塞来昔布联合奥沙利铂对人结肠癌裸鼠移植瘤生长的抑制作用

目的 观察塞来昔布或联合奥沙利铂对人结肠癌裸鼠移植瘤生长的影响并探讨其机制.方法 用人结肠癌HT-29细胞建立移植瘤模型,将裸鼠随机分为对照组、奥沙利铂组、塞来昔布组、联合用药组.给予相应药物35 d后,取移植瘤组织检测COX-2,VEGF mRNA和微血管密度.结果 塞来昔布组、奥沙利铂组和联合用药组抑瘤率分别为34.94%、30.53%和62.87%.奥沙利铂组COX-2,VEGF表达显著高于对照组(分别P＜0.05).奥沙利铂组微血管密度与对照组比较差异无统计学意义(P＞0.05).塞来昔布组和联合用药组COX-2,VEGF和MVD与对照组比较均显著下降(分别P＜0.05).结论 塞来昔布可抑制人结肠癌裸鼠移植瘤的生长和肿瘤血管生成.塞来昔布增加了奥沙利铂的抗肿瘤效果.     

塞来昔布联合依维莫司对恶性嗜铬细胞瘤裸鼠移植瘤的抑制作用

目的本研究通过观察环氧合酶2(Cox-2)抑制剂塞来昔布与哺乳动物雷帕霉素靶蛋白(mTOR)抑制剂依维莫司对大鼠嗜铬细胞瘤细胞PC12的裸鼠移植瘤生长的影响,探讨依维莫司对大鼠嗜铬细胞瘤肿瘤生长和血管生成的抑制作用。方法用大鼠嗜铬细胞瘤细胞PC12接种于裸鼠皮下,建立移植瘤模型,15d后将荷瘤裸鼠随机分为4组,每组12只,分别为依维莫司组(依维莫司灌胃1mg/kg)、塞来昔布组(塞来昔布100mg/kg灌胃)、联合组(依维莫司1mg/kg+塞来昔布100mg/kg灌胃)、对照组(生理盐水灌胃10mL/kg),用药3周,第4周后测量裸鼠移植瘤的体积变化以及裸鼠的生存时间,采用免疫组化方法检测肿瘤组织中血管内皮生长因子(VEGF)的表达,采用Western blotting法检测肿瘤组织中VEGF的表达。结果第4周时移植瘤体积:对照组为(4 159.72±651.84)mm3,依维莫司组为(2 816.49±332.05)mm3,塞来昔布组为(4 018.38±527.46)mm3,联合组为(1 035.28±177.30)mm3,联合组与前3组均存在显著性差异(P0.01)。平均生存时间:对照组(23.3±2.8)d,依维莫司组(36.8±3.6)d,塞来昔布组(26.4±2.4)d,联合组(45.9±4.5)d,用Kaplan-meier,Log-rank方法分析,联合组与前三组的生存函数的差异有统计学意义(P0.05)。实验组肿瘤组织的VEGF表达明显低于对照组(P0.05)。结论塞来昔布联合依维莫司对大鼠嗜铬细胞瘤裸鼠移植瘤有明显抑制作用,并可降低肿瘤组织中VEGF的表达。     

塞来昔布联合HMG-CoA还原酶抑制剂对人肝癌裸鼠皮下移植瘤生长的影响

目的探讨选择性环氧化酶-2(Cyclooxygenase-2,COX-2)抑制剂塞来昔布(celecoxib)联合HMG-CoA还原酶抑制剂氟伐他汀(fluvastatin)对实验性人肝癌裸鼠皮下移植瘤生长的影响。方法接种BEL-7402肝癌细胞株的裸鼠,分别予以塞来昔布,氟伐他汀及联合用药,并对肿瘤生长进行评估。ki67免疫组化染色检测肿瘤细胞增殖,TUNEL法检测凋亡,免疫蛋白印迹法(Western blot)检测Akt、磷酸化Akt(p-Akt)蛋白的表达。结果联合应用塞来昔布及氟伐他汀明显抑制肿瘤生长,其机制可能与抑制肿瘤细胞增殖、诱导凋亡以及抑制Akt磷酸化有关。结论本研究表明塞来昔布及氟伐他汀联合用药可能更有效地治疗肝癌,为进一步防治肝癌提供了新的方法。     

塞来昔布对裸鼠结肠癌移植瘤放疗增敏作用的实验研究

为探讨环氧化酶2（COX～2）抑制剂塞来昔布对裸鼠结肠癌移植瘤放疗的增敏作用,本研究应用人结肠癌SW480细胞建立裸鼠移植瘤模型,并将32只裸鼠随机分为A组（对照组）、B组（塞来昔布组）、C组（放疗组）和D组（塞来昔布＋放疗组）。观察各组裸鼠结肠癌移植瘤的生长情况。结果显示,B、C、D组移植瘤的生长明显受到抑制,干预后期移植瘤瘤体质量及体积均明显小于A组,P〈0．05;而D组移植瘤瘤体质量和体积显著小于B、C组,P〈0．05。结果表明,塞来昔布不仅能抑制裸鼠结肠癌移植瘤的生长,而且具有放疔增敏作用。     

COX 2抑制剂对膀胱癌细胞株裸鼠成瘤的影响

目的探讨COX 2抑制剂对膀胱癌T24细胞株裸鼠成瘤性的影响。方法BALB/c裸鼠27只分为3组,每只皮下接种膀胱癌T24细胞5×106活细胞数建立移植瘤动物模型。COX 2抑制剂药物干预组（吲哚美辛、塞来昔布）采用喂饲途径,吲哚美辛3 mg/kg,塞来昔布10 mg/kg;对照组给予生理盐水溶液药物的投给。30 d 后处死裸鼠,取瘤块称重,测量肿瘤体积,行免疫组化、半定量RT PCR、Wester Blot检测移植瘤COX 2表达。结果对照组细胞接种裸鼠后第5天可见肿瘤长出,第7天各组均有肿瘤长出,第30天后用药组移植瘤生长较对照组明显减慢。免疫组化染色、RT PCR、Western blot 结果均显示对照组COX 2表达明显,而药物干预组均少量表达。结论选择性与非选择性COX 2抑制剂在实验中表现出良好的抗肿瘤特性。     

环氧化酶-2抑制剂联合放疗对人前列腺癌裸鼠移植瘤的作用

我们应用塞来昔布(Cdecoxib)联合放疗治疗人前列腺癌裸鼠皮下移植瘤模型,观察其抗肿瘤和放射增敏作用,探讨其协同抑制肿瘤作用的机制.     

塞来昔布对人结肠癌细胞生长及裸鼠肝转移瘤形成的影响

目的探讨塞来昔布对体外培养的结肠癌细胞生长及裸鼠肝转移瘤的影响。方法以人结肠癌细胞株HT-29（COX-2高表达）和HCT-116（COX-2低表达）为研究对象，采用噻唑蓝（MTT）比色法检测塞来昔布对2种细胞的增殖抑制效应，应用流式细胞术检测2种细胞的周期分布情况；将2种细胞接种裸鼠，观察其肝转移瘤形成情况。结果①塞来昔布对人结肠癌细胞株生长的抑制作用呈时间、剂量依赖性效应（P〈0．05，P〈0．01），且对HT-29细胞的作用强于HCT-116细胞（P〈0．05）。②塞来昔布可改变结肠癌细胞株细胞周期的分布，明显降低其增殖指数。③塞来昔布具有明显的抑制裸鼠肝转移瘤生长的作用。结论塞来昔布可能通过抑制COX-2酶活性而抑制结肠癌细胞的分裂和增殖，诱导其凋亡，干预结肠癌的转移与复发。     

PTEN真核表达质粒对人膀胱癌裸鼠移植瘤的抑制效应

目的:探讨PTEN真核表达质粒对人膀胱癌裸鼠移植瘤的抑制作用。方法:将人膀胱癌细胞株BIU-87裸鼠背部皮下接种,成瘤后于瘤内多点注射重组真核表达质粒pBp-PTEN,设pBp空质粒和生理盐水为对照,观察肿瘤生长情况、PTEN表达的变化。结果:pBp-PTEN治疗组肿瘤变小,PTEN表达阳性率提高,与对照组比较,差异有统计学意义(P<0.05)。结论:PTEN真核表达质粒pBp-PTEN瘤内注射对人膀胱癌裸鼠移植瘤有一定的抑制作用。     

赛来昔布对人骨肉瘤类肿瘤干细胞移植瘤微血管生成的影响

[目的] 探讨cox-2抑制剂赛来昔布(Celecoxib)对骨肉瘤类肿瘤干细胞裸鼠移植瘤生长及微血管生成的影响.[方法] 无血清堵养法从骨肉瘤细胞株MG-3中分离出类肿瘤干细胞建立裸鼠移植瘤模型.30只成瘤裸鼠随机分 Celecoxib 组和对照组,Celcoxib:25 mg/ (kg·d),用药15 d,第27 d处死裸鼠,观察肿瘤体积、抑瘤率,免疫组化技术检测VEGF表达及CD34标记的MVD值.[结果] 分离的骨肉瘤类肿瘤干细胞有致瘤性,可以建立动物模型.Celecoxib抑瘤率为23.2%,Celecoxib组裸鼠移植瘤的体积、VEGF的表达、MVD值均显著低于对照组(P＜0.05).[结论] 骨肉瘤类肿瘤下细胞可以建立裸鼠骨肉瘤移植瘤模型.Celeeoxib可以抑制肿瘤生长,减少移植瘤组织VEGF的表达,减少微血管生成,具有抗血管生成作用.     

塞来昔布对裸鼠结肠癌移植瘤放疗增敏作用的机制研究

为探讨环氧化酶-2（COX-2）抑制剂塞来昔布对裸鼠结肠癌移植瘤放疗增敏作用的机制,本研究应用人结肠癌SW480细胞建立裸鼠移植瘤模型,并将32只裸鼠随机分为A组（对照组）、B组（塞来昔布组）、C组（放疗组）和D组（塞来昔布＋放疗组）,观察各组裸鼠结肠癌移植瘤的生长情况,并应用免疫组化法检测移植瘤组织中COX-2、8-catenin、血管内皮生长因子（VEGF）、CD34表达,并对CD34阳性血管进行计数,计算微血管密度（MVD）。结果显示,（1）干预30d后,B、C、D组移植瘤瘤体质量及体积均明显小于A组,P〈0．05;而D组移植瘤瘤体质量和体积明显小于B、C组,P〈0．05。（2）免疫组化检测显示,COX-2、β—catenin、VEGF及CD34在各组移植瘤组织中均呈阳性表达。B、c、D组COx-2、p—catenin、VEGF表达水平及MVD均明显低于A组,P〈0．05;而D组各指标明显低于B、c组,P〈0．05。（3）相关性分析显示,COX-2、VEGF、β-catenin及MVD,各指标两两之间均具有显著相关性,P〈O．05。结果表明,塞来昔布可能是通过抑制wnt信号通路来抑制肿瘤新生血管的生成,最终发挥放疗增敏作用。     

The pathology of cardiac xenografts

The pathology of cardiac xenografts has yielded critical insights into the mechanisms of xenograft rejection and the therapeutic procedures that might be applied to preventing or treating it. The conditions seen in rejecting cardiac xenografts include hyperacute rejection, acute vascular rejection, and cellular rejection. Hyperacute and acute vascular rejection of cardiac xenografts have features typical of humoral injury. Less is known about cellular rejection and only speculation can be offered about chronic rejection. Still, these features allow critical testing of pathogenetic mechanisms and therapies.     

Pathologic characteristics of transplanted kidney xenografts

For xenotransplantation to become a clinical reality, we need to better understand the mechanisms of graft rejection or acceptance. We examined pathologic changes in α1,3-galactosyltransferase gene-knockout pig kidneys transplanted into baboons that were treated with a protocol designed to induce immunotolerance through thymic transplantation (n=4) or were treated with long-term immunosuppressants (n=3). Hyperacute rejection did not occur in α1,3-galactosyltransferase gene-knockout kidney xenografts. By 34 days, acute humoral rejection led to xenograft loss in all three xenografts in the long-term immunosuppression group. The failing grafts exhibited thrombotic microangiopathic glomerulopathy with multiple platelet-fibrin microthrombi, focal interstitial hemorrhage, and acute cellular xenograft rejection. Damaged glomeruli showed IgM, IgG, C4d, and C5b-9 deposition. They also demonstrated endothelial cell death, diffuse endothelial procoagulant activation with high expression of tissue factor and vWF, and low expression of the ectonucleotidase CD39. In contrast, in the immunotolerance group, two of four grafts had normal graft function and no pathologic findings of acute or chronic rejection at 56 and 83 days. One of the remaining kidneys had mild but transient graft dysfunction with reversible, mild microangiopathic glomerulopathy, probably associated with preformed antibodies. The other kidney in the immunotolerance group developed unstable graft function at 81 days and developed chronic xenograft glomerulopathy. In summary, the success of pig-to-primate xenotransplantation may necessitate immune tolerance to inhibit acute humoral and cellular xenograft rejection.     

Long-term survival of pig-to-mouse Islet xenografts

Abstract: Several laboratories are currently able to prepare large amounts of purified porcine islets of proven in vitro viability. The long-term in vivo function of pig islet xenografts has been evaluated in both "nonimmunocompetent" animals (i.e., the nude mouse) and "immunocompetent" animals. In the nude mouse, documentation has been provided for pig islet function for up to 4 months, even though the issue of how quickly porcine islet xenografts restore normal blood glucose in this animal model is still controversial. Interestingly, pig islet xenografts drive glucose metabolism to maintain plasma glucose concentrations at the donor species levels. Porcine islets have been also transplanted into varying "immunocompetent" animals species. Long-term pig islet xenograft survival in rats and larger animals has been achieved by transplanting islets immunoisolated by either macro- or microencapsulation techniques. In the pig-to-mouse experimental model, freshly prepared, nonimmunoisolated islets survived long-term (for up to 50–60 days) when anti-CD4 antibody treatment was given temporarily posttransplant. Neither the addition of either mouse and/or pig anti-lymphocyte serum, nor the use of 1 week, low-temperature cultured, or cryopreserved islets did further prolong the survival. When 2 to 3 week cultured islets were transplanted into anti-CD4 antibody treated mice, function of the xenografts was observed at 100 days posttransplant in 75% of the animals. Thus, long-term survival of pig-to-mouse islet xenografts in both nonimmunocompetent and immunocompetent animals is achievable. Although further studies are needed to fully understand the hormonal and metabolic effects of the islet xenografts, as well as to extend some of the results obtained in mice to larger animal models, the in vivo data available so far support the use of pig islets for potential use in human xenotransplantation studies.