阿霉素预处理的小鼠红白血病细胞降低红白血病细胞的成瘤性

目的: 研究阿霉素(ADM)处理的小鼠红白血病(MEL)细胞是否可以发生免疫原性死亡,预先输注此细胞是否可以降低MEL细胞在昆明(KM)小鼠体内的成瘤性。方法: 用ADM诱导MEL细胞发生约70%凋亡率,即发生免疫原性死亡。 30只KM小鼠分3组,分别为小鼠红白血病模型组(模型组)、ADM诱导治疗组(ADM组)和空白对照组(对照组)。模型组经尾静脉输注PBS给KM小鼠,8 d后输注MEL细胞1×10⁶/只;ADM组经尾静脉输注ADM处理的MEL细胞给KM小鼠,9×10⁶/只,8 d后输注MEL细胞1×10⁶/只;对照组未行任何人为干预。观察各组小鼠的生存时间、濒死或第80 d 时外周血白细胞数目和体重。结果: 在体外使用4 mg/L 阿霉素作用于MEL细胞24 h后,诱导MEL细胞约70%凋亡率,发生了免疫原性死亡。在小鼠体内,观察80 d,对照组小鼠全部存活, 模型组全部成瘤死亡,ADM组有1只长期生存。ADM组与模型组相比较,生存时间延长(P<0.01),濒死或第80 d 时外周血白细胞数目降低(P<0.01),濒死或第80 d 时体重增加(P<0.01)。结论: 将发生免疫原性死亡的MEL细胞预先输注到KM小鼠体内,KM小鼠产生抗肿瘤免疫应答,降低了活性MEL细胞在KM小鼠体内的成瘤性,改善KM小鼠生存时间和生存质量。     

脂质体阿霉素对人鼻咽癌HNE-1细胞株增殖与凋亡作用的研究

目的:研究脂质体阿霉素对人鼻咽癌HNE-1细胞株增殖抑制和凋亡作用的影响.方法:本研究以人鼻咽癌HNE-I细胞株为研究对象,以游离阿霉素为对照,用四甲基偶氮唑蓝(MTT)法测定脂质体阿霉素对HNE-1的细胞毒作用;分别采用倒置显微镜和TUNEL法检测脂质体阿霉素作用于HNE-1细胞后细胞凋亡的形态学变化和细胞凋亡率.结果:脂质体阿霉素对HNE-1细胞的IC50是游离阿霉素的1/3倍;与游离阿霉素组相比较,倒置显微镜观察脂质体阿霉素组,发现该实验组细胞出现细胞凋亡形态学变化;脂质体阿霉素和游离阿霉素分别作用于HNE-1细胞的凋亡指数分别为11.27%±0.33%、43.57%±3.14%.结论:本实验研究显示,与游离阿霉素相比较,脂质体阿霉素对人鼻咽癌HNE-1细胞株具有较好的体外增殖抑制作用,能够诱导HNE-1细胞凋亡.     

阿霉素对大鼠肺缺血再灌注损伤的保护作用

目的观察阿霉素对大鼠肺缺血再灌注损伤(LIRI)的保护作用及其可能的机制。方法建立大鼠在体肺缺血再灌注模型。将健康Wistar大鼠54只随机分为手术对照组(C组)、缺血再灌注组(IR组)、阿霉素组(A组)。每组分别在缺血45min,再灌注60、120min3个时点处死6只大鼠,留取血浆和右肺组织,测定血清丙二醛(MDA)含量、肺组织干湿质量比值(D/W)、髓过氧化物酶(MPO)活性及肺组织中细胞凋亡指数(AI),并进行肺组织病理学检查。结果再灌注期间IR组MPO活性、AI、血清MDA升高,D/W降低,而预先给予阿霉素干预后可以减弱缺血再灌注诱导上述指标的变化。肺组织病理学检查显示阿霉素预先给药减轻肺缺血再灌注损伤。结论阿霉素对肺缺血再灌注损伤有保护作用,可能与其抑制氧自由基生成、中性粒细胞浸润及细胞凋亡有关。     

Adriamycin-induced interference with cardiac mitochondrial calcium homeostasis

Adriamycin (doxorubicin) is a potent and broad-spectrum antineoplastic agent, the clinical utility of which is limited by the development of a cumulative and irreversible cardiomyopathy. Although the drug affects numerous structures in different cell types, the mitochondrion appears to a principal subcellular target for the development of cardiomyopathy. This review describes evidence demonstrating that adriamycin redox cycles on complex I of the mitochondrial electron transport chain to liberate highly reactive free radical species of molecular oxygen. The primary effect of adriamycin on mitochondrial performance is the interference with oxidative phosphorylation and inhibition of ATP synthesis. Free radicals liberated from adriamycin redox cycling are thought to be responsible for many of the secondary effects of adriamycin, including lipid peroxidation, the oxidation of both proteins and DNA, and the depletion of glutathione and pyridine nucleotide reducing equivalents in the cell. It is this altered redox status that is believed to cause assorted changes in intracellular regulation, including the induction of the mitochondrial permeability transition and complete loss of mitochondrial integrity and function. Associated with this is the interference with mitochondrial-mediated cell calcium signaling, which is implicated as essential to the capacity of mitochondria to participate in bioenergetic regulation in response to external signals reflecting changes in metabolic demand. If taken to an extreme, this loss of mitochondrial plasticity may manifest in the liberation of signals mediating either oncotic or necrotic cell death, further perpetuating the cardiac failure associated with adriamycin-induced mitochondrial cardiomyopathy.     

三羟异黄酮对MCF-7/ADM细胞阿霉素耐药性的逆转作用

目的:探讨三羟异黄酮(GEN)单用及联合阿霉素(ADM)对人乳腺癌MCF-7/ADM细胞耐药性的影响。方法:分别将不同浓度GEN(8、15、30、60μg/mL)和阿霉素单独及联合与人乳腺癌MCF-7/ADM细胞体外共培养48、72 h,MTT法检测细胞抑制率(IR),计算耐药倍数和逆转倍数。结果:MCF-7/ADM细胞相对敏感株MCF-7/S的耐药倍数48 h为117.15倍、72 h为54.42倍。当GEN单独作用后可抑制MCF-7/ADM细胞生长,抑制作用与时间、浓度呈正相关。25μg/mL GEN联合阿霉素对MCF-7/ADM细胞生长抑制率明显高于单用阿霉素(P<0.01),其逆转倍数为7.53倍。结论:GEN可抑制人乳腺癌MCF-7/ADM细胞生长,联合阿霉素对肿瘤细胞生长抑制具有协同作用,GEN能够逆转MCF-7/ADM细胞对阿霉素的耐药性。     

热疗用阿霉素温敏纳米粒的制备及工艺优化

目的:制备热疗用阿霉素温敏纳米粒,并对其制备工艺进行优化。方法:合成两亲性温敏嵌段共聚物P(NI-PAM-co-DMAAM)-b-PCL,在水溶液中自组装形成温敏纳米粒。用滴注法制备载药温敏纳米粒,以包封率为评价指标,通过正交设计对温敏纳米粒制备工艺中温敏嵌段共聚物的浓度(A)、水相中阿霉素的浓度(B)、搅拌时间(C)等因素进行优化,对优化后工艺进行验证并在4℃下贮存90d考察其稳定性。结果:合成了两亲性温敏嵌段共聚物,其最低临界溶解温度(LCST)为40.3℃;最佳工艺为A0.15mg.mL-1、B0.045mg.mL-1、C1h,3批制剂的平均包封率为41.9,平均粒径(155±2.7)nm;90d内制剂外观、粒径和包封率无明显变化。结论:成功制备了阿霉素温敏纳米粒,且其制备工艺可行,质量稳定。     

CTOP和CHOP方案治疗外周T细胞淋巴瘤的临床随访分析

目的比较含吡喃阿霉素(THP)的CTOP方案与含阿霉素(ADM)的CHOP方案治疗外周T细胞淋巴瘤(PTCL)的疗效和不良反应。方法回顾性分析外周T细胞淋巴瘤临床特征,比较两种方案的不良反应、近期疗效和远期疗效。结果 29例PTCL中,可行疗效评估的25例,其中CTOP组14例,CHOP组11例;中位随访21.25个月。两组患者临床特征的均衡性比较好。CTOP组和CHOP组的总有效率、完全缓解率分别是78.6%和72.7%(P>0.05)、57.1%和54.5%(P>0.05),3,5年总生存率分别为57.7%和46.3%、32.1%和22.1%(P=0.012),CTOP组有好转趋势。25例患者共接受169个疗程化疗。骨髓抑制为主要不良反应,但两组差异无显著性(P>0.05),CHOP组心脏毒性、脱发、呕吐发生率明显高于CTOP组(P<0.05)。结论采用含THP的CTOP治疗PTCL疗效好,毒性较低,远期生存率较高,尤其对老年PTCL值得临床进一步研究。     

Apoptosis, autophagy, accelerated senescence and reactive oxygen in the response of human breast tumor cells to Adriamycin

Although the primary response to Adriamycin (doxorubicin) in p53 mutant MDA-MB231 and p53 null MCF-7/E6 breast tumor cells is apoptotic cell death, the residual surviving population appears to be in a state of senescence, based on cell morphology, beta galactosidase staining, induction of p21^waf1/cip1 and down regulation of cdc2/cdk1. Suppression of apoptosis in MDA-MB231 and MCF-7/E6 cells treated with Adriamycin using the broad spectrum caspase inhibitor, zvad-Fmk, results in substantial induction of autophagy. Overall sensitivity to Adriamycin, measured by clonogenic survival, is not altered in the cells undergoing autophagy, consistent with autophagy contributing to cell death in response to Adriamycin. The free radical scavengers, glutathione and N-acetyl cysteine attenuate the accelerated senescence response to Adriamycin in MCF-7 cells as well as in MDA-MB231 and MCF-7/E6 cells, but protect primarily the MCF-7 cells, indicating that reactive oxygen is unlikely to be directly responsible for Adriamycin toxicity in breast tumor cells. Expression of caspase 3 or induced expression of c-myc in MCF-7 cells fails to abrogate accelerated senescence induced by Adriamycin. Taken together, these studies suggest that accelerated senescence induced by Adriamycin is similar in cells with wild type p53 and in cells lacking functional p53 with regard to the upregulation of p21^waf1/cip1, down regulation of cdc2 and the involvement of reactive oxygen species. Furthermore, accelerated senescence, autophagy and apoptosis all appear to be effective in suppressing self-renewal capacity in breast tumor cells exposed to Adriamycin.     

黄芪甲甙对阿霉素心肌损伤的保护作用的研究

目的研究黄芪甲甙对阿霉素心肌损伤的保护作用。方法30只SD大鼠随机分为3组,对照组(C组),阿霉素组(ADR组),阿霉素+黄芪甲甙组(ADR+黄芪组)。观察大鼠心率和肝、肺干湿重比变化,检测心肌铜-锌-超氧化物歧化酶(CuZn-SOD)活力,半定量聚合酶链反应测定心肌CuZn-SOD基因表达及bcl-2,bax基因表达。结果与ADR组比较,ADR+黄芪组心率变化率明显下降(P<0.05),肝、肺干湿重比明显上升(P<0.05),心肌铜-锌-超氧化物歧化酶活力明显提高(P<0.05),铜-锌-超氧化物歧化酶基因表达增加(P<0.05),bcl-2基因表达增加而bax基因表达下降。结论黄芪甲甙对阿霉素心肌损伤有保护作用,其机制可能与其抑制氧化应激从而抑制心肌细胞凋亡有关。     

不同麻醉方法对阿霉素化疗后心肌影响的研究

目的研究阿霉素(adriamycin,ADM)化疗大鼠围麻醉期CK(肌酸激酶)、CKMB(肌酸激酶同功酶)和病理变化,探讨围麻醉期心肌损伤的程度与规律。方法32只大鼠随机分成A、B、C、D4组。A、B组:腹腔注射(ip)ADM;C、D组:ip相同容积的生理盐水。最后一次注药后3d实施麻醉:A、C组选择异氟醚麻醉;B、D组选择戊巴比妥钠麻醉。结果四组CK、CKMB值麻醉前或后均无显著差异,麻醉前后配对相比亦无显著差异。心肌病理改变:A、B组见心肌细胞变性、坏死,C、D组结果正常。四组心肌组织病理评分有显著差异(P<0.01)。结论不同麻醉方法对阿霉素化疗后心肌影响不同,异氟醚组心肌损伤较轻,而戊巴比妥钠组损伤严重,异氟醚更适合化疗后心肌损伤的麻醉。