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991.
The histone deacetylase inhibitor AN-9 has selective toxicity to acute leukemia and drug-resistant primary leukemia and cancer cell lines 总被引:7,自引:0,他引:7
Batova A Shao LE Diccianni MB Yu AL Tanaka T Rephaeli A Nudelman A Yu J 《Blood》2002,100(9):3319-3324
The novel prodrug of butyric acid, pivaloyloxymethyl butyrate (AN-9), a histone deacetylase inhibitor, shows great promise as an effective and relatively nontoxic anticancer agent for solid malignancies. However, little is known about its effects on hematopoietic malignancies. In this study, we show that 21 primary samples of acute leukemia were sensitive to the antiproliferative effects of AN-9, with a 50% inhibitory concentration (IC(50)) of 45.8 +/- 4.1 microM. In colony-forming assays, primary T-cell acute lymphoblastic leukemia (T-ALL) cells were 3-fold more sensitive to AN-9 than the normal hematopoietic progenitors, erythroid burst-forming units and granulocyte/monocyte colony-forming units. AN-9 induced apoptosis in the T-ALL cell line CEM. A common problem with cancer is chemoresistance, which is often typical of relapsed cancers. Remarkably, a T-ALL sample at diagnosis and an acute myeloid leukemia sample at relapse that were resistant to doxorubicin in vitro were sensitive to AN-9, with an IC(50) of 50 microM for both samples. More strikingly, samples from 2 infants with t(4;11) ALL obtained at diagnosis and relapse each were the most sensitive to AN-9, with IC(50) values of 25 microM and 17 microM, respectively. Furthermore, a doxorubicin-resistant clone of HL60, HL60/ADR, obtained by the transfection of the MDR-1 gene, was equally sensitive to AN-9 cytotoxicity as the parental cells. AN-9 induced the expression of p21 in an infant leukemia sample with 11q23 rearrangement, but not in T- or B-precursor ALL. Collectively, our results suggest that AN-9 is a selective agent for hematopoietic malignancies that can circumvent the mechanisms of chemoresistance limiting most conventional chemotherapy. 相似文献
992.
Intravenous injection of the supernatant fluids from human peripheral blood mononuclear cells (PBMC) incubated with lipopolysaccharide (LPS) caused fever in rabbits. The fever was in parallel with the levels of either interleukin-1 beta (IL-1 beta), IL-6, or tumor necrosis factor-alpha (TNF-alpha) in supernatant fluids. When incubating the platonin with the LPS-human PBMC, both the levels of IL-1 beta, IL-6, or TNF-alpha in supernatant fluids and the pyrogenicity of supernatant fluids were significantly suppressed. The febrile response to supernatant fluids from the LPS-stimulated PBMC was attenuated almost completely by adding anti-IL-1 beta, but not anti-IL-6 or anti-TNF-alpha, monoclonal antibody to supernatant fluids. In addition, both the fever and the increased levels of either IL-1 beta, IL-6, or TNF-alpha in rabbit serum following an intravenous administration of LPS were significantly attenuated by pretreatment with an intravenous dose of platonin. Furthermore, the fever induced by intravenous injection of IL-1 beta was reduced by pretreatment of rabbits with intravenous injection of platonin. The data indicate that platonin inhibits production of pyrogenic cytokines (in particular, IL-1 beta) from PBMC and results in antipyresis. 相似文献
993.
Xing L Liping X Rongqing Z Dawei C Lan S 《The Journal of pharmacy and pharmacology》2003,55(10):1359-1363
A simple and reproducible enzyme-linked immunosorbent assay (ELISA) was developed to determine the concentration of bee venom in rat plasma. The intra- and inter-assay coefficients of variation for the ELISA were less then 3% between 0.1 and 1,000 ng mL(-1) venom, and the sensitivity of the detection was 0.1 ng mL(-1). Total recovery of the bee venom added to rat plasma was determined. Using this ELISA, serum levels of bee venom were easily determined. The rats were administered a single intravenous injection or oral dose of bee venom (1 mg kg(-1) of body weight). The bioavailability of the bee venom under the two administrations was compared using pharmacokinetic parameters. Results showed that intravenous administration of bee venom produced high plasma concentrations with a short half-life. The area under the curve for oral administration was 10 times lower than for intravenous administration. This loss of bee venom may be due to the degradation that occurs in the enzymatic and acidic environment of the gastrointestinal tract. 相似文献
994.
Objective: Clinically meaningful recovery from acute mania may not be captured by conventionally reported response categorizations. We defined new and stringent criteria for remission in bipolar mania. Using a cohort of patients with acute mania randomized to treatment with either olanzapine or placebo, we contrasted remission rates to findings using previously reported but more lenient categorical outcome measures of response and euthymia.
Methods: We pooled and reanalyzed results through 3 weeks from two published randomized double-blind trials of olanzapine versus placebo for treating acute bipolar mania ( 1, 2 ). Response was previously defined as ≥ 50% decrease from baseline to endpoint total Young Mania Rating Scale ( 3 ) (Y-MRS) scores, and euthymia as an endpoint total Y-MRS score of ≤ 12. In this report, remission required an endpoint total Y-MRS score of ≤ 7, and an endpoint total Hamilton Depression Rating Scale, (HAM-D21) ( 4 ) score of ≤ 7 and an endpoint Clinical Global Impression Scale – Bipolar version, CGI-BP ( 5 ), overall severity score of ≤ 2.
Results: Olanzapine treated subjects achieved statistically significantly greater rates of clinical response, euthymia and remission than those assigned to placebo, 55% versus 29.5%, 50% versus 27%, and 18% versus 7%, respectively.
Conclusions: Olanzapine monotherapy resulted in discernable clinical improvements in mania in over 50% of subjects and just under 20% of subjects achieved a near complete resolution of manic and accompanying depressive symptoms after 3 weeks of treatment. Full remission is an important but potentially elusive goal during short-term management of acute mania. 相似文献
Methods: We pooled and reanalyzed results through 3 weeks from two published randomized double-blind trials of olanzapine versus placebo for treating acute bipolar mania ( 1, 2 ). Response was previously defined as ≥ 50% decrease from baseline to endpoint total Young Mania Rating Scale ( 3 ) (Y-MRS) scores, and euthymia as an endpoint total Y-MRS score of ≤ 12. In this report, remission required an endpoint total Y-MRS score of ≤ 7, and an endpoint total Hamilton Depression Rating Scale, (HAM-D21) ( 4 ) score of ≤ 7 and an endpoint Clinical Global Impression Scale – Bipolar version, CGI-BP ( 5 ), overall severity score of ≤ 2.
Results: Olanzapine treated subjects achieved statistically significantly greater rates of clinical response, euthymia and remission than those assigned to placebo, 55% versus 29.5%, 50% versus 27%, and 18% versus 7%, respectively.
Conclusions: Olanzapine monotherapy resulted in discernable clinical improvements in mania in over 50% of subjects and just under 20% of subjects achieved a near complete resolution of manic and accompanying depressive symptoms after 3 weeks of treatment. Full remission is an important but potentially elusive goal during short-term management of acute mania. 相似文献
995.
Intestinal transformation results in transforming growth factor-beta-dependent alteration in tumor cell-cell matrix interactions 总被引:3,自引:0,他引:3
BACKGROUND: An alteration in the expression of and response to transforming growth factor-beta 1 (TGF-beta 1) appears to be an important event during colorectal carcinogenesis. However, the precise role of TGF-beta 1 in colorectal carcinogenesis is not clear. We have previously described in detail the changes in cell proliferation and differentiation caused by chronic exposure to TGF-beta 1. In this study we sought to better characterize the changes in tumor cell-cell matrix interactions seen during TGF-beta 1-mediated intestinal transformation. METHODS: Rat intestinal epithelial cells (RIE) and RIE cells transformed by chronic exposure to TGF-beta 1 (RIE-Tr) were treated with TGF-beta 1 and production of components of the plasmin/plasminogen system measured by ELISA and Western blotting. TGF-beta 1 effects on invasion and adhesion were determined in vitro. The role of urokinase on TGF-beta 1-mediated invasion and adhesion were determined using immunoneutralization. The role of COX-2 was determined using a specific COS-2 inhibitor. RESULTS: TGF-beta 1 had no effect on RIE-1 adhesion to collagen types I and IV, fibronectin, and laminin, or invasion through collagen types I and IV. However, 5 ng/mL TGF-beta 1 significantly increased the invasiveness and decreased the adhesiveness of RIE-Tr. This effect of TGF-beta 1 on RIE-Tr was associated with a significant increase in plasmin activity secondary to increased expression of uPA. TGF-beta 1 had no effect on either uPA receptor or PAI-1 in this system. Antibodies to uPA completely blocked the TGF-beta 1-mediated invasiveness of the RIE-Tr cells and returned their adhesiveness to basement membrane proteins to baseline. Addition of the selective Cox-2 inhibitor SC-58125 resulted in a dose-dependent decrease in TGF-beta 1-mediated invasion and uPA expression. CONCLUSION: This study provides additional evidence for TGF-beta 1 as a tumor promoter during intestinal carcinogenesis and a possible new mechanism for Cox-2-related colon carcinogenesis. 相似文献
996.
乳腺癌患者外周血DNA p53基因突变的检测及其与预后关系的研究 总被引:15,自引:3,他引:12
目的 探讨乳腺癌患者外周血中DNAp53基因突变与预后的关系。方法 对126例乳腺癌患者和92例正常对照者血浆DNA含量进行检测。外周血浆中DNA由Qiagen纯化柱纯化,组织标本DNA抽提方法参照非有机化方法。应用PCR—SSCP方法检测DNA中p53基因5,6,7,8外显子点突变。结果 健康妇女外周血中DNA的平均值为21ng/ml,而乳腺癌患者为211ng/ml(P<0.01)。126例乳腺癌患者中有46例(35.6%)原发瘤中检出p53突变,其中30例(65.2%)患者外周血DNA中检出p53基因突变。乳腺癌患者外周血中DNA p53基因突变与临床分期、肿瘤大小、淋巴结转移情况和雌激素受体状况密切相关(P<0.05)。肿瘤原发灶与外周血中均检出DNA p53基因突变者预后较差,22例发生复发或转移的患者中,有13例(59.0%)外周血中检出DNA p53基因突变。结论 乳腺癌患者外周血中DNA p53基因的突变,可作为一种预后指标和提示肿瘤早期复发和远处转移的预后因子。 相似文献
997.
998.
Jin LH Shao QJ Luo W Ye ZY Li Q Lin SC 《International journal of cancer. Journal international du cancer》2003,107(5):696-699
Axin is a recently identified tumor suppressor that plays an important role in liver and colon cancers. To gain further insights into the structure and function of Axin in controlling cell growth, we analyzed 54 colorectal cancer tissues for mutations in AXIN1 gene. We employed PCR amplification with 23 sets of primers against introns that encompassed the whole coding region of AXIN1 followed by single-strand conformation polymorphism (SSCP) analysis. After subcloning and sequencing analysis of the reamplified DNA from the aberrant bands, we found, in addition to 3 silent mutations, 6 missense point mutations in different functionally important regions. The missense mutation rate is hence 11%, suggesting that Axin deficiency may contribute to the onset of colorectal tumorigenesis. 相似文献
999.
HDAC1在肺腺癌细胞株A549中的表达及TSA对细胞增殖、凋亡的影响 总被引:1,自引:1,他引:0
背景与目的:研究表明组蛋白去乙酰化酶(histonedeacetylase,HDAC)在多种肿瘤细胞中高表达,组蛋白去乙酰化酶1(HDAC1)抑制剂制滴菌素A(trichostatinA,TSA)能抑制肿瘤细胞的生长。而缺氧是恶性肿瘤的重要特征,本实验拟研究HDAC1在低氧肺腺癌细胞株A549中的表达及TSA对细胞增殖、凋亡的影响。方法:实验设常氧组(对照组)及低氧组(实验组),实验组设A~F组,即低氧6h组(A组),低氧6h加TSA组(B组),低氧12h组(C组),低氧24h组(D组),低氧24h加TSA组(E组),低氧48h组(F组)。用蛋白印迹法(Westernblot)检测A549细胞在不同时间低氧条件下HDAC1的表达,用四甲基偶氮唑蓝(MTT)比色、免疫组化和流式细胞仪、原位凋亡(Tunel)法检测A549细胞在不同时间低氧条件下的增殖和凋亡率以及TSA对其的影响,用RT-PCR检测A549细胞在不同时间低氧条件下HDAC1mRNA的表达及TSA对其的作用。结果:对照组HDAC1蛋白质表达的A值为138±11,实验A、C、D、F组A值分别为78±4.0、86±5.0、124±3.0、120±9.0。对照组HDAC1mRNA的A值与β-actinmRNAA值的比值0.68±0.03,A、B、D、E组HDAC1mRNA的A值与β-actinmRNAA值的比值分别为0.46±0.03、0.45±0.02、0.70±0.03、0.33±0.02。对照组PCNA的A值0.13±0.03、A、B、D、E组PCNA的A值分别为0.10±0.02、0 相似文献
1000.
单价抗CD20抗体诱导人B细胞淋巴瘤Raji细胞的凋亡 总被引:1,自引:0,他引:1
Liu YX Fan DM Xiong DS Xu YF Shao XF Xu YS Peng H Yang M Qin L Zhu ZP Yang CZ 《癌症》2003,22(12):1249-1253
背景与目的:抗CD20抗体和片段已应用于非霍奇金淋巴瘤的临床治疗,但仍需要开发新的抗CD20抗体和片段(未修饰的或放射性标记的),以治疗对美罗华(利妥昔单抗)无反应的患者。鼠源性抗CD20抗体HI47的嵌合抗体片段Fab和F(ab)'2已被构建。本研究目的是观察HI47(鼠抗-CD20抗体)和其嵌合抗CD20抗体片段抑制肿瘤细胞生长和诱导肿瘤细胞凋亡的作用。方法:用免疫荧光法测定抗CD20抗体与CD20+人B细胞淋巴瘤Raji细胞的结合能力;MTT法测定抗CD20抗体片段对Raji细胞生长的影响;用膜联蛋白Ⅴ染色和DNA琼脂糖凝胶电泳检测和验证抗CD20抗体片段诱导Raji细胞凋亡。结果:HI47和其嵌合的抗CD20抗体片段均可与CD20+Raji细胞结合,结合率可达90%以上;HI47不能与美罗华竞争结合Raji细胞;HI47和其嵌合的抗CD20抗体片段浓度为100μg/ml对Raji细胞的抑制率分别为:(57.0±1.5)%、(65.2±2.5)%、(77.2±3.2)%;单价的抗CD20抗体片段Fab(20μg/ml)能够诱导Raji细胞的凋亡,早期凋亡率为17%。结论:HI47的嵌合抗体片段对Raji细胞有抑制作用,能诱导Raji细胞的凋亡。 相似文献