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81.
Zheng Wang Jian Zhou Jia Fan Chang-Jun Tan Shuang-Jian Qiu Yao Yu Xiao-Wu Huang Zhao-You Tang 《Journal of cancer research and clinical oncology》2009,135(5):715-722
Purpose Immunosuppressive therapy after liver transplantation for hepatocellular carcinoma (HCC) is one of the major contributory
factors for HCC recurrence and metastasis. Sirolimus, a potent immunosuppressant, has been reported to be an effective inhibitor
in a variety of tumors. The present study is designed to explore whether sirolimus could block the growth and metastatic progression
of HCC.
Methods MHCC97H cells were used as targets to explore the effect of sirolimus on cell cycle progression, apoptosis, proliferation,
and its antiangiogenic mechanism. LCI-D20, a highly metastatic model of human HCC in nude mice, was also used as the model
tumor to explore the effect of sirolimus on tumor growth and metastatic progression.
Results In vitro, sirolimus induced cell cycle arrest at the G1 checkpoint and blocked proliferation of MHCC97H cells but did not
induce apoptosis. In vivo, sirolimus prevented tumor growth and metastatic progression in LCI-D20. Intratumoral microvessel
density and circulating levels of VEGF in tumor-bearing mice were also significantly reduced in sirolimus treatment group.
Quantitative RT-PCR showed that sirolimus down-regulated the mRNA expression of VEGF and HIF-1a, but not of bFGF, and TGF-b
in MHCC97H cells. Furthermore, western blot analysis confirmed that sirolimus also decreased expression of HIF-1a at protein
level, in parallel with the down-regulation of the levels of VEGF protein excretion in a time-dependent manner as compared
to untreated control cells following anoxia.
Conclusions The immunosuppressive macrolide sirolimus prevents the growth and metastatic progression of HCC, and suppresses VEGF synthesis
and secretion by downregulating HIF-1a expression. Sirolimus may be useful for clinical application in patients who received
a liver transplant for HCC.
Z. Wang and J. Zhou contributed equally to this work. 相似文献
82.
Wilson D Johnston F Holt D Moreton M Engelmayer J Gaulier JM Luthe H Marquet P Moscato D Oellerich M Mosso R Streit F Brunet M Fillee C Schmid R Wallemacq P Barnes G 《Clinical biochemistry》2006,39(4):378-386
OBJECTIVES: This study evaluated the analytical characteristics of the new Abbott microparticle enzyme immunoassay (MEIA) for sirolimus. DESIGN AND METHODS: The protocol consisted of nine sections: evaluation of antibody specificity, linearity, detection limit, quantification limit, endogenous interferents, exogenous interferents, precision, proficiency testing panel, and method comparison. RESULTS: The mean analytical detection limit was 0.68 microg/L. The sirolimus concentration corresponding to a total CV of 20% was 1.5 microg/L. Linearity of response was demonstrated across the dynamic range of the assay. Total precision (CVs) at QC control levels from 5 to 22 microg/L ranged from 5.7 to 12.6%. Assay standardization was found to be in good agreement with LC/MS/MS as compared with target values for spiked sirolimus proficiency samples from an international sirolimus proficiency testing program. Good correlations (R values) of the immunoassay were observed in comparisons to LC/MS/MS. R values tended to be lower in comparisons with LC/UV methods. Across both LC-based methods and all study sites, there was approximately 25% overall positive slope bias due to cross reactivity of the MEIA antibody to metabolites of sirolimus. The assay cross-reactivity to metabolites of sirolimus parent drug ranged from 6 to 63%. Assay interferences were minimal with the exception of hematocrit, which presented a negative relationship to measured sirolimus concentration. CONCLUSIONS: The MEIA demonstrated acceptable analytical characteristics for use for routine monitoring of sirolimus immunosuppressive therapy, and is a viable alternative to HPLC-based methods for sirolimus monitoring. 相似文献
83.
Aims/hypothesis
The Edmonton Protocol for islet transplantation has provided hope for type 1 diabetic patients. However, this protocol requires lifelong immunosuppression, specifically sirolimus, a cellular antiproliferate. The effect of sirolimus on human pancreatic ductal cells (HDCs) is not known. This may be important since HDCs are believed to be islet precursors. Since neonatal porcine islets (NPIs), which contain many ductal precursor cells, could be a potential clinical source of islets, we also tested the effects of sirolimus on this tissue.Methods
HDCs (n=4), NPIs (n=9) and human islets (n=5) were cultured with and without sirolimus (20 ng/ml) for 6 days.Results
HDCs and NPIs cultured with sirolimus showed a 50 and 28% decrease, respectively, in cell number relative to control (p<0.05). Control cultures expanded 1.65- and 2.44-fold relative to time 0. Decreases in cell number of sirolimus-treated HDCs were not due to apoptosis as measured by TUNEL staining. No functional effects on human islets or NPIs were observed following static incubation with high glucose. Treatment of syngeneically transplanted and naïve BALC/c mice with sirolimus resulted in altered OGTT profiles with prolonged elevation of hyperglycaemia and weight gain. There was no difference in graft and organ insulin content between treatment groups.Conclusions/interpretation
Our results indicate that sirolimus decreases ductal cell numbers in culture and alters glucose-stimulated insulin secretion in vivo. The administration of sirolimus to islet transplant recipients is likely to impair graft function as a result of decreasing ductal neogenesis and induction of insulin resistance. 相似文献84.
《Pharmaceutical development and technology》2013,18(3):279-287
AbstractObjective: The purpose of the present investigation was to prepare a plasma stable, pH-sensitive niosomal formulation to enhance Sirolimus efficacy and selectivity.Materials and methods: pH-sensitive niosomal formulations bearing PEG-Poly (monomethyl itaconate)-CholC6 (PEG-PMMI-CholC6) copolymers and cholesteryl hemisuccinate (CHEMS) were prepared by a modified ethanol injection method and characterized with regard to pH-responsiveness and stability in human serum. The ability of pH-sensitive niosomes to enhance the Sirolimus cytotoxicity was evaluated in vitro using human erythromyeloblastoid leukemia cell line (K562) and compared with cytotoxicity effect on human umbilical vein endothelial cells (HUVEC).Results and discussion: This study showed that both formulations can be rendered pH-sensitive property and were found to rapidly release their contents under mildly acidic conditions. However, the CHEMS-based niosomes lost their pH-sensitivity after incubation in plasma, whereas, PEG-PMMI-CholC6 niosomes preserved their ability to respond to pH change. Sirolimus encapsulated in pH-sensitive niosomes exhibited a higher cytotoxicity than the control conventional formulation on K562 cell line. On the other hand, both pH-sensitive niosomes showed lower antiproliferative effect on HUVEC cells.Conclusion: Plasma stable, pH-sensitive PEG-PMMI-CholC6-based niosomes can improve the in vitro efficiency and also reduce the side effects of Sirolimus. 相似文献
85.
雷帕霉素靶蛋白(mTOR)信号通路与肿瘤细胞的增殖、周期调控等多种病理过程密切相关.雷帕霉素通过抑制mTOR起到抗肿瘤作用,但其容易产生耐药等缺点导致临床应用受限,耐药机制主要与mTOR受抑后负反馈激活磷脂酰肌醇3-激酶-蛋白激酶B(PI3K-Akt)有关.mTOR通路相关蛋白的双重抑制剂等药物有望逆转其耐药. 相似文献
86.
目的 观察雷帕霉素对大鼠深Ⅱ度烧伤创面自噬的表达及对烧伤创面早期加深的作用.方法 Wistar大鼠背部深Ⅱ度烧伤,治疗组腹腔注射雷帕霉素,对照组腹腔注射等量溶媒,观察两组烫伤后6h、1d、2d、3d创面组织自噬体,自噬标志蛋白LC3、Beclin-1的表达及变化;TUNEL法检测创面凋亡;同时检测烧伤后创面局部多普勒血流(LDF)值,创面组织中IL-8、Na-K-ATP酶、髓过氧化物酶(MPO)活性和丙二醛(MDA)的含量变化,HE染色及Masson染色显示创面组织坏死及加深程度.结果 治疗组与对照组相比,电镜下可见自噬体增多,LC3、Beclin-1表达明显增高,创面凋亡率明显低于对照组;治疗组创面LDF值及Na-K-ATP酶活性比对照组明显升高,IL-8、MPO活性和MDA的含量较对照组明显下降,创面深度较对照组减轻.结论 雷帕霉素使大鼠深Ⅱ度烧伤创面自噬增强,抑制烧伤创面早期加深. 相似文献
87.
目的探讨雷帕霉素抑制JAK/STAT信号通路在大鼠梗阻性黄疸中对肿瘤坏死因子-α(TNF-α)表达的影响。方法采用胆总管结扎方法建立大鼠梗阻性黄疸模型,将54只SD大鼠随机分为假手术组(A组)18只,梗阻性黄疸+STAT抑制剂雷帕霉素处理组(B组)18只,梗阻性黄疸组(C组)18只,A、B、C三组分别于术后1、3、5d处死大鼠,每个时间段6只。监测各时间段大鼠肝功能酶学变化,Westernblot法检测受试样品TNF-α蛋白表达,RT-PCR测各组不同时间段TNF-αmRNA的表达。结果与假手术组比较,两梗阻性黄疸组肝功能酶学差异显著,TNF-α蛋白及基因表达升高明显,与雷帕霉素干预组比较,梗阻性黄疸组TNF-α蛋白及基因表达升高明显,有统计学差异(P<0.01)。结论雷帕霉素可能通过抑制JAK/STAT信号转导通路降低梗阻性黄疸大鼠TNF-α表达,减少对肝细胞的损伤,对肝脏起到一定的保护作用。 相似文献
88.
89.
目的:制备西罗莫司乳膏并探究其对小鼠慢性皮炎湿疹模型的疗效。方法:制备O/W型西罗莫司乳膏并建立制剂的含量测定方法。选取70只SD小鼠分为7组,分别为空白对照组,模型组,西罗莫司低(0.1%)、中(0.5%)、高(1%)剂量组,他克莫司组和吡美莫司组。除空白对照组外,其余各组制备小鼠慢性皮炎湿疹模型,采用7%2,4-二硝基氯苯丙酮溶液致敏,0.3%2,4-二硝基氯苯溶液多次激发。各组于致敏后开始给药,2次/d,持续14 d,以小鼠耳朵肿胀度为指标,并采用ELISA法测定血清中IFN-γ、IL-4等细胞因子的浓度。结果:制得的西罗莫司乳膏匀展性好,西罗莫司在1.0100.0μg·ml-1浓度范围内线性关系良好(r=0.999 9),平均回收率为99.7%,RSD为0.7%(n=9)。西罗莫司乳膏能显著抑制小鼠耳朵肿胀度(P<0.05),改善小鼠耳部的红肿情况(P<0.01),同时促进小鼠血清中IFN-γ的表达,并降低IL-4的表达。结论:药效学实验表明,西罗莫司对小鼠慢性皮炎湿疹有一定疗效,为西罗莫司外用制剂的研究提供了实验依据。 相似文献