奎宁与三种逆转剂联合对耐药细胞系K562／HHT多药耐药逆转作用的 …

目的：寻找有效的多药耐药联合逆转剂，方法：用ＭＴＴ法、联合效应分析和流式细胞测定技术研究奎宁分别与环孢菌素Ａ、他莫西酚、潘生丁（ＤＰＭ）联合逆转耐药细胞系Ｋ５６２／ＨＨＴ对柔红霉素（ＤＮＲ）和尖杉酯碱（ＨＨＴ）耐药。结果：逆转倍数是单用药的２－３倍，达到或超过单用２倍剂量的逆转效果，逆转 是有联合协同作用，其中Ｑｕｉｎ与ＤＰＭ或Ｔａｍ联合的协同作用大于Ｑｕｉｎ与ＣｓＡ联合，可增加细胞内ＤＮＲ浓度。     

异搏定与它莫西芬联合逆转高三尖杉酯碱耐药的体外研究

目的：降低逆转剂的毒副作用，提高耐药的逆转效果。方法：用异搏定（ＶＥＲ）和它莫西芬（ＴＡＭ）单独或联合体外逆转高三尖杉酯碱（ＨＨＴ）耐药，药敏试验采用半固体琼脂集落培养法。结果：ＶＥＲ和ＴＡＭ单独或联合均不能增强ＨＨＴ对Ｋ５６２敏感细胞的杀伤；而在ＨＨＴ耐药细胞株（Ｋ５６２／Ｈ２０）中，无细胞毒性剂量４μｍｏｌ／Ｌ和８μｍｏｌ／Ｌ的ＶＥＲ或ＴＡＭ均能明显逆转Ｋ５６２／Ｈ２０细胞对ＨＨＴ的耐药，ＩＣ５０由４４６．８±０．０８μｇ／Ｌ分别下降为４５．１±０．０２，２２．４±０．０３或８５．１±０．０３，２６．４±０．０２μｇ／Ｌ。采用临床可达到血药浓度的２μｍｏｌ／ＬＶＥＲ与４和８μｍｏｌ／ＬＴＡＭ联合，耐药细胞的ＩＣ５０分别降为３０．４±０．０２和４．３±０．０４μｇ／Ｌ，后者的ＩＣ５０与敏感株相近。以恒定浓度比ＶＥＲ与ＴＡＭ联合（１∶４）逆转ＨＨＴ耐药，联合指数值均＜１，有明显的协同作用。结论：单独使用ＶＥＲ或ＴＡＭ仅能部分逆转耐药，两者联合有明显的协同作用。     

汉防己甲素逆转白血病细胞耐药的研究

用ＭＴＴ法测定柔红霉素（ＤＮＲ）的细胞毒性（ＬＣ＿（５０））及荧光法测定细胞内ＤＮＲ浓度，发现汉防己甲素（ＴＴＤ）通过提高耐药细胞系Ｋ５６２／Ａ０２细胞内ＤＮＲ浓度，增加ＤＮＲ对Ｋ５６２／Ａ０２细胞的毒性作用。加ＴＴＤ组与未加ＴＴＤ组相比，ＩＣ＿（５０）值下降了９４．１％，有显著的统计学意义。与异搏定（ＶＲＰ）相比，二者均为钙通道阻滞剂，耐药逆转效果也相当，但ＴＴＤ较ＶＲＰ安全，副作用轻微，实验用量临床可以接受。     

环孢霉素A逆转复发难治性白血病多药耐药的临床研究

目的：探讨环孢霉素Ａ（ＣｓＡ）逆转复发难治性急性白血病的临床意义及推广价值。方法：采用免疫组织化学ＡＢＣ法，ｐ１７０单抗ＪＳＢ－１检测复发难治性白血病的ｐ１７０表达，并对阳性患者随机分组，用ＣｓＡ加联合化疗进行逆转多药耐药研究，同时采用高效液相色谱法检测ＣｓＡ血药浓度，探讨ＣｓＡ血药浓度和逆转疗效间的关系。结果：ｐ１７０在复发难治性白血病中有高表达；ＣｓＡ有较好逆转复发难治性白血病多药耐药的作用（Ｐ＜０．０５）；ＣｓＡ血药浓度和逆转疗效呈正相关。结论：ＣｓＡ可能成为安全有效的逆转药物，在治疗复发难治性ＡＬ中有较大临床意义及推广价值。     

环孢菌素A与维拉帕米并用逆转去甲氧柔红霉素的交叉耐药性的实验研究

多药耐药基因ｍｄｒ 1产物Ｐ 糖蛋白 (Ｐ ｇｐ)过度表达是耐药的重要原因之一。为探讨白血病细胞耐药机制及逆转方法 ,我们建立了高三尖杉酯碱 (ＨＨＴ)耐药细胞株 ,并观察了其Ｐ ｇｐ的表达及环孢菌素Ａ (ＣｓＡ)和维拉帕米 (Ｖｅｒ)在逆转耐药中并用的效果。材料和方法1　药品　ＨＨＴ (Ｓｉｇｍａ公司 )、柔红霉素 (ＤＮＲ ,法玛西亚普强公司 )、去甲氧柔红霉素 (Ｉｄａ ,法玛西亚普强公司 )和阿糖胞苷(Ａｒａ Ｃ ,Ｐｈａｒｍａｃｉａ＆Ｕｐｊｏｈｎ公司 )、长春新碱 (ＶＣＲ ,上海华联制药公司 )、足叶乙甙 (Ｖｐ16 ,上海医药工业研究院…     

白细胞介素2和α干扰素逆转白血病细胞多药耐药的研究

目的：探讨细胞因子对人白血病细胞系Ｋ５６２／Ｓ及其多药耐药细胞系Ｋ５６２／Ａ０２的影响。方法：以ＭＴＴ法测定小剂量细胞因子作用后柔红霉素（ＤＮＲ）的毒性变化；用荧光法测定细胞内药物浓度；用免疫组化法检测ｐ－膜糖蛋白（ｐ－ｇｐ）变化；用ＲＴ－ＰＣＲ法检测多药耐药基因（ｍｄｒ－１）ｍＲＮＡ。结果：发现ＤＮＲ对Ｋ５６２／Ａ０２及Ｋ５６２／Ｓ的半数抑制率（ＩＣ５０）分别为４５．０８μｇ／ｍｌ及０．６０７μｇ／ｍｌ。α干扰素（ＩＦＮ－α）和白细胞介素２（ＩＬ－２）作用２４小时可增加ＤＮＲ对Ｋ５６２／Ａ０２的细胞毒作用，与未加药组相比ＩＣ５０下降为１６．３９及１１．９６μｇ／ｍｌ，但不影响Ｋ５６２／Ｓ细胞（ＩＣ５０无明显改变）。且ＩＦＮ－α、ＩＬ－２可提高细胞内ＤＮＲ浓度，从未加药组的２１５１ｎｇ／ｍｇ蛋白到２５７０及２５０３ｎｇ／ｍｇ蛋白。但ｐ－ｇｐ及ｍｄｒ－１ｍＲＮＡ无明显改变。结论：ＩＦＮ－α、ＩＬ－２可增加ＤＮＲ对Ｋ５６２／Ａ０２细胞的毒性作用，增加Ｋ５６２／Ａ０２细胞内的药物浓度，但不是通过下调ｍｄｒ－１ｍＲＮＡ机制而起逆转作用。     

多药耐药基因反义寡核苷酸逆转肿瘤细胞耐药的初步研究

目的：克服肿瘤细胞的多药耐药（ＭＤＲ）。方法：用人工合成互补于ｍｄｒ１基因５′端转录起始部位的反义寡核苷酸（ＯＤＮ），直接转染耐药细胞株ＫＢ－８－５细胞，或以脂质体ｌｉｐｏｆｅｃｔｉｎ为载体进行基因转染实验，通过ＭＴＴ法检测细胞对柔红霉素（ＤＮＲ）的敏感性，流式细胞仪分析细胞内ＤＮＲ含量及免疫组化方法确定细胞表面糖蛋白（Ｐｇｐ）的表达水平。结果：ＯＤＮ可增加ＫＢ－８－５细胞内的ＤＮＲ浓度从而提高耐药细胞对ＤＮＲ的敏感性，ｌｉｐｏｆｅｃｔｉｎ进一步加强上述作用。在ＤＮＲ浓度为３．０ｍｇ／Ｌ组中，约有７４．４３％的被转染细胞对ＤＮＲ敏感而致死，基本达到药物敏感细胞株ＫＢ－３－１的水平。ＯＤＮ转染的ＫＢ－８－５细胞的Ｐｇｐ为弱阳性表达，低于阳性对照ＫＢ－８－５细胞的Ｐｇｐ表达水平。结论：ＯＤＮ的逆转作用可能与其互补结合的ｍｄｒ１ｍＲＮＡ降解或直接阻滞了Ｐｇｐ合成使其表达降低有关。     

干扰素逆转白血病细胞多药耐药性的研究及机制的初步探讨

以人白血病细胞系Ｋ５６２／Ｓ及多药耐药细胞系Ｋ５６２／Ａ０２为对象，通过ＭＴＴ法测柔红霉素（ＤＮＲ）细胞毒性（ＩＣ５０），用流式细胞仪及荧光法测细胞内ＤＮＲ浓度，逆转录－多聚酶链反应法检测多药耐药基因ｍＲＮＡ，发现小剂量ＩＦＮ－α（５００Ｕ／ｍｌ）可增加ＤＮＲ对Ｋ５６２／Ａ０２细胞的毒性作用。加用ＩＦＮ－α与未加用组相比，ＩＣ５０下降至原来的１／１３．７，而ＩＬ－２（２５０Ｕ／ｍｌ）、ＧＭ－ＣＳＦ（０．１５μｇ／ｍｌ）、ＴＮＦ（２５０Ｕ／ｍｌ）作用组与对照组ＩＣ５０无明显改变。并发现ＩＦＮ－α可提高耐药系Ｋ５６２／Ａ０２细胞内ＤＮＲ浓度，在１５０分钟时升高了６．３倍。ｍｄｒ１ｍＲＮＡ在ＩＦＮ－α作用组与对照组无明显改变，认为ＩＦＮ－α不是通过下调ｍｄｒ１ｍＲＮＡ而达逆转作用     

赛庚啶逆转多药耐药细胞K562／A02：对柔红霉素耐药的研究

赛庚啶逆转多药耐药细胞Ｋ５６２／Ａ０２对柔红霉素耐药的研究祁明芳魏素芳汪明春许敏华齐静杨纯正我们研究了赛庚啶（ＣＰＨ）对Ｋ５６２／Ａ０２柔红霉素（ＤＮＲ）敏感性和细胞内蓄积的影响。报告如下。材料和方法１细胞系Ｋ５６２／Ａ０２多药耐药细胞系和Ｋ５６２／...     

川芎嗪对白血病HL-60/VCR细胞多药耐药的逆转及其机制研究

多药耐药（ＭＤＲ）的产生是造成难治性白血病的主要原因,因此逆转白血病ＭＤＲ已成为提高白血病化疗疗效的一种重要手段。目前用于临床的逆转剂主要有环孢霉素Ａ（ＣｓＡ）和维拉帕米（ＶＰ）等,但其毒性相对较大,许多患者难于耐受。据此,我们采用低毒、价廉的中药钙...     

Complete inhibition of P-glycoprotein by simultaneous treatment with a distinct class of modulators and the UIC2 monoclonal antibody

P-glycoprotein (Pgp) is one of the active efflux pumps that are able to extrude a large variety of chemotherapeutic drugs from the cells, causing multidrug resistance. The conformation-sensitive UIC2 monoclonal antibody potentially inhibits Pgp-mediated substrate transport. However, this inhibition is usually partial, and its extent is variable because UIC2 binds only to 10 to 40% Pgp present in the cell membrane. The rest of the Pgp molecules become recognized by this antibody only in the presence of certain substrates or modulators, including vinblastine, cyclosporine A (CsA), and SDZ PSC 833 (valspodar). Simultaneous application of any of these modulators and UIC2, followed by the removal of the modulator, results in a completely restored steady-state accumulation of various Pgp substrates (calcein-AM, daunorubicin, and 99mTc-hexakis-2-methoxybutylisonitrile), indicating near 100% inhibition of pump activity. Remarkably, the inhibitory binding of the antibody is brought about by coincubation with concentrations of CsA or SDZ PSC 833 approximately 20 times lower than what is necessary for Pgp inhibition when the modulators are applied alone. The feasibility of such a combinative treatment for in vivo multidrug resistance reversal was substantiated by the dramatic increase of daunorubicin accumulation in xenotransplanted Pgp+ tumors in response to a combined treatment with UIC2 and CsA, both administered at doses ineffective when applied alone. These observations establish the combined application of a class of modulators used at low concentrations and of the UIC2 antibody as a novel, specific, and effective way of blocking Pgp function in vivo.     

中药复方君子汤联合环孢霉素A逆转白血病细胞諯562/VCR耐药性的实验研究

本研究观察中药复方君子汤(FFJZ)联合环孢霉素A(cyclosporine A,CsA)逆转白血病耐药细胞系K562/VCR细胞耐药性的效果,以便寻找有效的联合逆转剂.采用MTT法、流式细胞术研究FFJZ联合CsA逆转白血病耐药细胞系K562/VCR耐药性的作用.结果表明FFJZ联合CsA在体外对K562/VCR细胞的耐药性有明显的逆转作用(p＜0.01),能提高K562/VCR细胞对阿霉素(ADM)的敏感性,且在药物有效浓度范围内对细胞本身无毒性作用.FFJZ联合CsA对K562/VCR细胞的P-gp表达的阳性率无明显影响.结论复方君子汤联合环孢霉素A可能成为治疗白血病多药耐药的安全有效的耐药逆转药物.     

The farnesyltransferase inhibitor R115777 (tipifarnib) in combination with tamoxifen acts synergistically to inhibit MCF-7 breast cancer cell proliferation and cell cycle progression in vitro and in vivo

Cross-talk between receptor tyrosine kinases and estrogen receptor is at least partly responsible for the development of acquired resistance to endocrine therapies. Hence, targeting receptor tyrosine kinases and their downstream partners with inhibitors/antagonists may reverse this resistance. Although ras mutations are rare in breast cancer (2%), aberrant function of Ras signal transduction pathways is common. We therefore investigated the efficacy of the farnesyltransferase inhibitor (FTI) R115777 (tipifarnib) in combination with tamoxifen in MCF-7 human breast cancer models both in vitro and in vivo. There was a synergistic antiproliferative interaction between R115777 and 4-hydroxy-tamoxifen in vitro as calculated by median effect analysis. The combination resulted in a significantly greater G(1) arrest than either drug alone and this was associated with marked inhibition of cyclin D1 and induction of the cell cycle inhibitor p27(kip1). Combining R115777 with either tamoxifen or estrogen withdrawal in vivo produced a significantly greater inhibition of tumor growth and lower xenograft cell proliferation than either therapy alone. These results suggest that the combination of this FTI with endocrine therapy may be of therapeutic benefit in the treatment of breast cancer. Enhanced G1 arrest due to modulation of cell cycle regulatory proteins may be the underlying mechanism for the positive interaction between FTIs and tamoxifen.     

Synergistic interactions between the dual serotonergic, noradrenergic reuptake inhibitor duloxetine and the non-steroidal anti-inflammatory drug ibuprofen in inflammatory pain in rodents.

OBJECTIVES: The present study was undertaken to characterize whether the pharmacologic interaction between duloxetine, a balanced serotonergic and noradrenergic reuptake inhibitor, and the non-steroidal anti-inflammatory drug ibuprofen was simply additive, less than additive, or greater than additive (i.e., synergistic) in preclinical models of visceral and inflammatory pain, specifically acetic acid-induced writhing in mice and carrageenan-induced thermal hyperalgesia and mechanical allodynia in rats. METHODS: In the writhing test, male CF-1 mice were injected intraperitoneally with 0.55% acetic acid and 5 min later the number of writhes was counted over a 5-min period. In the carrageenan models, male Sprague-Dawley rats were injected with a 1.5% carrageenan solution into the ventral surface of the hind paw; hypersensitivity to thermal and mechanical stimuli was subsequently evaluated 2h post-carrageenan. RESULTS: Vehicle or a dose of duloxetine alone (1-100 mg/kg), ibuprofen alone (10-300 mg/kg), or duloxetine and ibuprofen in combination in a dose-ratio of 1:10 duloxetine:ibuprofen were orally administered 30 or 60 min before testing. Isobolographic analysis of the effects of duloxetine in combination with ibuprofen revealed a significant synergistic (greater than additive) interaction between duloxetine and ibuprofen both for reducing acetic acid-induced writhing and carrageenan-induced thermal hyperalgesia, but were additive for reversing mechanical allodynia. CONCLUSIONS: Our data indicate that duloxetine and ibuprofen have synergistic efficacy in a visceral and an inflammatory pain model in rodents, and suggest that duloxetine and ibuprofen in combination may provide a useful approach to the clinical treatment of persistent pain, particularly inflammation-related pain.     

环孢菌素A、雷洛昔芬及其联合应用逆转K562/A02细胞多药耐药的研究

本研究探讨环孢菌素A（CsA）、雌激素受体抑制荆雷洛昔芬及其联合应用对K562／A02细胞多药耐药的逆转作用。采用甲基四唑蓝法（MTT）测定柔红霉素（DNR）的半数抑制量，RT-PCR法检测mdr1基因mRNA表达水平，FCM检测P-gp的表达和细胞内DNR浓度。结果表明：DNR对K562／A02和K562细胞的IC50分别为23．51和0．29mg／L，雷洛昔芬（2．5mg／L）及CsA（1mg／L）单用和两药联合处理K562／A02细胞时，DNR的IC50值分别为5．98、8．15和3．68mg／L，两药对DNR作用K562细胞的IC50没有影响。CsA及雷洛昔芬单独作用后耐药株mdr1mRNA下调微弱，联合用药下调效果明显。CsA及雷洛昔芬均可降低P-gP蛋白的表达，且具有协同作用。同时还观察到逆转剂雷洛昔芬和CsA作用后细胞内柔红霉素浓度增加，两药联合作用时效果增强。结论：CsA及雷洛昔芬均可逆转耐药。且联合作用效果增强。     

Structure-activity relationship: analyses of p-glycoprotein substrates and inhibitors

OBJECTIVE: A large number of structurally and functionally diverse compounds act as substrates or modulators of p-glycoprotein (p-gp). Some of them possess multiple drug resistance (MDR)-reversing activity, but only a small number of them have entered clinical study. In order to uncover the factors which exert a significant impact on the interaction between substrates/modulators and p-gp, we have performed structure-activity relationship (SAR) analyses, including molecular modelling, two-dimensional (2D) and three-dimensional (3D) parameter-frame-setting analysis, quantitative structure activity relationship (QSAR) analysis among substrates/modulators, as well as clinically promising MDR-reversing agents. METHODS: The physicochemical parameters C log P, CMR and all regression equations were derived by using C log P version 4.0 and the latest CQSAR software, respectively. Molecular modelling and all other parameter calculations were performed by using HyperChem version 5.0 program, after geometry optimization and energy minimization using the AM1 semiempirical method. RESULTS: SAR analyses indicate that MDR reversal activity is correlated with the lipophilicity (C log P), molecular weight (log Mw), longest chain (Nlc) of the molecule and the energy of the highest occupied orbital (Ehomo). In addition, the presence of a basic tertiary nitrogen atom in the structure is also an important contributor to p-gp inhibitory activity. Some separation in space is achieved for different subsets of p-gp substrates and inhibitors using Nlc, C log P and Ehomo as three independent parameters in the 3D-parameter-frame setting. CONCLUSION: A highly effective p-gp modulator candidate should possess a log P value of 2.92 or higher, 18-atom-long or longer molecular axis, and a high Ehomo value, as well as at least one tertiary basic nitrogen atom. The results obtained may be useful in explaining drug-p-gp interactions for different compounds, including drug interactions and the development of new MDR chemosensitizers.     

In vitro synergism between daptomycin and fosfomycin against Enterococcus faecalis isolates with high-level gentamicin resistance.

Daptomycin and fosfomycin are two agents which inhibit different steps in peptidoglycan synthesis. We studied the in vitro activities of these drugs, alone and in combination, by time-kill techniques against 21 clinical isolates of Enterococcus (Streptococcus) faecalis demonstrating high-level resistance to gentamicin. Combinations of fosfomycin and daptomycin exhibited synergistic bactericidal activity (100-fold decrease in CFU per milliliter at 24 h compared with daptomycin alone) against all strains (mean +/- standard deviation of increment in killing = 2.7 +/- 0.7 log10 CFU/ml). In a subgroup of strains against which daptomycin (5 micrograms/ml) alone was bactericidal (greater than 3 log10 killing), synergistic activity was demonstrable only when the concentration of daptomycin was lowered to 0.25 to 0.5 microgram/ml. A 50% dilution of human serum diminished the bactericidal activity of daptomycin alone at 24 h but did not affect killing observed with the daptomycin-fosfomycin combination. The inhibition of peptidoglycan synthesis by the combination was greater than the inhibition observed with either drug alone. The combination of daptomycin and fosfomycin exhibited consistent synergistic bactericidal activity against strains of E. faecalis possessing high-level resistance to gentamicin. This synergism may be the result of sequential inhibition of early steps in peptidoglycan synthesis.     

LBH589或联合硼替佐米逆转髓系白血病耐药及其分子机制研究

目的 探讨新一代组蛋白去乙酰化酶抑制剂LBH589联合蛋白酶体抑制剂硼替佐米逆转急性髓系白血病(AML)细胞耐药效应及其分子机制.方法 耐药AML细胞株HL-60/ADM和难治性AML原代细胞与不同浓度LBH589、硼替佐米或两者联合进行体外培养,采用MTT法检测细胞增殖活力,Hoechst33342染色和Annexin V-FITC/PI双染流式细胞术检测细胞凋亡,用阿霉素摄取率并结合细胞增殖抑制率评估逆转耐药效应.进一步检测处理前后细胞MRP1及信号通路蛋白变化.结果 LBH589、硼替佐米均能够抑制HL-60/ADM和难治性AML原代细胞增殖,诱导凋亡,其中21 nmol/LLBH589和12 nmol/L硼替佐米联合时作用最强,经Calcusyn软件分析证明两者联合具有明显的协同作用(CI值分别为0.531和0.498).联合组MRP1阳性率为(57.78±3.34)%,显著低于LBH589、硼替佐米单药组[(76.06±5.17)%和(71.83±4.53)%,P值均＜0.05],而单药组与对照组之间差异也有统计学意义(P值均＜0.01).联合组细胞内阿霉素摄取率为(64.81±3.69)%,明显高于单药组[(28.96±2.52)%和(37.29±3.71)%](P值均＜0.05).LBH589联合硼替佐米可以明显抑制磷酸化Akt和磷酸化IKKα/β蛋白的表达,降低PI3K/Akt/NF-κB通路的活性,明显上调P53蛋白的表达,抑制NF-κB P65、Bcl-2、XIAP和MRP1蛋白活性,促进Caspase-8、Caspase-3和PARP的裂解激活.结论 LBH589、硼替佐米能够抑制耐药AML细胞增殖和促进凋亡,并逆转耐药,两者联合具有明显的协同作用.PI3K/Akt/NF-κB信号传导通路受抑或阻断可能是其主要的作用机制.

Abstract：

Objective To investigate reversal effect of histone deacetylase inhibitor LBH589 alone or in combination with proteasome inhibitor bortezomib on drug resistance in acute myeloid leukemia(AML) and its mechanism.Methods Ex vivo cultures of HL-60/ADM cells and fresh refractory AML cells were treated with LBH589, bortezomib or their combination at varying concentrations.Proliferation capacity, apoptosis rate and reversal of drug resistance were evaluated by MTT assay, dual staining of Hoechst33342 and AnnexinVFITC/PI by flow cytometry, and adriamycin uptake rate with proliferation inhibition, respectively.The change of signal pathway at protein level was analyzed by Western blot.Results Synergistic cytotoxicity was observed in the combination treatment with LBH589 and bortezomib against HL-60/ADM cells, as well as the fresh AML cells, the most powerful synergy being observed at 21 nmol/L LBH589 plus 12 nmol/L bortezomib,with CI values of 0.531 and 0.498, respectively by Calcusyn software analysis.Moreover, the accumulation of adriamycin in HL-60/ADM cells was increased more in combination treatment[(64.81 +3.69)%]than in either LBH589[( 28.96 + 2.52 ) %]or bortezomib[( 37.29 ± 3.71 ) %]alone ( P ＜ 0.05 ), and so did the uptake rate of adriamycin being (64.81 ± 3.69 ) %, ( 28.96 ± 2.52 ) % and ( 37.29 ± 3.71 ) % respectively (P ＜ 0.05 ).The combination treatment induced multiple apoptotic molecules co-action and intracellular drug accumulation contributed to the synergistic cytotoxity, including caspase activation, PARP cleavage, XIAP downregulation, p53-dependent suppression of Bcl-2 and MRP1 expression via the inhibition of phosphoinositide 3-kinase ( PI3K )/Akt/nuclear factor-κB ( NF-κB ) signaling pathway. Conclusions Combination treatment of drug resistant AML cells with LBH589 and bortezomib produces a synergistic effect of in creasing sensitivity to chemotherapy.The mechanism may be mainly resulted from inhibition of PI3K/Akt/NF-κB signaling pathway.     

Synergy of Penicillin-Netilmicin Combinations Against Enterococci Including Strains Highly Resistant to Streptomycin or Kanamycin

The in vitro activity of combinations of penicillin and netilimicin was determined against 20 clinical isolates of enterococci and compared with that obtained in simultaneous tests with penicillin/sisomicin, penicillin/streptomycin, and penicillin/kanamycin. Synergy between the two drugs in each combination was determined by the use of quantitative kill curves and was defined as a killing by the combination at least 100-fold greater than that produced by the most effective drug alone. Penicillin/netilmicin and penicillin/sisomicin combinations were found to be synergistic against the majority of isolates tested, including strains resistant to penicillin/streptomycin or penicillin/kanamycin combinations. This synergy with penicillin could be demonstrated at a concentration of 相似文献   

青藤碱对肾移植大鼠静脉血白细胞介素6的影响

背景:青藤碱具有镇静、镇痛、镇咳、抗心律失常、抗炎和免疫抑制等药理作用,近年来对其抗排斥作用的研究逐步深入.白细胞介素6是参与细胞介导移植物损伤的重要细胞因子,在诊断急性排斥反应及评价抗排斥反应的疗效方面具有重要的临床意义.目的:通过检测青藤碱对肾移植受体鼠静脉血中自细胞介素6质量浓度的影响,分析青藤碱对大鼠肾移植后急性捧斥反应的抑制作用以及与环孢素A是否存在协同效应.设计、时间及地点:随机对照动物实验,于2008-03/2009-03在广州医学院第二附属医院外科实验室完成.材料:选择近交系F344大鼠60只和近交系Wistar大鼠80只.方法:建立近交系大鼠F344→Wistar肾移植动物模型48对,受体大鼠按照同期随机的原则分为4组,每组12只.生理盐水组给予生理盐水腹腔注射,1次/d;青藤碱组给予青藤碱腹腔注射,1次/d:环孢素A组给予环孢素A腹腔注射,1次/d;青藤碱+环孢素A组给予青藤碱+环孢素A腹腔注射,1次/d.以未做处理的Wistar大鼠12只为对照组.主要观察指标:肾移植后第7天,应用酶联免疫吸附法检测受体大鼠静脉血白细胞介素6的质量浓度:完整留取移植肾行病理切片,观察病理改变,依据Banff标准对急性排斥反应病理改变进行分级评分.结果:青藤碱组、环孢素A组、青藤碱+环孢素A组受体鼠的血自细胞介素6质量浓度均显著低于生理盐水组(P＜0.96);青藤碱组与环孢素A组差异无显著性意义(P＞0.05);青藤碱+环孢素A组显著低于青藤碱组、环孢素A组(P＜0.05).病理切片按移植肾排斥反应组织学分级标准进行分级,生理盐水组3或4级;青藤碱组1或2级;环孢素A组1或2级;青藤碱+环孢素A组0或1级.结论:青藤碱对间种异体大鼠肾移植急性捧斥反应起到了较为确切的免疫抑制作用,能明显下调白细胞介素6的质量浓度,并与环孢素A存在协同作用.