埃坡霉素衍生物在乳癌治疗中的临床应用进展

<正>埃坡霉素(epothilone)与紫杉类一样,都是作用于细胞微管的药物。埃坡霉素家族包括16个成员,由大环内酯构成,1992年由Holf和Reichenbach从粘杆菌的发酵肉汤中分离出来。Bollag等首先报道了埃坡霉素潜在的抗肿瘤作用。埃坡霉素A和B具有相     

埃坡霉素高产菌株的选育及发酵培养基的优化

以埃坡霉素产生菌粘细菌纤维堆囊菌为出发菌株,经亚硝基胍诱变处理后,在含有前体丙酸盐的平板中筛选抗性突变株,得到一株高产突变株N-19,埃坡霉素产量为18.5 mg/L,比出发菌株提高了69.7.通过优化发酵培养基的碳、氮源组成,埃坡霉素产量达36.1 mg/L,此时埃坡霉素B和埃坡霉素A的比值为0.4:在摇瓶发酵过程中补加前体丙酸盐,埃坡霉素B和埃坡霉素A的比值增至2.1.     

抗肿瘤药物埃坡霉素的研究进展

埃坡霉素(Epothilone)是由纤维素堆囊粘液菌分泌的一类十六员大环内酯类化合物,其作用机制与紫杉醇相同,但在抗肿瘤谱、抗肿瘤活性、安全性、水溶性及合成方法等方面均优于紫杉醇,已引起了生物、医学、制药及有机合成等学科领域的高度重视,是目前学术界密切关注的、医药学界寄于厚望的前景广阔的一类新型抗肿瘤药物。1　埃坡霉素的化学结构EpothiloneA F是从SorangiumCellulosumStrain90分离得到的天然产物,是一类十六员大环内酯类化合物[1] 。从结构上看(见图1) ,EpothiloneA与B、EpothiloneC与D仅在碳12上取代基R不同,A、C中为氢,B…     

埃博霉素B、D及其衍生物的研究进展

埃博霉素是以微管为靶点的大环内酯类药物.已经或正在开发的几种埃博霉素类药物有:埃博霉素B内酰胺衍生物、埃博霉素D、埃博霉素B、埃博霉素F、埃博霉素A,其中埃博霉素D内酰胺衍生物极有可能成为高效候选抗肿瘤新药.本文从结构特点和作用机制出发,重点综述埃博霉素B、D及其衍生物的研发进展.     

抗肿瘤药物埃坡霉素的研究进展

埃坡霉素(Epothilone)是由纤维素堆囊粘液菌分泌的一类十六员大环内酯类化合物，其作用机制与紫杉醇相同，但在抗肿瘤谱、抗肿瘤活性、安全性、水溶性及合成方法等方面均优于紫杉醇，已引起了生物、医学、制药及有机合成等学科领域的高度重视，是目前学术界密切关注的、医药学界寄于厚望的前景广阔的一类新型抗肿瘤药物。     

抗肿瘤药物埃坡霉素生物合成进展

介绍新型抗肿瘤药物埃坡霉素在合成方面的近期发展.从埃坡霉素生物合成碳架起源与生物合成基因簇两个方向的研究结果表明,两者具有良好的一致性.与步骤繁杂的化学全合成相比,基于发酵的生物合成法更为可行.     

埃坡霉素高产菌株的选育

采用紫外-亚硝酸盐复合诱变法对纤维堆囊菌(Sorangium cellulosum)ATCC 15384进行诱变,结合红霉素抗性筛选,筛得一株遗传稳定的埃坡霉素高产菌株纤维堆囊菌UNl6H127,埃坡霉素A(Epo A)和埃坡霉素B(Epo B)的产量为289.9和25.14μg/L,总产量(EpoA+Epo B,315.04μg/L)是出发菌株的23.8倍.     

埃坡霉素抗肿瘤作用及药动学研究

埃坡霉素是一类新型抗微管蛋白解聚类化合物,在体内外均有强大广谱的抗肿瘤活性,且对紫杉醇耐药的肿瘤有效。本文综述多种埃坡霉素类药物近年来的抗肿瘤作用及药动学研究进展。     

埃坡霉素B对A549人肺腺癌细胞的体内外抗肿瘤药效学研究

目的:观察埃坡霉素B在体内外对A549人肺腺癌细胞生长的抑制作用。方法:用MTT法观察埃坡霉素B体外作用72h对A549人肺腺癌细胞增殖的抑制作用;用A549人肺腺癌裸鼠移植瘤模型评价埃坡霉素B在1.0、0.5、0.25mg/kg剂量下,给药2~3次后的体内抗肿瘤活性。结果:实验结果显示,埃坡霉素B在体外对人肺腺癌细胞A549抑制作用的IC50为(0.53±0.11)nmol/L,实际检测的最大抑制率为68.6%。体内实验表明受试物对A549人肺腺癌裸鼠移植瘤具有较强的抑制作用,并呈现出良好的剂量依赖性。给予1.0、0.5、0.25mg/kg受试物,第一次实验,其对A549裸鼠移植瘤的抑制率分别为78.6%、58.8%和48.3%;第二次实验,其对A549裸鼠移植瘤的抑制率分别为84.2%、76%和68.2%。阳性药物紫杉醇15mg/kg多次给药的抑瘤率分别为56.0%和85.7%。结论:埃坡霉素B在体内外对A549人肺腺癌具有较强的抑制作用。     

埃博霉素作用机制和临床药理的研究进展

埃博霉素是由纤维堆囊菌分离得到的一类16元大环内酯类抗生素,其具有比紫衫炕类更强的微管稳定作用和抗肿瘤活性,对紫杉烷类耐药的肿瘤细胞仍具有较好的细胞毒性;综述2010年-2012年间关于埃博霉素的产生菌、生物合成和发酵表达、抗肿瘤机制以及临床药理研究的文献资料,并对其研究进展作一分析。     

埃博霉素类药物国内外生产情况及市场分析

随着恶性肿瘤对人类健康的危害性逐年增加,研发新颖抗肿瘤药物迫在眉睫。微生物来源的埃博霉素类药物具有微管稳定作用,其选择性高、活性强、毒性较低,有望取代紫杉醇成为新一代抗肿瘤药物,具有巨大的市场前景。鉴于政治、科技、经济、文化环境的不同,其市场情况及研发动态也出现一定变化。本文对当前这类药物国内外生产情况、研发动态及市场前景进行分析,并提供建议,预期能为企业生产经营方向的选择、医院临床用药等起到导向作用。     

埃博霉素类抗肿瘤药物的研究进展

具稳定微管作用的新型埃博霉素抗肿瘤药物类抗肿瘤活性显著,正在开发的多个品种应用前景良好.本文综述埃博霉素及该类药物的研究进展.     

Induction of apoptosis in human ovarian cancer cells by new anticancer compounds,epothilone A and B

Epothilones are a new group of compounds with action mechanisms similar to taxanes. The aim of this study was to compare the effects of epothilone A (Epo A) and epothilone B (Epo B) on ovarian cancer cell line SKOV-3 with those of paclitaxel (PTX), a classic taxane. We evaluate glycoprotein P (P-gp) activity in the ovarian cancer cell line. Apoptotic and necrotic cell levels were measured by double staining with Hoechst 33258 and propidium iodide (PI) as well as Annexin V staining. The production of reactive oxygen species (ROS) and changes in mitochondrial membrane potential (ΔΨm) in cells exposed to Epo A, Epo B and PTX were studied using specific fluorescence probes, DCFH₂-DA (2′,7′-dichlorodihydrofluorescein diacetate) and JC-1 (5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethylbenzimidazolcarbocyanine). The cytotoxic activity of the drugs was determined by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide) test. All probes were analyzed in both the presence and absence of the antioxidant N-acetylcysteine (NAC). The results obtained demonstrated that the antiproliferative capacity of Epo A and Epo B in SKOV-3 cell line (measured as IC₅₀ after 72 h continuous treatment) was six and five times greater than that of PTX’s respectively. Epothilones induced timecourse-dependent apoptosis and necrosis. Apoptotic and necrotic events were partially blocked by NAC, indicating ROS played a substantial role in epothilone-induced apoptosis. Cell death was also associated with a decrease in mitochondrial membrane potential, which was more pronounced after treatment with epothilones as compared to paclitaxel.     

纤维堆囊菌Soce90菌株发酵合成新型抗癌物质epothilones的营养控制

Ｅｐｏｔｈｉｌｏｎｅｓ是从粘细菌纤维堆囊菌（Ｓｏｒａｎｇｉｕｍｃｅｌｕｌｏｓｕｍ）中新分离的一类具有抗肿瘤活性的次级代谢产物。本文研究了影响纤维堆囊菌Ｓｏｃｅ９０菌株合成ｅｐｏｔｈｉｌｏｎｅｓ的条件。结果表明：菌体的生长状态对产物的合成有影响，指数期接种物、低氮高碳培养条件、某些盐离子、氨基酸和乙酸盐对ｅｐｏｔｈｉｌｏｎｅｓ的合成有益。以此获得较为稳定ｅｐｏｔｈｉｌｏｎｓ产量的条件因素     

Activity of epothilones

Epothilones represent a novel class of anticancer drugs which inhibit the cell cycle and strongly influence cell division. The biological activity of epothilones is associated with their capacity to bind to the protein tubulin of microtubules and to disturb the dynamic equilibrium between microtubule assembling and disassembling. Consequently, in dividing cells, it leads to mitotic arrest and to apoptotic cell death. A number of epothilones demonstrate a potent inhibitory effect on cell proliferation in human tumor cell lines, as well as antitumor activity in experimental animals bearing human tumor xenografts. This review will focus on the recent preclinical studies of the in vitro and in vivo activities of four epothilones, EPO-906, BMS-247550, KOS-862 and BMS-310705. Several epothilones are undergoing clinical evaluation and are promising candidates for advanced cancer therapy.     

Epothilones in the treatment of cancer

Epothilones are cytotoxic macrolides with a similar mechanism of action to paclitaxel but with the potential advantage of activity in taxane-resistant settings in preclinical models. The epothilones ixabepilone, patupilone, BMS-310705, KOS-862 and ZK-EPO are in early clinical trials for cancer treatment. Phase I studies have shown that dose-limiting toxicities of epothilones are generally neurotoxicity and neutropoenia although initial studies with patupilone indicated that diarrhoea was dose limiting. Neuropathy induced by ixabepilone may be schedule dependent. Over 20 Phase II studies of epothilones in cancer treatment have been reported, and significant activity in taxane-sensitive tumour types (such as breast, lung and prostate cancers) has been noted. Response rates in taxane-refractory metastatic breast cancer are relatively modest, but ixabepilone and patupilone have shown promising efficacy in hormone-refractory metastatic prostate cancer and in taxane-refractory ovarian cancer.     

埃博霉素的生物合成

埃博霉素是由黏细菌纤维堆囊菌产生的次级代谢产物。与紫杉醇相似,它们可以抑制微管解聚,使细胞有丝分裂终止在G2-M期。在P-糖蛋白表达型的多药耐药性肿瘤细胞系中维持很大的毒性,而且比紫杉醇有更好的水溶性。全合成埃博霉素虽然可以实现,但是与发酵方法相比尚无经济可行性。现就埃博霉素生物合成基因簇的克隆和异源表达,以及对Red／ET重组技术在埃博霉素生物合成中的应用进行了详细阐述。     

Studies on the biosynthesis of epothilones: hydroxylation of Epo A and B to epothilones E and F

When Sorangium cellulosum So ce90 is grown without XAD adsorber resin there is a steady state of epothilone A and B biosynthesis and hydroxylation of these products to epothilones E and F. This biotransformation at position C-21 of the thiazole ring is not restricted to producers of epothilones. It is carried out by a substrate induced monooxygenase. Epothilones E and F are further degraded by opening of the lactone ring by an esterase. Steps of degradation of different strains of S. cellulosum are compared.