共查询到18条相似文献,搜索用时 62 毫秒
1.
哺乳动物雷帕霉素靶蛋白(mTOR)信号途径在多种恶性肿瘤中存在异常激活或变异,该途径激活可以调控肿瘤细胞的增殖、存活以及转移能力,进而导致恶性肿瘤发生发展。雷帕霉素及其衍生物通过阻断mTOR通路的信号传递,抑制胃癌细胞生长,促进肿瘤坏死,并能与其他化疗药物产生协同作用,有望为胃癌预防和治疗提供有效的方法。 相似文献
2.
哺乳动物雷帕霉素靶蛋白(mTOR)及其信号通路控制着蛋白质合成、细胞的生长和代谢以及血管的生成等.其信号通路在胃癌中常被高度激活,与胃癌进展及预后密切相关.雷帕霉素及其衍生物可通过阻断mTOR通路的信号传递,抑制胃癌细胞生长,促进肿瘤坏死,并能与其他化疗药物产生协同作用,有望为胃癌预防和治疗提供有效的方法. 相似文献
3.
哺乳动物雷帕霉素靶蛋白(mTOR)及其信号通路控制着蛋白质合成、细胞的生长和代谢以及血管的生成等.其信号通路在胃癌中常被高度激活,与胃癌进展及预后密切相关.雷帕霉素及其衍生物可通过阻断mTOR通路的信号传递,抑制胃癌细胞生长,促进肿瘤坏死,并能与其他化疗药物产生协同作用,有望为胃癌预防和治疗提供有效的方法. 相似文献
4.
正乳腺癌是威胁妇女健康的主要恶性肿瘤之一,随着肿瘤分子生物学研究的发展,分子靶向药物在乳腺癌治疗中取得了一定的疗效,单克隆抗体赫赛汀(Herceptin)是针对乳腺癌Her-2基因的第一个分子靶向药物,为乳腺癌临床治疗带来了突破,但是只有30%的Her-2阳性的乳腺癌患者能从单药中获益,而部分患者可能出现该药物的原发耐药和继发耐药,随着分子靶向药物研究的不断深入,选择 相似文献
5.
哺乳类动物雷帕霉素靶蛋白(mTOR)抑制剂的抗肿瘤作用已被熟知,传统的mTOR抑制剂包括雷帕霉素及其衍生物,早期已应用于临床。目前mTOR小分子抑制剂如磷脂酰肌醇激酶3 激酶(PI3K)/mTOR双重抑制剂、Torin1等陆续被发现在肿瘤治疗中有着独特的作用。 相似文献
6.
哺乳动物雷帕霉素靶蛋白(mTOR)作为生长因子和氨基酸特别是亮氨酸所激发的信号通路的汇合点,在肿瘤细胞中起中心调控作用.近些年,人们逐渐认识到mTOR的反馈激活机制是影响雷帕霉素及其类似物抗肿瘤疗效的重要因素之一.因此,针对mTOR的反馈激活机制及联合应用相关抑制剂协同阻断这一机制的研究成为肿瘤防治的新热点. 相似文献
7.
8.
《中国肿瘤临床与康复》2017,(12)
目的探讨m TOR抑制剂依维莫司与紫杉醇共同抑制耐阿霉素乳腺癌(MCF-7/ADR)细胞株生长的机制。方法在培养耐阿霉素乳腺癌细胞株(MCF-7/ADR)中加入一定量的依维莫司和紫杉醇,采用MTT法对加入依维莫司和紫杉醇的细胞IC50含量进行检测,然后根据检测结果来进行依维莫司与紫杉醇浓度的设置,并计算联合用药的效果。采用流式细胞术对MCF-7/ADR细胞在不同药组作用下48h后的凋亡率进行检测。采用Western blot方法对各组细胞内的m TOR、p-m TOR、PI3K、p-PI3K、AKT、p-AKT、4EBP1和p-4EBP1蛋白表达情况进行检测。结果依维莫司和紫杉醇抑制MCF-7/ADR细胞增殖的半数抑制浓度(IC50)分别为32.58μg/ml和9.59μg/ml,两者合用抗增殖作用大于紫杉醇或依维莫司单用,组合指数均小于0.9。与只用紫杉醇对MCF-7/ADR细胞进行处理相比,联合使用依维莫司和紫杉醇能更好地诱导MCF-7/ADR细胞凋亡。Western blot结果显示,紫杉醇和依维莫司合用可明显加强对m TOR、p-m TOR、PI3K、p-PI3K、p-AKT、4EBP1和p-4EBP1表达的抑制作用。结论依维莫司合用紫杉醇,可增强对MCF-7/ADR细胞增殖抑制和凋亡的诱导作用,其机制可能是下调m TOR信号通路及上、下游信号蛋白表达和磷酸化。 相似文献
9.
10.
磷脂酰肌醇3-激酶/丝氨酸-苏氨酸蛋白激酶(phosphatidylinositol3-kinase/serine-threonine protein kinase,PI3K/Akt)信号通路活化是肿瘤细胞增殖、转移和抗凋亡的重要环节,已证实与乳腺癌芳香化酶抑制剂(aromatase inhibitors,AIs)抵抗以及曲妥珠单抗耐药有关。PI3K/Akt信号通路抑制剂联合AIs或人类表皮生长因子受体2(human epidermal growth factor receptor-2,HER2)靶向治疗在雌激素受体阳性晚期乳腺癌临床试验中显示出较好的有效性,能够显著改善患者的无进展生存时间,其中以PI3K/Akt/哺乳类动物雷帕霉素靶蛋白(mammalian target of rapamycin,m TOR)通路抑制剂依维莫司的研究及其临床应用最为成熟。本文对依维莫司在复发、转移和耐药乳腺癌治疗中的作用进行综述。 相似文献
11.
Mammalian target of rapamycin (mTOR) is the key regulator of cell growth and proliferation. Alterations in the mTOR signaling pathway can lead to neoplastic transformation and progression. The inhibition of mTOR blocks the progression of the cell cycle from G1 to S phase, leading to cell growth arrest and apoptosis. Thus, mTOR is a promising target for the treatment of human malignancies. Rapamycin and its analogues, including temsirolimus, everolimus, and AP23573, block the mTOR signaling pathway and induce a cellular state akin to starvation, with significant antitumor activity in a variety of malignancies, including renal cell carcinoma (RCC). Current data from ongoing clinical trials suggest that mTOR-targeted therapy with rapamycin derivatives is well tolerated with significant clinical activity in patients with advanced-stage RCC. Specifically, temsirolimus as monotherapy has demdemonstrated improved progression-free and overall survival in patients with poor-risk advanced-stage RCC. Everolimus has also demonstrated promising antitumor activity in patients with metastatic RCC. However, optimal dose, treatment schedule, selection of patients, and appropriate combination strategies with other novel agents need to be defined for mTORtargeted therapies in the treatment of advanced-stage RCC. 相似文献
12.
13.
凋亡抑制因子存活素的研究进展 总被引:16,自引:2,他引:14
凋亡抑制因子存活素(survivin)在细胞中呈周期依赖性表达,与有丝分裂期纺锤体微管相互作用,调节G2/M期,并可直接抑制caspase-3和caspase-7的活性。在肿瘤发生发展中,存活素与肿瘤细胞的凋亡负相关,与细胞增殖活性和血管生成正相关。在人类肿瘤中,存活素表达上调可预示生存期缩短和预后不良。体内、外研究中应用存活素反义核酸和突变体可诱导肿瘤细胞凋亡,使肿瘤细胞的生长减弱,并可增加肿瘤细胞对化疗和X射线辐射的敏感性。提示存活素可能是肿瘤诊断和治疗的新靶点。 相似文献
14.
Differential effects of rapamycin on mammalian target of rapamycin signaling functions in mammalian cells 总被引:8,自引:0,他引:8
Rapamycin and its analogues have shown promising anticancer activities in preclinical and clinical studies. However, the mechanism whereby rapamycin inhibits signaling through the mammalian target of rapamycin (mTOR) remains poorly understood. Here, we show that the FKBP12/rapamycin complex is an essentially irreversible inhibitor of mTOR kinase activity in vitro. However, we observe no suppression of mTOR catalytic activity after immunoprecipitation from rapamycin-treated cells. These results suggest either that rapamycin acts as a reversible kinase inhibitor in intact cells or that the cellular effects of rapamycin are not mediated through global suppression in mTOR kinase activity. To better understand the cellular pharmacology of rapamycin, we compared the individual and combined effects of rapamycin and kinase-inactive mTOR expression on a panel of mTOR-dependent cellular responses. These studies identified glycolytic activity, amino acid transporter trafficking, and Akt kinase activity as novel, mTOR-modulated functions in mammalian cells. Whereas kinase-inactive mTOR did not enhance the decreases in cell size and glycolysis induced by rapamycin, expression of this mTOR mutant significantly enhanced the inhibitory effects of rapamycin on cell proliferation, 4EBP1 phosphorylation, and Akt activity. Unexpectedly, amino acid transporter trafficking was perturbed by kinase-inactive mTOR but not by rapamycin, indicating that this process is rapamycin insensitive. These results indicate that rapamycin exerts variable inhibitory actions on mTOR signaling functions and suggest that direct inhibitors of the mTOR kinase domain will display substantially broader anticancer activities than rapamycin. 相似文献
15.
16.
《European journal of cancer (Oxford, England : 1990)》2014,50(3):486-495
BackgroundIn patients with solid tumours, daily everolimus dosing demonstrated dose proportionality and linear pharmacokinetics. A meta-analysis was conducted to characterise the relationship between everolimus Cmin and efficacy and safety and the effect of CYP3A4 and P-glycoprotein (PgP) substrate/inhibitor/inducer coadministration on everolimus trough concentration (Cmin).MethodsIndividual patient data from five phase 2/3 studies, in which steady state, predose pharmacokinetic samples were taken from patients with solid tumours administered everolimus 10 mg/day, were pooled.FindingsEfficacy and safety were evaluable for 945 and 938 patients, respectively. A 2-fold increase in everolimus Cmin increased the likelihood of tumour size reduction (odds ratio 1.40, 95% confidence interval (CI) 1.23–1.60), was associated with a trend for reduced risk of progression-free survival events (risk ratio [RR] 0.90, 95% CI 0.69–1.18) and increased the risk of grade ⩾3 pulmonary (RR 1.93, 95% CI 1.12–3.34), stomatitis (RR 1.49, 95% CI 1.05–2.10) and metabolic (RR 1.30, 95% CI 1.02–1.65) events. Coadministering everolimus with strong CYP3A4 and PgP inhibitors increased everolimus Cmin by 10% and 20%, respectively; coadministration with CYP3A4 inducers reduced Cmin by 7%.InterpretationA 2-fold increase in everolimus Cmin was associated with improved tumour size reduction and increased risk of high-grade pulmonary, metabolic and stomatitis events.FundingNovartis Pharmaceuticals Corporation. 相似文献
17.
Lanie K Francis Yazan Alsayed Xavier Leleu Xiaoying Jia Ujjal K Singha Judith Anderson Michael Timm Hai Ngo Ganwei Lu Alissa Huston Lori A Ehrlich Elizabeth Dimmock Suzanne Lentzsch Teru Hideshima G David Roodman Kenneth C Anderson Irene M Ghobrial 《Clinical cancer research》2006,12(22):6826-6835
PURPOSE: The phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (mTOR) pathway and the heat shock protein family are up-regulated in multiple myeloma and are both regulators of the cyclin D/retinoblastoma pathway, a critical pathway in multiple myeloma. Inhibitors of mTOR and HSP90 protein have showed in vitro and in vivo single-agent activity in multiple myeloma. Our objective was to determine the effects of the mTOR inhibitor rapamycin and the HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) on multiple myeloma cells. EXPERIMENTAL DESIGN: Multiple myeloma cell lines were incubated with rapamycin (0.1-100 nmol/L) and 17-AAG (100-600 nmol/L) alone and in combination. RESULTS: In this study, we showed that the combination of rapamycin and 17-AAG synergistically inhibited proliferation, induced apoptosis and cell cycle arrest, induced cleavage of poly(ADP-ribose) polymerase and caspase-8/caspase-9, and dysregulated signaling in the phosphatidylinositol 3-kinase/AKT/mTOR and cyclin D1/retinoblastoma pathways. In addition, we showed that both 17-AAG and rapamycin inhibited angiogenesis and osteoclast formation, indicating that these agents target not only multiple myeloma cells but also the bone marrow microenvironment. CONCLUSIONS: These studies provide the basis for potential clinical evaluation of this combination for multiple myeloma patients. 相似文献
18.
Karen W L Yee Zhihong Zeng Marina Konopleva Srdan Verstovsek Farhad Ravandi Alessandra Ferrajoli Deborah Thomas William Wierda Efrosyni Apostolidou Maher Albitar Susan O'Brien Michael Andreeff Francis J Giles 《Clinical cancer research》2006,12(17):5165-5173
PURPOSE: Everolimus (RAD001, Novartis), an oral derivative of rapamycin, inhibits the mammalian target of rapamycin (mTOR), which regulates many aspects of cell growth and division. A phase I/II study was done to determine safety and efficacy of everolimus in patients with relapsed or refractory hematologic malignancies. EXPERIMENTAL DESIGN: Two dose levels (5 and 10 mg orally once daily continuously) were evaluated in the phase I portion of this study to determine the maximum tolerated dose of everolimus to be used in the phase II study. RESULTS: Twenty-seven patients (9 acute myelogenous leukemia, 5 myelodysplastic syndrome, 6 B-chronic lymphocytic leukemia, 4 mantle cell lymphoma, 1 myelofibrosis, 1 natural killer cell/T-cell leukemia, and 1 T-cell prolymphocytic leukemia) received everolimus. No dose-limiting toxicities were observed. Grade 3 potentially drug-related toxicities included hyperglycemia (22%), hypophosphatemia (7%), fatigue (7%), anorexia (4%), and diarrhea (4%). One patient developed a cutaneous leukocytoclastic vasculitis requiring a skin graft. One patient with refractory anemia with excess blasts achieved a major platelet response of over 3-month duration. A second patient with refractory anemia with excess blasts showed a minor platelet response of 25-day duration. Phosphorylation of downstream targets of mTOR, eukaryotic initiation factor 4E-binding protein 1, and/or, p70 S6 kinase, was inhibited in six of nine patient samples, including those from the patient with a major platelet response. CONCLUSIONS: Everolimus is well tolerated at a daily dose of 10 mg daily and may have activity in patients with myelodysplastic syndrome. Studies of everolimus in combination with therapeutic agents directed against other components of the phosphatidylinositol 3-kinase/Akt/mTOR pathway are warranted. 相似文献