人卵巢腺癌原位移植与皮下种植裸小鼠模型的对比研究

目的建立人卵巢腺癌裸小鼠皮下和原位移植瘤及其自发转移瘤模型,比较其生物学特性。方法利用高转移卵巢腺癌细胞株HO8910先制备裸小鼠皮下种植瘤模型,然后将瘤组织运用显微外科的方法植入裸鼠右侧卵巢包膜内,原位移植成功后继续在鼠间卵巢包膜内传代,用组织病理学、电镜及染色体核型分析验证模型,并比较2种模型在生物学特性上的差异。结果小鼠皮下与卵巢原位成瘤率均为100%(分别为3/3和10/10),原位移植瘤转移率为50%,转移开始出现时间2周。卵巢包膜间传代,平均第2～4代出现卵巢癌的脏器转移。2组荷瘤鼠中位生存时间分别为(28.000±1.095)d和(40.000±0.894)d,差异有统计学意义(P0.05);2种模型的组织形态和超微结构类似,均显示人类染色体的特点;免疫组化均表达CA125、CK抗体。结论 2种模型均展现了人卵巢腺癌的生物学特点,其中原位移植瘤模型是研究卵巢腺癌的良好平台和抗癌药物筛选更客观的模型。     

视黄酸在体内外对胃癌细胞转移及其相关蛋白的影响

目的:从体内外探讨全反式视黄酸(ATRA)对人胃癌细胞转移及其相关蛋白影响.方法:胃癌细胞接种到裸鼠脾包膜,每隔两天灌胃给予ATRA 0.7 mg/kg,6周后处死裸鼠,取出所有在脾和肝形成的肿瘤,一些肿瘤被固定和包埋,另一些肿瘤保存在液氮中用于后续实验.用蛋白质印迹法测定蛋白水平;通过免疫组化显示微血管;采用粘附实验测定细胞粘附能力.结果:ATRA灌胃后,脾移植瘤和肝转移瘤受到明显抑制(50％),血管生成也受到抑制.尽管ATRA在体内外调节nm23和mts1/p16蛋白的方式不同,但高比值的nm23:mtsl/p16与低粘附性相关.ATRA在体内外诱导ICAM-1蛋白表达.结论:ATRA显著抑制移植瘤生长及其向肝转移,这一过程可能与对转移相关蛋白nm23,mstl/p16和ICAM-1的调控有关.     

阿霉素对裸小鼠人肝癌原位移植瘤多药耐药性的影响

目的　探讨阿霉素对裸小鼠原位移植人肝癌多药耐药性的影响 ,并研究其耐药机制。方法　人肝癌 (BEL 740 2 )裸小鼠原位移植 ,用阿霉素腹腔注射诱导耐药 ,经MTT法检测原代培养的耐药细胞对抗癌药的敏感性 ,以流式细胞仪检测癌细胞表面mdr1基因产物P170的表达及功能。以裸小鼠原位移植人肝癌模型观察阿霉素对耐药组的疗效。结果　移植瘤组织形态及生物学方面符合人肝癌特征 ,耐药细胞表面P170表达为 75 45 %± 5 6 7% ,而对照组表达仅 4 2 5 %± 1 2 8% (P <0 0 1) ,对阿霉素的耐药倍数提高了 16 7倍 ,对羟基喜树碱和表阿霉素具有交叉耐受性(13 7倍和 7 5倍 )。耐药细胞表面P170有较强的药物外排功能。诱导后的肝癌在体内对阿霉素获得了明显的抗性。结论　阿霉素较易诱导原位移植于裸小鼠的人肝癌多药耐药性的产生 ,耐药机制主要与P170的过度表达有关     

SarCNU治疗荷人脑胶质瘤裸小鼠模型NHG—1的疗效观察

为探讨新型抗癌药SarCNU治疗人脑胶质瘤的疗效，采用腹腔给药，观察荷皮下和脑内胶质瘤裸小鼠模型体内肿瘤生长情况。结果：SarCNU能显著抑制肿瘤生长，延长荷瘤动物生存期。SarCNU与BCNU和VM26相比，具有更强的抑制肿瘤生长作用。     

放线菌素23—21对人低分化鼻咽癌细胞系裸小鼠移植瘤的抑制作用

采用人低分化鼻咽癌细胞系裸小鼠移植瘤模型,研究了放线菌素23-21的抗瘤作用。结果表明放线菌素23-21的50μg/kg(LD_(50) 1/10)抑瘤率为58％(p<0.05)。光电镜检查,给药组瘤细胞严重变性坏死,且引起核仁分离和微球体形成的超微结构变化。说明放线菌素23-21能抑制人低分化鼻咽癌细胞系裸小鼠移植瘤的生长,提示放线菌素23-21可能有抑制核仁rRNA合成的作用。     

云芝糖肽对裸鼠人肺腺癌抗癌作用的研究

ＰＳＰ（ｐｏｌｙｓａｃｃｈｉｄｅ－ｐｅｐｔｉｄｅ）是一种新型的免疫调节剂，经理化分析表明同日本产的ＰＳＫ（Ｋｒｅｓｔｉｎ）相一致。本研究证明．ＰＳＰ１～２ｇ·ｋｇ－１连续口服给药１５～２０ｄ，对裸鼠人肺腺癌有明显的抑制作用，抑制率为５０％～７０％。在抑制肿瘤生长的同时，未见有血液系统和体重方面的变化。放射免疫法测定表明ＰＳＰ不会引起血浆ＣＡＭＰ和ＣＧＭＰ水平的改变，提示其抗癌机制可能与环核苷酸系统无关。     

罗格列酮增强顺铂对肺腺癌裸鼠移植瘤生长的抑制作用

目的观察罗格列酮(ROZ)和顺铂(DDP)合用对人肺腺癌A549细胞裸小鼠移植瘤生长的抑制作用,并初步探讨其作用机制。方法采用A549细胞株建立人肺腺癌裸鼠模型,将28只成瘤雌裸小鼠随机分成7组:①对照组(生理盐水0.2ml);②DDP低剂量组(1mg.kg-1);③DDP高剂量组(4mg.kg-1);④ROZ低剂量组(10mg.kg-1);⑤ROZ高剂量组(30mg.kg-1);⑥DDP低剂量组+ROZ低剂量组;⑦DDP低剂量组+ROZ高剂量组,隔天腹腔注射给药,共8次。于最后一次给药后48h处死各组小鼠,收集瘤标本行光镜观察,免疫组化检测PPARγ、PTEN和pAkt蛋白表达情况。结果①各实验组肿瘤的生长明显受到抑制,瘤质量明显低于对照组(P<0.01)。低、高剂量ROZ联合用药组较低剂量顺铂组抑瘤作用明显增强(P<0.05),其瘤重抑制率分别为52.11%和83.8%。②免疫组化:低、高剂量罗格列酮组与对照组比较,PPARγ、PTEN的表达上调,而pAkt的表达呈现下调,差异具有显著性(P<0.05),联合用药组该调节作用进一步增强(P=0.00)。③不良反应:高剂量顺铂组出现不良反应,其余各组无明显不良反应。结论罗格列酮能够增强顺铂对人肺腺癌A549细胞裸鼠移植瘤生长的抑制作用,其作用机制可能与罗格列酮激活PPARγ,上调PTEN的表达和抑制pAkt的表达有关。     

聚乙二醇干扰素α-1b对荷ACHN肿瘤裸鼠的治疗作用

目的：比较不同剂量聚乙二醇干扰素α-1b（PEG IFN α-1b）对荷人肾腺癌细胞（ACHN）瘤裸鼠的治疗效果。方法：制备荷ACHN瘤鼠模型，分溶剂对照及PEG IFNα-1b 50，150和300μg组。给药组每只鼠每周1次皮下注射不同剂量的PEG IFN α-1b，溶剂对照组注射等体积溶剂，连续5周给药。每周1次测量肿瘤体积和动物体重，第5周末取肿瘤测其体积与重量。结果：第5周末各组肿瘤体积分别为给药前的258．9％，152．0％，95．5％和67．5％，三个给药组按肿瘤重量计算肿瘤抑制率分别为28．91％，37．68％和49．53％（P〈0．05）。结论：每周1次，连续5周皮下注射PEG IFN α-1b可以显著抑制ACHN荷瘤裸鼠肿瘤的生长，其中300μg剂量组的效果最好。     

The antitumor effects of IFN- beta against human renal cell carcinoma in athymic nude mice

IFN-beta was more active than recombinant interferon-alpha (rIFN-alpha) and interferon-gamma (rIFN-gamma) in a human renal cell carcinoma transplanted in nude mice. In 3 out of 5 mice, the tumor completely disappeared and viable tumor cells were not observed at a daily dose of 5 x 10(5) U/mouse. Combination with anti-asialo GM1 antibody did not influence the tumor growth inhibition by IFN-beta. Mononuclear cells around damaged cancer cells were found not to be macrophages. Although the role of mononuclear cells remained unknown, the antitumor activity of IFN-beta seemed to depend on its direct cellular action. IFN-beta may be a useful agent in some renal cell carcinomas.     

胃癌细胞株MKN-45裸鼠移植瘤模型的建立与应用

目的建立低分化高转移性胃癌细胞株MKN-45裸鼠移植瘤模型,并观察该移植瘤对抗癌药物的敏感性。方法 5×106个MKN-45胃癌细胞接种于裸鼠右侧胁部脂肪垫下,观察成瘤情况。接种2周后,分别将荷瘤小鼠分为生理盐水对照组与化疗药物组,其中化疗药物组给予1 mg·kg-1紫杉醇与5 mg·kg-1氟尿嘧啶,1周1次,连续3周;生理盐水对照组则给予生理盐水。实验结束后采用HE染色观察移植瘤病理组织学特点,采用免疫组化法检测移植瘤的核增殖抗原Ki-67与波形蛋白(vim-entin)及钙黏蛋白(E-cadherin)表达情况。结果接种的12只裸鼠均荷瘤成功,且移植瘤成瘤时间早,肿瘤大小及形状较一致,并保持了原发肿瘤vimentin高表达与E-cadherin低表达等重要的生物学特征。使用临床抗癌药物紫杉醇与氟尿嘧啶联合处理3周,结果与生理盐水对照组相比,化疗组肿瘤生长速度明显放缓,肿瘤体积明显缩小,肿瘤组织Ki-67表达下降,新生血管减少,肿瘤细胞凋亡明显,但vimentin与E-cadherin表达变化不明显。结论胃癌细胞株MKN-45裸鼠移植瘤模型建立成功,为开展胃癌发病机制及治疗药物药理作用等研究提供了理想的实验平台。     

姜黄素对A549裸鼠移植瘤影响的网状Meta分析

目的：评价姜黄素对A549裸鼠移植瘤影响。方法：系统检索主要中文数据库,纳入数据库中有关姜黄素对A549裸鼠移植瘤影响的动物实验,采用SYRCLE动物实验风险评估工具评价纳入研究质量,STATA13.0软件对数据进行合并分析。结果：共纳入7个研究,网状Meta分析结果显示,与空白相比姜黄素能够减轻瘤重,缩小肿瘤体积,降低肿瘤微血管密度,在姜黄素基础上,加用顺铂可以增加疗效。结论：姜黄素对A549肺癌细胞裸鼠移植瘤的生长具有明显抑制作用。     

Teratogenic drugs inhibit the differentiation of fetal rat limb buds grafted in athymic (nude) mice

Forelimb buds of day-14 rat fetuses were cut into pieces and transplanted subcutaneously into athymic (nude) mice. On the 7th, 9th, and 11th days after grafting, the nude mice were treated with various drugs including rat teratogens. On the 20th day, the grafted tissue was examined macroscopically and histologically. While control grafts showed substantial growth and tissue differentiation similar to that observed in vivo, the differentiation of grafts was significantly inhibited by the treatment with 5-fluorouracil, cyclophosphamide, hydroxyurea, cycloheximide, mitomycin C, caffeine, aspirin, retinol palmitate, all-trans-retinoic acid, and ascorbic acid. Hydrocortisone, tetracycline, and thalidomide did not adversely affect the differentiation of grafts. Thus, the susceptibility of transplanted rat limb buds was generally close to the teratologic sensitivity of rat fetuses in vivo. The heterotransplantation method of embryonic tissues may be useful as a new experimental system in developmental toxicology.     

Therapeutic trends in pancreatic ductal adenocarcinoma (PDAC)

Introduction: Prognosis remains dismal for pancreatic ductal adenocarcinoma (PDAC). Genomics and proteomics have depicted heterogeneity in PDAC. Collectively, this information could be useful in improving diagnosis, prognosis, modalities of therapy, treatment responses, deciphering drug resistance and new drug development.

Areas covered: We describe major advances in the cellular and molecular subtypes based on next-generation sequencing and their predictive and prognostic value in PDAC patients. We review aberrant genes involving in defined cellular processes in PDAC. Finally, the current state of drug development with novel investigational agents targeting cell fate, cell survival, genomic instability, tumor-stroma, and immune checkpoints are discussed.

Expert opinion: Molecular techniques have revealed distinct driver mutations in PDAC. Common genes and cellular processes are dysregulated in the pathogenesis of PDAC. These cellular processes categorized by aberrant pathways include control cell fate, genome maintenance, and cell survival. Dysregulation of the tumor microenvironment promotes an intense fibrosis and immune suppression that play a major role in drug resistance. New information on tumor biology has led to the development of targeted/stromal therapies, immunotherapies or combinations with current chemotherapy in PDAC. New drug development targeting multiple hallmarks of PDAC we hope will positively impact the quality and survival of PDAC patients.