic trioxide, 5-Fu and saline were injected into abdominal cavity of the nude mice respectively. The volumes of tumor and general conditions of the nude mice and structural changes of the liver and kidney were observed. Morphologic changes were studied under electron microscope. Expression of AFP was investigated by immunohistochemical method. RESULTS: As(2)O(3) could inhibit the growth of tumor. The tumor growth inhibitory rate in mice treated with 2.5 mg/kg As(2)O(3) was 53.42% on the tenth day. The tumor growth inhibitory rate in mice treated with 5 mg/kg As(2)O(3) was 79.28% on the fifth day and 96.58% on the tenth day respectively. As(2)O(3) did not damage the liver and kidney of nude mice, or affect the blood system. Typical apoptotic morphological changes were found under electron microscope, and the change of mitochondria was obvious. The expression rate of AFP declined after treatment. CONCLUSION: Arsenic trioxide can induce apoptosis of human hepatoma cells, and inhibit proliferation of tumor with no obvious side effects on liver and kidney.     

砷剂和维甲酸对急性早幼粒细胞白血病凝血异常作用的临床研究

目的研究全反式维甲酸(ATRA)或三氧化二砷(As2O3)治疗急性早幼粒细胞白血病(APL)对患者凝血异常的作用,探讨APL患者出血形成机制.方法采用逆转录-聚合酶链反应(RT-PCR)检测APL细胞凝血酶调节蛋白(TM)和组织因子(TF)mRNA的转录;同时采用ELISA法测定患者治疗期间血浆的相关凝血参数及细胞促凝活性(PCA)的改变,临床监测APL患者出血症状变化.结果 APL患者在ATRA治疗期间血浆及APL细胞表面TM表达均显著上调,从治疗前血浆含量(5.07±0.53) μg/L,渐进上升到治疗后第5天(21.86±5.32) μg/L,达完全缓解(CR)后接近正常水平;而TM抗原由治疗前的(14.31±1.60)ng /107到治疗后20天上升至(21.61±6.82)ng /107细胞;血浆P选择素、可溶性纤维蛋白单体复合物和D-二聚体(D-D),在As2O3或ATRA治疗APL患者期间,均较治疗前显著下降(P值均<0.01);同时发现APL细胞TFmRNA异常表达增高,用ATRA或As2O3治疗APL患者期间均具有下调TF mRNA和蛋白表达的作用,在ATRA或As2O3治疗期间,TF抗原由治疗前的(14.81±6.23)ng/L,均呈显著下降,治疗20天后均未能检测到TF的表达 (P＜0.01),APL细胞的PCA亦呈显著下调,同时伴随临床出血症状明显改善.结论 As2O3或ATRA均可显著下调TF mRNA及其表达,减低PCA从而迅速纠正APL患者严重的出血症状.