重组人血管内皮抑素对食管癌细胞生长抑制作用的研究

目的　探讨重组人血管内皮抑素（恩度）对食管癌细胞生长的抑制作用。方法　用ＭＴＴ法检测恩度对食管癌细胞-１０９和人脐静脉内皮细胞（ＨＵＶＥＣ）的增殖抑制作用;建立Ｅｃａ-１０９细胞裸鼠移植瘤模型,观察不同浓度恩度对移植瘤生长的影响;免疫组织化学检测瘤组织微血管密度（ＭＶＤ）;ＥＬＩＳＡ方法检测荷瘤动物血清ＶＥＧＦ的浓度。结果　与空白对照组比较,恩度能抑制Ｅｃａ-１０９和ＨＵＶＥＣ细胞的增殖（Ｐ均＜０.０5）,并有效抑制食管癌移植瘤的生长（Ｐ＜０.０５）,检测荷瘤组织中ＭＶＤ计数较空白对照组明显降低（Ｐ＜０.０５）,荷瘤动物血清ＶＥＧＦ浓度也明显低于空白对照组（Ｐ＜０.０５）。结论 恩度能有效抑制食管癌细胞及移植瘤的生长。     

大剂量重组人血管内皮抑素对肺癌转移瘤的实验研究*

目的　探讨大剂量重组人血管内皮抑素（恩度）单药对肺癌的作用。方法　建立肺癌裸鼠转移瘤模型,检测腹腔给药和皮下注射两种途径恩度（５０ｍｇ／ｋｇ）在实验ＳＤ大鼠中的血药浓度,同时分别设生理盐水对照组和恩度１０、２０、５０、１００、２００ｍｇ／（ｋｇ·ｄ）组,观察小鼠的生存情况,计算生存期以及肺部转移灶数量。结果　恩度腹腔给药和皮下注射两种途径药代动力学相似,半衰期约为２４ｈ。１００ｍｇ／（ｋｇ·ｄ）恩度组小鼠的中位生存期达６１天,较对照组延长１０天。小鼠肺部转移病灶数量与恩度剂量有一定相关性,１００ｍｇ／（ｋｇ·ｄ）恩度组转移灶数量最少,与对照组比较有统计学上显著差异（Ｐ＜０.０５）。结论　在肺癌转移瘤模型中,大剂量恩度能够有效地抑制肺癌的生长,生存期延长,生存质量较好。     

腹腔内应用重组人血管内皮抑制素联合氟尿嘧啶治疗恶性腹水的初步探讨

目的：观察腹腔内注入抗肿瘤新药重组人血管内皮抑制素注射液（恩度）联合氟尿嘧啶（５-ＦＵ）治疗恶性腹水的近期疗效和安全性。方法：经细胞学检查确诊的恶性腹水肿瘤患者３６例（食管癌１例、胃癌１０例、结直肠癌１５例、肝细胞癌和胰腺癌各５例）,接受腹腔内注入恩度联合５-ＦＵ的方案治疗,其中５-ＦＵ１.０ｇ以及恩度６０ｍｇ匀速缓慢腹腔注入,每周重复１次;恩度治疗前和治疗中进行腹水ＶＥＧＦ的测定。按照ＷＨＯ腹水评价标准评价近期疗效,参照Ｋａｒｎｏｆｓｋｙ评分（ＫＰＳ）变化评价生活质量（ＱＯＬ）,按照ＮＣＩＣＴＣ３.０版的药物毒性分级标准评价化疗不良反应。用药１周期即可评价不良反应以及近期疗效。结果：全组３６例患者中,接受恩度的周期数为２～４,中位周期数为３,总共完成的周期数为１０２个。获得ＣＲ４例,ＰＲ１３例,即客观有效率（ＲＲ）４７.２％（１７／３６）;腹水缓解持续时间１０～１０５天,中位缓解时间５１天。而ＱＯＬ改善率为５５.６％（２０／３６）。３２例患者治疗前腹水ＶＥＧＦ水平异常升高,根据其治疗后ＶＥＧＦ水平下降的比例将患者分为ＶＥＧＦ下降≥２５％组和ＶＥＧＦ下降＜２５％组,前者有效率和生活质量改善率明显比后者高（Ｐ值分别为０.００３和０.００２）。３～４级不良反应主要与化疗药物有关,包括白细胞下降５.６％（２／３６）、血小板下降２.８％（１／３６）、恶心呕吐５.６％（２／３６）以及腹泻２.８％（１／３６）。结论：腹腔内恩度联合５-ＦＵ治疗恶性腹水是一种安全、可行的治疗手段,具有较好的近期疗效,并能改善生活质量,其作用机制可能与抑制腹水ＶＥＧＦ的水平有关,值得临床进一步深入观察。     

重组人血管内皮抑制素联合顺铂治疗肺癌的实验研究

目的：探讨重组人血管内皮抑制素（恩度）联合化疗对肺癌的作用。方法：建立肺癌裸鼠移植模型１６只,随机分为４组：空白对照组、恩度组、顺铂组、恩度联合顺铂组。治疗结束第２天处死裸鼠,测量肿瘤体积和质量,免疫组化法测微血管密度（ＭＶＤ）及瘤组织血管内皮生长因子（ＶＥＧＦ）的表达。结果：治疗结束后,空白对照组、恩度组、顺铂组和联合组的肿瘤体积分别为（４ ６８４.９±４９９.３）ｍｍ^３、（３ ９０３.４±３２７.４）ｍｍ^３、（２ ６８９.６±２３２.９）ｍｍ^３和（２ ００７.９±３１７.３）ｍｍ^３（Ｐ＜０.０５）。恩度组、顺铂组和联合组的肿瘤抑制率分别为１３.５％、１８.９％和３５.１％（Ｐ＜０.０５）。免疫组化结果显示,联合组肿瘤ＭＶＤ低于其他各组（Ｐ＜０.０５）;用药组ＶＥＧＦ的表达与空白对照组比较有统计学差异（Ｐ＜０.０５）。结论：肺癌裸鼠移植瘤模型中恩度与顺铂联合抗肿瘤作用较单药明显增强,能够有效地抑制肺癌的生长。     

转移性软组织肉瘤化疗联合重组人血管内皮抑素治疗的有效性和安全性观察

目的 软组织肉瘤(soft tissue sarcomas,STS)是一种罕见的异质性恶性肿瘤,约80％患者术后两年内出现远处转移,且以多柔比星为基础的一线化疗,疗效依然不理想.本研究评价化疗联合重组人血管内皮抑素(恩度)治疗转移性软组织肉瘤的疗效及安全性.方法 回顾性分析天津医科大学肿瘤医院2007-01-01-2015-06-30收治的66例转移性STS病例,其中44例接受单纯化疗作为对照组,22例接受化疗联合恩度作为试验组.短期疗效评价包括客观反应率(objective response rate,ORR)、疾病控制率(diaease control,DCR)和安全性评价.随访观察无进展生存期(progression-free survival,PFS)和总生存期(overall survival,OS).结果 对照组和试验组ORR分别为13.6％和22.7％(x2=0.341,P=0.559),DCR分别为59.1％和77.3％(x2=2.135,P=0.144).对照组和试验组的中位PFS分别为6.9个月(95％CI为4.4～9.5)和12.5个月(95％CI为8.2～16.8),差异有统计学意义(x2=4.882,P=0.027),中位OS分别为15.4个月(95％CI为i0.2～20.7)和23.4个月(95％CI为16.4～30.3),差异有统计学意义,x2=4.506,P=0.034.对照组和试验组的1年生存率分别为58.1％和85.0％,2年生存率分别为24.6％和48.6％.大多数不良反应为轻到中度的呕吐,腹泻、骨髓抑制和心脏毒性,比较两组的不良反应差异无统计学意义,P＞0.05.结论 虽然化疗联合恩度没能控制转移性STS疾病进展,但是延长了患者的PFS及OS,且不良反应可以耐受.     

经肝动脉灌注重组人血管内皮抑制素联合TACE治疗兔VX 2肝癌及肿瘤血管生成的评估

目的：经肝动脉灌注重组人血管内皮抑制素（recombinant human endostatin，rh-endostatin）联合经导管动脉内化疗栓塞术（transcathet artefial chemoembolization，TACE）治疗兔VX2肝癌后，对其疗效进行评估，并分析肿瘤周边CT灌注特征及微血管密度（microvascular density，MVD）、血管内皮生长因子（vascular endothelial growth factor，VEGF）表达的变化，探讨CT灌注参数、MVD及VEGF之间的相关性。方法：30只VX2肝癌兔随机分为3组，每组10只。A组：rh-endostatin＋TACE；B组：单纯TACE；C组：对照组。3组于治疗前均行CT平扫，治疗后2周行CT灌注成像，获取肿瘤周边血流量（blood flow，BF），血容量（blood volume，BV）；毛细血管表面渗透面积（permeability surface area product，PS）值。扫描后立即处死动物，组织切片用于免疫组织化学法检测MVD、VEGF表达。结果：A、B组肝癌生长率均明显低于C组（P〈0．01）；A组肿瘤BF、BV、PS值较B、C组明显增高（P〈0．05），MVD、VEGF较B、C组明显减低（P〈0．01）。B、C组之间BF、BV、PS、MVD及VEGF差异均无统计学意义（P〉0．05）。在3组中，肿瘤VEGF与MVD之间均呈显著正相关（P〈0．01），A组中BF、BV、PS分别与MVD、VEGF呈线性正相关（P〈0．05），而B、C组中BF、BV、PS与MVD、VEGF无线性相关性（P〉0．05）。结论：肝动脉灌注rh-endostatin联合TACE治疗肝癌能减慢肿瘤的生长速度，显著地抑制治疗后肿瘤新生血管的形成。肿瘤CT灌注参数不总是能反映其病理参数MVD、VEGF的变化。     

芬太尼对人肝癌细胞bel-7404生长与凋亡的影响

目的探讨芬太尼对人肝癌细胞bel-7404生长及凋亡的影响。方法体外培养人肝癌bel-7404细胞,分F1、F2、F13、F4,4个实验组和1个对照组,实验组分别在RPMI-1640培养液中加入5ng／ml（F1）、50ng／ml（F2）、500ng／ml（F3）、5000ng／ml（F4）芬太尼,对照组不加芬太尼,所有样本孵育24h后,用倒置显微镜观察细胞形态学改变,应用MTT法和克隆形成实验检测细胞的增殖活性,应用流式细胞仪检测细胞凋亡率与细胞周期。结果各实验组人肝癌bel-7404细胞MTT和克隆形成率明显低于对照组（P〈0．01）,细胞凋亡百分比显著高于对照组（P〈0．05）。芬太尼浓度≥50ng／ml时,随着浓度的增加,凋亡率逐渐增高,细胞周期中G0／G1期比例逐渐增加,S期细胞比例逐渐减少,与对照组比较差异具有统计学意义（P〈0．05）。结论芬太尼可剂量依赖性抑制人肝癌细胞bel-7404的生长,干扰肝癌细胞增殖周期,诱导肝癌细胞凋亡。     

重组人血管内皮抑素联合吉西他滨、顺铂方案双途径给药治疗晚期非小细胞肺癌的临床研究

目的　研究重组人血管内皮抑素（恩度）联合吉西他滨＋顺铂方案双途径给药治疗中晚期非小细胞肺癌（ＮＳＣＬＣ）的有效性和安全性。方法　选择ＮＳＣＬＣ患者４０例,分为恩度联合ＧＰ方案双途径给药治疗组（试验组）和单纯ＧＰ方案双途径治疗组（对照组）,每组２０例。试验组方案为：吉西他滨１０００ｍｇ／ｍ２＋顺铂５０ｍｇ／ｍ２＋恩度３０ｍｇ,肿瘤靶动脉灌注ｄ１;恩度１５ｍｇ静滴,ｄ２～ｄ１３;吉西他滨１０００ｍｇ／ｍ２静滴,ｄ８。对照组仅用ＧＰ方案动脉灌注,剂量、方法同试验组,静脉化疗用吉西他滨单药,方法、剂量同试验组。比较两组患者的有效率（ＲＲ）、疾病控制率（ＤＣＲ）、１年生存率、无进展生存期（ＰＦＳ）、总生存期（ＯＳ）和毒副反应等方面的差异。结果　试验组与对照组比较,ＲＲ分别为４５％和１０％（Ｐ＜０.０５）,ＤＣＲ分别为１００％和９０％（Ｐ＞０.０５）,１年生存率分别为５５％和３０％（Ｐ＞０.０５）,ＰＦＳ分别为７.５个月和５.９个月（Ｐ＜０.０５）,ＯＳ分别为１２.７个月和１２.３个月（Ｐ＞０.０５）。两组均未出现严重毒副反应,且组间比较差异无统计学意义。结论　恩度联合ＧＰ方案双途径治疗晚期ＮＳＣＬＣ临床疗效确切,用药安全,无进展生存时间有所延长,但总体生存期改善不明显,其最佳用药方式有待进一步深入研究。     

毕赤酵母表达重组人内皮抑素对小鼠肺腺癌LA795生长和转移的抑制作用

背景与目的：肿瘤的生长和转移有赖于新生血管的生成,内皮抑素能抑制肿瘤的血管生成。本研究旨在观察毕巴斯德酵母（pichia.pastoris.GS115)分泌表达的重组人内皮抑素（recombinant human endostatin,rhES)对小鼠肺腺癌LA795生长和转换的抑制作用。方法：挑取一株高效分泌表达rhES的毕赤巴斯德酵母菌株,利用甲醇进行大量诱导表达;用肝素亲和层析的方法纯化目的蛋白;将接种LA795肺腺癌细胞的T739小鼠随机分成两组,分别给予rhES和PBS皮下注射,每日1次,连续14天;观察两组小鼠肿瘤生长情况,测量肿瘤体积大小,并观察两组小鼠肿瘤肺部转移情况。结果：经甲醇诱导的毕赤巴斯德酵母菌株高效分泌表达了rhES;动物实验研究发现rhES能显著抑制小鼠肺腺癌LA795的生长,rhES治疗组肿瘤大小与对照组比较具有显著性差异（P＜0．001）,抑瘤率达到66．4％,并且有效抑制了肿瘤的肺部转移。结论：利用毕赤酵母作为宿主分泌表达的rhES具有良好的生物学活性,可显著抑制小鼠肺腺癌LA795的生长和转移。     

重组人血管内皮抑素联合顺铂对Ｓ１８０肉瘤ＶＥＧＦ和ＭＭＰ-９表达的影响

目的　观察重组人血管内皮抑素（恩度）联合顺铂对Ｓ１８０肉瘤Ｃ５７ＢＬ／６鼠模型以及小鼠肿瘤组织中血管内皮生长因子（ＶＥＧＦ）和基质金属蛋白酶-９（ＭＭＰ-９）表达的影响。方法　建立Ｓ１８０肉瘤Ｃ５７ＢＬ／６鼠模型,成瘤后随机分为对照组、恩度组、顺铂组、顺铂＋恩度联合组,检测肿瘤组织中ＶＥＧＦ及ＭＭＰ-９的表达。结果　成瘤后对照组、恩度组、顺铂组、顺铂＋恩度联合组中的ＶＥＧＦ及ＭＰＰ-９表达Ｈ评分分别为５１.４±２.５、４８.４±５.３、４１.４±５.２、３２.３±３.９和４７.２±３.６、４６.１±６.１、３６.５±６.４、３１.３±３.２;与对照组比较,顺铂组和联合组均有显著差异（Ｐ＜０.０５）;顺铂组与联合组之间亦有显著差异（Ｐ＜０.０５）。结论　恩度联合顺铂能够显著抑制ＶＥＧＦ及ＭＭＰ-９的表达,减少肿瘤血管生成,从而减少肉瘤浸润及转移。     

重组人血管内皮抑制素联合达卡巴嗪增强抗黑素瘤作用及其机制研究

目的:探讨重组人血管内皮抑制素(recombinant human endostatin, rh-endostatin)联合达卡巴嗪(Dacarbazine)能否增强抗黑素瘤作用,并初步分析其作用机制.方法:分别采用MTT法和FCM法检测重组人血管内皮抑制素单药及其联合达卡巴嗪对黑素瘤B16F10细胞增殖和凋亡的影响;Western印迹法检测重组人血管内皮抑制素对黑素瘤细胞中细胞外信号调节激酶(extracellular signal-regulated kinase,ERK)磷酸化的影响;建立C57BL/6黑素瘤荷瘤小鼠模型,研究重组人血管内皮抑制素联合达卡巴嗪能否增强体内抗黑素瘤的作用.结果:重组人血管内皮抑制素、达卡巴嗪以及两药联合处理对黑素瘤B16F10细胞增殖的抑制率分别为(9.67±2.89)%、(22.67±3.06)%和(30.33±1.16)%,差异有统计学意义(P<0.05);重组人血管内皮抑制素组黑素瘤细胞的ERK分子磷酸化水平明显降低.接种肿瘤18 d时,重组人血管内皮抑制素组、达卡巴嗪组和两药联合组荷瘤小鼠的肿瘤体积分别为(6.45±1.24)cm3、(8.94±2.04)cm3和(4.56±0.98)cm3,两药联合组的肿瘤体积明显低于达卡巴嗪单药组(P<0.05).结论:重组人血管内皮抑制素联合达卡巴嗪体外可增强抗黑素瘤B16F10细胞增殖的作用,体内可增强达卡巴嗪对荷瘤小鼠黑素瘤生长的抑制作用,并提高荷瘤小鼠的存活率.推测抑制黑素瘤细胞中ERK分子酪氨酸磷酸化可能是重组人血管内皮抑制素发挥其抗黑素瘤作用的机制之一.     

恩度联合放射治疗对Lewis肺癌小鼠生长以及碳酸酐酶Ⅸ和乏氧诱导因子表达的影响

目的 研究使用抗血管生成药物联合放射治疗的荷瘤小鼠肿瘤组织中碳酸酐酶Ⅸ(CA Ⅸ)和乏氧诱导因子-1α(HIF-1α)mRNA的表达变化,并对组织基因表达变化的可能机制进行探讨。方法 建立Lewis肺癌模型,将32只成瘤小鼠随机分为对照组(Control组)、恩度组(ES组)、放射治疗组(RT组)和恩度联合放疗组(ES+RT组),从治疗当天开始,隔日测量肿瘤体积,绘制肿瘤生长曲线。治疗结束后剥离瘤体,使用Real-time PCR方法对各处理组肿瘤组织中CA Ⅸ及HIF-1α mRNA的表达情况进行检测。结果 从肿瘤生长曲线可以看出:ES+RT组与其余三组比较差异有统计学意义(P＜0.05),说明联合组抑瘤效果最好。以对照组为参照,ES组、RT组、ES+RT组CA Ⅸ mRNA的扩增倍数均下降,差异均有统计学意义(P＜0.05),ES+RT组下降最明显。以对照组为参照,ES组、RT组、ES+RT组的HIF-1α mRNA扩增倍数均下降,RT组、ES+RT组具有统计学意义(P＜0.05),ES组差异并无统计学意义(P＞0.05)。HIF-1α mRNA与CA Ⅸ mRNA表达呈正相关(r=0.68,P＜0.01)。结论 恩度联合放疗显著抑制Lewis肺癌小鼠肿瘤的生长;同时能够改善肿瘤乏氧状况,抑制HIF-1α和CA Ⅸ mRNA的表达,可能是放疗增敏作用的机制之一。     

恩度联合经肝动脉化疗栓塞治疗原发性肝癌患者的临床疗效及对患者血管新生的影响

目的:探究原发性肝癌行恩度联合经肝动脉化疗栓塞（TACE）治疗的临床疗效及对血管新生的影响。方法:选取2015年5月至2017年5月本院收治的原发性肝癌患者86例为研究对象。按随机数表法分患者为两组,对照组（n=43）行单纯TACE治疗,研究组(n=43)行恩度联合TACE治疗。观察两组临床疗效,血清基质金属蛋白酶-9（MMP-9）、血管内皮生长因子（VEGF）、骨桥蛋白（OPN）水平,血管新生控制情况及不良反应发生率。结果:研究组临床治疗有效率为72.09%,高于对照组51.16%（P＜0.05）。治疗后研究组血清MMP-9、VEGF、OPN水平相比治疗前差异无统计学意义（P＞0.05）,而对照组水平均相比治疗前升高（P＜0.05）,且均高于研究组（P＜0.05）。研究组新生血管控制情况优于对照组（P＜0.05）,不良反应发生率（18.60%）与对照组（23.26%）相比差异无统计学意义（P＞0.05）。结论:恩度联合TACE治疗原发性肝癌可明显稳定MMP-9、VEGF、OPN水平,抑制血管新生,疗效确切,安全可靠。     

Modulatory effects of acetazolomide and dexamethasone on temozolomide-mediated apoptosis in human glioblastoma T98G and U87MG cells

Acetazolomide (ACZ) and dexamethasone (DXM) alleviate vasogenic edema and inflammation in glioblastoma patients. Temozolomide (TMZ) is used for treating glioblastoma. We compared modulatory effects of ACZ and DXM on TMZ mediated apoptosis in human glioblastoma T98G and U87MG cells. Cells were treated with drug(s) for 6 h and then left in drug-free medium for 48 h. Although ACZ or DXM alone did not induce apoptosis, TMZ alone induced significant amount of apoptosis. Interestingly, ACZ pretreatment enhanced apoptosis while DXM pretreatment decreased apoptosis. These results suggest that combination chemotherapy with ACZ and TMZ may control inflammation and enhance apoptosis in glioblastoma.     

重组人血管内皮抑制素联合EP方案对小细胞肺癌细胞株NCI-H446的增殖抑制和促细胞凋亡作用

目的:本研究旨在评估依托泊苷(etoposide,VP-16)、顺铂(cisplatin,DDP)(EP方案)联合重组人血管内皮抑制素对小细胞肺癌(small-cell lung cancer,SCLC) NCI-H446细胞的促凋亡和抑制细胞增殖的协同作用.方法:EP方案、重组人血管内皮抑制素单药以及EP方案联合重组人血管内皮抑制素作用于NCI-H446细胞72 h后,采用CCK-8(cell counting kit-8)法测定药物对NCI-H446细胞的增殖抑制作用,FCM检测药物对NCI-H446细胞的细胞周期分布的影响,ELISA法检测药物对NCI-H446细胞分泌血管内皮细胞生长因子(vascularendothelial cell growth factor,VEGF)水平的影响.结果:EP方案联合重组人血管内皮抑制素的细胞增殖抑制率明显高于EP方案组(P＜0.01).EP方案组和EP方案联合重组人血管内皮抑制素组的NCI-H446细胞大多被阻滞于G1期,EP方案联合重组人血管内皮抑制素组的NCI-H446细胞凋亡率显著高于EP方案组(P＜0.01).与EP方案和重组人血管内皮抑制素单药相比,EP方案联合重组人血管内皮抑制素可显著抑制NCI-H446细胞分泌VEGF(P＜0.05).结论:EP方案联合重组人血管内皮抑制素在抑制SCLC NCI-H446细胞增殖和促细胞凋亡方面,具有协同作用.     

Combined therapeutic effects of vinblastine and rapamycin on human neuroblastoma growth, apoptosis, and angiogenesis.

PURPOSE: Vinblastine and rapamycin displayed synergistic inhibition of human neuroblastoma-related angiogenesis. Here, we studied the antitumor activity of vinblastine and rapamycin against human neuroblastoma. EXPERIMENTAL DESIGN: Cell proliferation, cell cycle progression, and apoptosis were evaluated by measuring (3)H-thymidine incorporation, bromodeoxyuridine uptake, and phosphatidylserine exposure, respectively. The in vivo sensitivity of neuroblastoma cells to vinblastine and rapamycin was determined in orthotopic neuroblastoma-engrafted mice. Angiogenesis was assessed by the chick embryo chorioallantoic membrane assay. RESULTS: Each compound alone was able to induce a dose-dependent significant inhibition of cell proliferation, with a dramatically enhanced antiproliferative effect for the drugs used in combination. A marked G(2)-M cell cycle arrest with a nearly complete depletion of S phase was associated. The combined treatment triggered an increased apoptosis compared with either drug tested alone. A significant inhibition of tumor growth and microvessel area was obtained in neuroblastoma-bearing mice when treated with vinblastine or rapamycin alone, and a more dramatic effect with the combined treatment, compared with control mice. The therapeutic effectiveness, expressed as increased life span, was statistically improved by the combined therapy, compared with mice treated with either drug tested separately. Histologic evaluation of primary tumors showed that the combined treatment inhibited proliferation and angiogenesis and induced apoptosis. Combined treatment of neuroblastoma cells and neuroblastoma-bearing mice with vinblastine and rapamycin induced the down-modulation of both vascular endothelial growth factor production and vascular endothelial growth factor receptor 2 expression. In the chorioallantoic membrane assay, angiogenesis induced by human neuroblastoma biopsy specimens was significantly inhibited by vinblastine and rapamycin. CONCLUSIONS: These results may be relevant to design new therapeutic strategies against neuroblastoma.     

大剂量地塞米松联合硼替佐米及沙利度胺治疗多发性骨髓瘤合并肾衰竭的临床研究

 【摘要】　目的　观察以大剂量地塞米松为基础的常规化疗加用硼替佐米及沙利度胺治疗后对多发性骨髓瘤合并急性肾衰竭患者的影响。方法　对23例伴肾衰竭的新发骨髓瘤患者均采用大剂量地塞米松加用硼替佐米和沙利度胺治疗,观察患者在用药前后肾损害的改善情况。结果　严重肾衰竭的12例患者中逆转1例,好转6例,总有效率58.3 %;肾衰竭的11例患者中逆转4例,好转5例,总有效率81.8 %。全部病例总有效率69.5 %（16／23）。对原发病骨髓瘤治疗总有效率60.9 %（14／23）。中位显效时间为2个月（1～5个月）。3年总体生存率为56.5 %,中位生存期34.4个月。结论　大剂量地塞米松联合硼替佐米和沙利度胺对新发骨髓瘤患者的肾衰竭逆转率高,对原发病治疗效果较好,不良反应少、安全可靠、见效快,可作为一线治疗用药。     

Combined antitumor effects of TNF and G-CSF on a human medulloblastoma xenograft line

Summary The antitumor effects of TNF and G-CSF on a xenograft line of human medulloblastoma were examined. (Method): 1) A human medulloblastoma xenograft line was transplanted into nude mice. Tumor bearing nude mice were divided into the following eight groups: untreated controls (C); those receiving a subcutaneous injection of G-CSF for one week (G1); for four weeks (G2); those receiving an intratumoral injection of TNF for four weeks (Tit); an intravenous injection of TNF (Tiv); those receiving a combination of G1 and Tit (G1 + Tit); a combination of G2 and Tit (G2 + Tit); and a combination of G2 and Tiv (G2 + Tiv). The relative tumor weight in each group was calculated and any antitumor effects were examined by calculating a tumor growth inhibition ratio. 2) Tumor bearing nude mice were divided into the following two groups: those receiving a subcutaneous injection of G-CSF and an intravenous injection of TNF (G + T); and only an intravenous injection of TNF (T). We evaluated the pathological findings from the tumors at 0 h, 0.5 h, 1 h, 3 h, 6 h, 12 h, 24 h and 48 h after the TNF injection. Routine H.E. staining and immunostaining using antigranulocyte and antimacrophage antibodies were performed. (Results): 1) The tumor growth inhibition ratio was 0.112, 0.190, 0.287, 0.451, 0.347, 0.635, and 0.622 at G1, G2, Tit, Tiv, G1 + Tit, G2 + Tit, G2 + Tiv group. A combined antitumor effect was clearly seen in the G2 + Tit and the G2 + Tiv groups. 2) The tumor was fragmented by the infiltration of many inflammatory cells 24 hours after TNF injection. Many more macrophages were observed in the tumors of G + T mice than in the T mice. Granulocytes were observed only in the tumors of the G + T mice.     

Combination effects of TAS-103, a novel dual topoisomerase I and II inhibitor, with other anticancer agents on human small cell lung cancer cells

Purpose: TAS-103 [6-((2-(dimethylamino) ethyl)amino)-3-hydroxy-7H-indeno(2,1-c)quinolin-7-one dihydrochloride] is a newly synthesized dual inhibitor of topoisomerase I and II. Since anticancer drugs are used in combination with other drugs for effective chemotherapy, we investigated the cytotoxic effect of TAS-103 in combination with other conventional anticancer agents, such as cisplatin, vindesine, doxorubicin, 5-fluorouracil, and the antitopoisomerase inhibitors SN-38 and etoposide in vitro. Methods: Inhibition of the growth of the human small-cell lung cancer cell line SBC-3 was evaluated using the tetrazolium dye (MTT) assay. Drug interactions were evaluated by isobologram analysis and the determination of combination indices supplemented by a three-dimensional model. Results: Simultaneous use of TAS-103 and cisplatin had a supradditive effect, but combinations of TAS-103 with other drugs had an additive or marginally subadditive effect. Three-dimensional model analysis added more information about the synergistic concentration ranges of two drugs (cisplatin 200–400 nM and TAS-103 7–10 nM). Sequential use of TAS-103 and cisplatin had only an additive effect. Conclusion: These results suggest that the concomitant use of TAS-103 and cisplatin has a greater cytotoxic effect on cancer cells than single drug use, and may provide a beneficial effect in the treatment of small-cell lung cancer. Received: 23 March 1998 / Accepted: 15 September 1998     

Anti-cancer effects of a novel compound HS-113 on cell growth, apoptosis, and angiogenesis in human hepatocellular carcinoma cells

Hepatocellular carcinoma (HCC) is one of the most common malignancies, yet there have been no significant advances in effective therapeutics. In this study, HS-113 was synthesized as a novel compound, N-(5-(2-bromobenzyl) thiazole-2-yl) benzofuran-2-carboxamide and its cytotoxic activity and anti-cancer effect were examined in human HCC cells. HS-113 strongly suppressed growth of HCC cells in a dose-dependent manner, induced apoptosis by increasing the proportion of sub-G1 apoptotic cells, and caused cell cycle arrest at G0/G1 phase. Also, HS-113 increased the expression of p27 and decreased that of cyclin D1 associated with cell cycle arrest. Apoptosis by HS-113 was confirmed by DAPI and TUNEL staining, and the increases of the cleaved PARP and caspase-3 were observed. Furthermore, HS-113 decreased protein expression of HIF-1α and secretion of VEGF, and inhibited the tube formation of HUVECs. These results showed that HS-113 not only inhibited cell growth and angiogenesis, but also induced apoptosis of human HCC cells. We suggest that HS-113 may be a potential candidate for cancer therapy against HCC.