CN1185112A - 黄酮木酯素在制备对子宫、卵巢和乳腺具有抗增殖活性的药物中的应用 - Google Patents
黄酮木酯素在制备对子宫、卵巢和乳腺具有抗增殖活性的药物中的应用 Download PDFInfo
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Abstract
本发明涉及黄酮木酯素如西利马林、水飞蓟素、水飞蓟宁、水飞蓟丁、其混合物、提取物和含有它们的制剂在治疗(和预防)子宫、卵巢和乳腺肿瘤中的应用。这些黄酮木酯素已被用于治疗各种病源引起的肝病,而且它们令人惊奇地对Ⅱ型雌激素受体具有显著的亲和力,对子宫、卵巢和乳腺的肿瘤细胞系具有抗增殖活性。
Description
本发明涉及黄酮木酯素(flavanolignane)单独或与已知的化疗药组合在制备用于治疗和预防子宫、卵巢和乳腺肿瘤的药物中的应用。
近来,已发现某些类黄酮具有抗肿瘤活性(Verna,癌症研究(CancerResearch)48,5754,1988)和对某些肿瘤具有化学预防活性(Cassady,天然产物杂志(J.Nat.Prod.)53,23,1990)。特别是槲皮黄酮-一种在植物中几乎普遍存在的类黄酮,已证明它除与常用的化疗药具有协同活性外,还对人白血病细胞的增殖具有一定的抑制活性(Larocca,英国血液学杂志(Br.J.of Haematology)75,489,1990)且对其它细胞系具有一定的抑制活性(Scambia,英国癌症杂志(Br.J.Cancer)62,942,1990-国际癌症杂志(Int.J.Cancer)46,1112,1990-癌症化疗药理学(Cancer Chemother.Pharmacol.)28,255,1991-妇科肿瘤学(Gynecologic Oncology)45,13,1992)。尽管还不知道这种增殖抑制作用的机理,但它似乎与这种类黄酮和II型雌激素受体的相互作用有关(Markaverich,类固醇生物化学杂志(J.Steroid Biochem.)30,71,1988)。最初由Clark(生物化学杂志(J.Biol.Chem.)253,7630,1978)描述的大鼠子宫中的这些受体与真正的雌激素受体(ER)不同,因为它们的存在浓度较高且对雌二醇的离解亲和常数(KD:10-20nM)低于雌激素受体的离解亲和常数(KD:0.2-1nM)。
现已令人惊奇地发现黄酮木酯素对II型雌激素受体具有高亲和力且对子宫、卵巢和乳腺中对顺铂和阿霉素具有抗药性的肿瘤细胞系具有非常显著的抗增殖活性,其中的西利马林已广泛用于治疗各种病源引起的肝病(hepatopathias),它的三种主要组分已知为水飞蓟素、水飞蓟宁、水飞蓟丁和脱氢水飞蓟素且具有以下报道的结构:
水飞蓟宁 水飞蓟宁水飞蓟丁为证明黄酮木酯素的抗增殖作用,已经在该化合物的存在下测定了来自各种人体肿瘤的不同稳定细胞系的生长曲线,并评价了它们与卵巢癌样品中的II型EBS相互作用的能力。]
已经在卵巢肿瘤或其它器官肿瘤上进行了对雌激素受体结合的测定,这些肿瘤采用加有小牛血清和200单位/ml青霉素的Dulbecco改性培养基作为培养基以单层进行培养。用于试验的细胞每周进行胰蛋白酶酶化(trypsinated)并以8×10-4/ml的密度置于平板上,在含5%CO2的潮湿空气气氛中于37℃温育。为控制这些产品的抗增殖活性,将这些细胞以4×104/ml的浓度放入孔(Falcon 3046,Becton Dickinson NY)中。24小时后用新鲜培养基更换原培养基并加入溶于无水乙醇中的黄酮木酯素。在不存在活性成分下仅用载体以相同的试验条件处理对照组。在72小时的试验时间里,以24小时的时间间隔重复上述处理。将对照组的生长与处理样品的生长进行比较,通过直接计数细胞来评价对细胞增殖的抑制。
对于这些受体的剂量,将24小时后的细胞用标量的标记雌二醇(3H-E240Ci/mmol,Amershan UK)单独或在100倍用量的己烯雌酚存在下在4℃下温育2.5小时。
温育时间结束后,迅速用新鲜底物洗涤细胞,再用1M NaOH温育30分钟。用闪烁仪测量放射性并由含或不含己烯雌酚的制剂之间的不同来计算结合特异性。根据文献(Raneletti,1988)的常规方法,结果表达为每个细胞的结合位点数。
将对照组的生长与处理组的生长进行比较,通过直接计数细胞来评价对细胞增殖的抑制。
对不同细胞系的结果示于图1和表I及表V中。具体来说,图1示出了水飞蓟素对A2780 WT的抗增殖活性,A2780 WT是一种对ER呈阴性,对II型呈阳性的卵巢癌细胞系。
两组试验备重复三次,结果取其平均值。标准偏差低于10%。
该抗增殖活性是剂量依赖性的。表I所示的是浓度为0.01μM-20μM的水飞蓟素在细胞增殖中的有关数据;水飞蓟素对不同的细胞系表现出剂量依赖性抗增殖作用,包括那些对化疗药具有抗药性的细胞系(MCF-7ADRr,A2780 CIS),其IC50为4.8-24μM。
表 I:水飞蓟素对不同的稳定细胞系的抗增殖作用细胞系 测试数* 细胞种类 暴露时间 IC50(μM)A2780 WT 8 卵巢癌细胞 72h 12A2780 CIS 5 卵巢癌细胞 72h 14
CIS抗性OVCA-433 3 卵巢癌细胞 72h 4.8MCF-7 ADRr 5 乳腺癌细胞 72h 24
ADR抗性*各试验一式三份
为了进一步研究水飞蓟素的抗增殖活性,研究其对A2780 WT细胞周期的作用。如表II所示,细胞荧光分析表明水飞蓟素降低S相细胞的百分数,并使G0/G1相细胞的百分数稍微增加。
表II:水飞蓟素对A2780 WT在细胞周期不同相中的分布的作用处理*
对照组 水飞蓟素(10μM)
G0/G1 58.7** 70.5
S 31 20.9
G2/M 10.3 8.6* A2780WT细胞用或不用10μM水飞蓟素培养2天。** 结果表达为细胞周期各相中的细胞百分数。
基于这些结果,试验水飞蓟素对某些化疗药,特别是顺铂(CIS)和阿霉素(ADR)的作用的增强。如表III所示,与单独使用相应剂量的药物相比,当水飞蓟素与CIS组合使用时,观察到对生长的协同抑制作用。
将水飞蓟素与ADR组合使用得到类似结果(表IV)。
为证明水飞蓟素与阿霉素或顺铂组合的这种作用是协同作用还是加合作用,用Berenbau(高级癌症研究(Adv.Cancer Res.),25,269,1981)的isobolic方法分析数据。在亲本(A2780 WT,表III)和抗性(MCF 7,ADR r,表IV)细胞系中所得组合指数均低于1,从而证明两种药物的组合具有协同抗增殖活性。表III:CIS-水飞蓟素组合对A2780WT细胞系的协同抗增殖作用CIS 水飞蓟素 % CIS 水飞蓟素 组合指数(μg/ml) (μM) 对照 (μg/ml) (μM)0.1 0.1 67 0.23 2.9 0.460.25 0.1 58 0.31 6.4 0.810.5 0.1 37 0.54 >50 <0.921 0.1 18 >1 >50 <1.000.1 1 54 0.34 8.2 0.41 0.25 1 35 0.56 >50 <0.460.5 1 25 0.82 >50 <0.621 1 12 >1 >50 <1.02表IV: ADR与水飞蓟素组合对MCF-7 ADRr细胞系的协同抗增殖作用ADR 水飞蓟素 % ADR 水飞蓟素 组合指数(μg/ml) (μM) 对照 (μM/ml) (μM)0.1 0.1 80 0.6 0.1 1.160.5 0.1 76 0.9 0.36 0.771 0.1 69 2.5 2.2 0.442.5 0.1 62 5.4 7 0.515 0.1 47 >10 35 <0.5010 0.1 39 >10 >50 <1.00
不仅对稳定化的细胞系,而且对人肿瘤细胞原始培养物观察水飞蓟素及其类似物的抗增殖活性。各种被测试的黄酮木酯素具有类似的性能。在表V中,列出了水飞蓟素、水飞蓟宁、西利马林和脱氢水飞蓟素的有关数据。在这些试验中水飞蓟素和异水飞蓟素的非对映异构体形式也同样具有活性。表V:不同黄酮木酯素对A2780WT细胞生长的作用化合物 试验数 暴露时间 IC50(μM)水飞蓟素 8 72h 12脱氢水飞蓟素 3 72h 2.88水飞蓟宁 3 72h 12西利马林 3 72h 15
此外,通过按照文献的常用条件测量植入裸露的无胸腺小鼠中的肿瘤大小,证明上述黄酮木酯素可体内抑制细胞增殖。以1-100mg/Kg的剂量处理这些动物,发现被测试的肿瘤以高个体百分数明显消退,直到消失。已证明该产品对人卵巢、乳腺和子宫肿瘤的活性高于已知药物如它莫西芬。
水飞蓟宁、脱氢水飞蓟素和水飞蓟素的两种非对映异构体形式显示出特别显著的活性。在体外试验中,黄酮木酯素直接使用,而在体内试验中,使用其与磷脂的配合物,如EP-A-0209038中所述。
根据本发明,黄酮木酯素可经口或通过输注给药:对于经口给药,作为载体特别有用的是天然或合成磷脂,因为它们与所述化合物形成上述的脂溶性稳定配合物;以及含有中链脂肪酸甘油三酯的液体半合成甘油酯或能增进单一化合物、其天然混合物或含有它们的提取物的生物利用率的类似物。
对人来说,黄酮木酯素剂量为50-1500mg/天,主要通过口服给药。
本发明还涉及用于抗肿瘤治疗的组合物,含有组合形式的西利马林黄酮木酯素和抗肿瘤药,它们同时、依次或单独使用。
下列实施例进一步说明本发明。
实施例1
含有水飞蓟素与大豆卵磷脂的配合物的硬明胶胶囊:组成:水飞蓟素-大豆卵磷脂配合物 300mg羧甲基纤维素钠 16mg滑石 6mg硬脂酸镁 3mg
实施例2
含有脱氢水飞蓟素的软明胶胶囊:组成:脱氢水飞蓟素 250mg液体半合成甘油酯 300mg部分氢化的植物油 49mg大豆卵磷脂 1mg
实施例3
含有西利马林与天然大豆磷脂的配合物的硬明胶胶囊:组成:西利马林-大豆磷脂配合物 360mg羧甲基纤维素钠 21mg滑石 6mg硬脂酸镁 3mg
实施例4
含有水飞蓟宁与大豆卵磷脂的配合物的硬明胶胶囊:组成:水飞蓟宁-大豆卵磷脂配合物 200mg羧甲基纤维素钠 10mg滑石 3mg硬脂酸镁 2mg
Claims (5)
1.黄酮木酯素在制备对II型雌激素受体具有拮抗活性和抗增殖活性的药物中的用途,该黄酮木酯素选自西利马林、水飞蓟素、水飞蓟宁、水飞蓟丁、脱氢水飞蓟素、其混合物或含有它们的提取物。
2.黄酮木酯素与磷脂的配合物在制备对II型雌激素受体具有拮抗活性和抗增殖活性的药物中的用途,该黄酮木酯素选自西利马林、水飞蓟素、水飞蓟宁、水飞蓟丁、脱氢水飞蓟素、其混合物或含有它们的提取物。
3.对II型雌激素受体具有拮抗活性和抗增殖活性的药物组合物,含有选自西利马林、水飞蓟素、水飞蓟宁、水飞蓟丁、脱氢水飞蓟素、其混合物或含有它们的提取物的黄酮木酯素作为活性成分,任意性地以与磷脂的配合物形式和任意性地与抗肿瘤药组合,同时、依次或单独使用。
4.根据权利要求3的组合物,适于口服给药。
5.根据权利要求4的组合物,含有液体半合成中链脂肪酸甘油酯作为载体。
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ITMI951047A IT1274549B (it) | 1995-05-23 | 1995-05-23 | Uso di flavanolignani per la preparazione di medicamenti ad attivita' antiproliferativa nei tumori dell'utero,dell'ovaio e del seno |
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN100402023C (zh) * | 2003-06-21 | 2008-07-16 | 山东绿叶天然药物研究开发有限公司 | 一种水飞蓟素软胶囊及其制备方法 |
CN109432084A (zh) * | 2018-12-26 | 2019-03-08 | 温州医科大学 | 一种抗癌组合物及其在药物制备中的应用 |
CN112494479A (zh) * | 2020-12-28 | 2021-03-16 | 华中科技大学同济医学院附属同济医院 | 茶黄素在制备卵巢功能保护药物方面的应用 |
Families Citing this family (63)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2432560A1 (fr) | 1978-08-02 | 1980-02-29 | Texas Instruments Inc | Procede de decapage de metaux, en particulier d'aluminium, au plasma de tetrachlorure de silicium |
US6379714B1 (en) | 1995-04-14 | 2002-04-30 | Pharmaprint, Inc. | Pharmaceutical grade botanical drugs |
EP1361210B1 (en) * | 1996-08-12 | 2008-12-24 | Celgene Corporation | Novel immunotherapeutic agents and their use in the reduction of cytokine levels |
US6239114B1 (en) * | 1997-09-26 | 2001-05-29 | Kgk Synergize | Compositions and methods for treatment of neoplastic diseases with combinations of limonoids, flavonoids and tocotrienols |
US6486193B2 (en) | 1998-12-31 | 2002-11-26 | Aventis Pharmaceuticals Inc. | 3-substituted pyrrolidines useful as inhibitors of matrix metalloproteinases |
WO2000066232A2 (fr) | 1999-04-30 | 2000-11-09 | Salomon S.A. | Chassis articule |
FR2792846B1 (fr) | 1999-04-30 | 2001-07-27 | Salomon Sa | Patin a roues en ligne du type a platine superieure articulee |
KR100342942B1 (ko) * | 1999-07-05 | 2002-07-02 | 민경윤 | 카르두스 마리아누스 추출물 또는 이로부터 정제된 실리빈을함유하는 경구용 마이크로에멀젼 조성물 |
US20010025027A1 (en) * | 2000-03-07 | 2001-09-27 | Sonis Stephen T. | Inhibition of ceramide for the prevention and treatment of oral mucositis induced by antineoplastic drugs or radiation |
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WO2002083124A1 (en) * | 2000-10-06 | 2002-10-24 | Probiochem, Llc | A composition and method of sustaining chemotherapeutic effect while reducing dose of chemotherapeutic agent using cox-2 inhibitor and statin |
WO2002064083A2 (en) * | 2000-11-30 | 2002-08-22 | The Children's Medical Center Corporation | Synthesis of 3-amino-thalidomide and its enantiomers |
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EP1314438A1 (en) * | 2001-11-23 | 2003-05-28 | Nutricia N.V. | Anti-proliferative composition |
MXPA05003889A (es) * | 2002-10-15 | 2005-06-22 | Celgene Corp | Farmacos inhibidores de citosina selectiva para tratar sindrome mielodisplastico. |
US7776907B2 (en) * | 2002-10-31 | 2010-08-17 | Celgene Corporation | Methods for the treatment and management of macular degeneration using cyclopropyl-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-3-oxoisoindoline-4-yl}carboxamide |
US20040091455A1 (en) * | 2002-10-31 | 2004-05-13 | Zeldis Jerome B. | Methods of using and compositions comprising immunomodulatory compounds for treatment and management of macular degeneration |
KR20050061586A (ko) * | 2002-10-31 | 2005-06-22 | 셀진 코포레이션 | 황반 변성의 치료를 위한 조성물 |
MXPA05004777A (es) * | 2002-11-06 | 2005-07-22 | Celgene Corp | Metodos de uso y composiciones que comprenden farmacos inhibidores selectivos de citocina para el tratamiento y el manejo de padecimientos mieloproliferativos. |
EP1581205A1 (en) * | 2002-11-18 | 2005-10-05 | Celgene Corporation | Methods of using and compositions comprising (+)-3-(3,4-dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide |
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US20080027113A1 (en) * | 2003-09-23 | 2008-01-31 | Zeldis Jerome B | Methods of Using and Compositions Comprising Immunomodulatory Compounds for Treatment and Management of Macular Degeneration |
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US8877780B2 (en) | 2006-08-30 | 2014-11-04 | Celgene Corporation | 5-substituted isoindoline compounds |
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RU2478635C2 (ru) | 2006-10-19 | 2013-04-10 | СИГНАЛ ФАРМАСЬЮТИКАЛЗ, ЭлЭлСи | Гетероарильные соединения, содержащие их композиции и способы лечения с применением этих соединений |
US8710272B2 (en) | 2007-01-08 | 2014-04-29 | Androscience Corporation | Compounds with (1 E, 6E)-1,7-bis-(3,4-dimethoxyphenyl)-4,4-disubstituted-hepta-1,6-diene-3,5-dione structural scaffold, their biological activity, and uses thereof |
US8236852B2 (en) | 2007-01-08 | 2012-08-07 | Androscience Corporation | Compounds with (substituted phenyl)-propenal moiety, their derivatives, biological activity, and use thereof |
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WO2010093434A1 (en) | 2009-02-11 | 2010-08-19 | Celgene Corporation | Isotopologues of lenalidomide |
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US8853175B2 (en) | 2011-01-10 | 2014-10-07 | Celgene Corporation | Phenethylsulfone isoindoline derivatives and their use |
WO2012097116A2 (en) | 2011-01-14 | 2012-07-19 | Celgene Corporation | Isotopologues of isoindole derivatives |
CN106083812A (zh) | 2011-03-11 | 2016-11-09 | 细胞基因公司 | 3‑(5‑氨基‑2‑甲基‑4‑氧‑4h‑喹唑啉‑3‑基)‑哌啶‑2,6‑二酮的固体形式及其药物组合物和用途 |
US20140221427A1 (en) | 2011-06-22 | 2014-08-07 | Celgene Corporation | Isotopologues of pomalidomide |
JP2014526508A (ja) | 2011-09-14 | 2014-10-06 | セルジーン コーポレイション | シクロプロパンカルボン酸{2−[(1s)−1−(3−エトキシ−4−メトキシ−フェニル)−2−メタンスルホニル−エチル]−3−オキソ−2,3−ジヒドロ−1h−イソインドール−4−イル}−アミドの製剤 |
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AU2019281613B2 (en) * | 2018-06-09 | 2022-09-08 | Jiangsu Atom Bioscience And Pharmaceutical Co., Ltd. | Compound for treatment or prevention of liver diseases |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2261434A (en) * | 1991-11-15 | 1993-05-19 | Inverni Della Beffa Spa | New radical scavenging and antipoperoxidant flavanolignans their preparation and formulations for therapeutic use |
CN1047944C (zh) * | 1993-06-26 | 2000-01-05 | 曾庆通 | 一种治疗慢性肝炎的中药胶囊 |
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Cited By (3)
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CN100402023C (zh) * | 2003-06-21 | 2008-07-16 | 山东绿叶天然药物研究开发有限公司 | 一种水飞蓟素软胶囊及其制备方法 |
CN109432084A (zh) * | 2018-12-26 | 2019-03-08 | 温州医科大学 | 一种抗癌组合物及其在药物制备中的应用 |
CN112494479A (zh) * | 2020-12-28 | 2021-03-16 | 华中科技大学同济医学院附属同济医院 | 茶黄素在制备卵巢功能保护药物方面的应用 |
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