CN1878471A - 用于癌症治疗的沙棘组合物 - Google Patents
用于癌症治疗的沙棘组合物 Download PDFInfo
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- CN1878471A CN1878471A CNA2004800332660A CN200480033266A CN1878471A CN 1878471 A CN1878471 A CN 1878471A CN A2004800332660 A CNA2004800332660 A CN A2004800332660A CN 200480033266 A CN200480033266 A CN 200480033266A CN 1878471 A CN1878471 A CN 1878471A
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Abstract
提供了用治疗有效量的沙棘叶、浆果和种子的提取物预防和治疗癌症的方法和组合物。公开了这些组合物在癌症治疗的不同阶段的新用途。提供了相对于COX-1优先抑制COX-2的包含沙棘提取物的新组合物。提供了除沙棘外还包含治疗有效量的至少一种化学治疗剂的组合物。
Description
本申请要求2003年9月22日提交的美国临时专利申请号60/505,053的优先权,该临时申请的内容在此全部引用作为参考。本申请还涉及2004年9月8日提交的美国申请系列号___(代理人诉讼卷号544302000100),其特意在此全部引用作为参考。
本发明技术领域
本发明一般涉及在疾病状态治疗期间使用沙棘提取物的领域。更特别地,本发明提供了用于预防及治疗疾病状态(包括癌症)的方法和沙棘浆果和叶子提取物的组合物。
发明背景
由于DNA损伤产生了癌细胞。多数时间当DNA受到损伤时,细胞死亡或能修复DNA。在癌细胞中,受损伤的DNA不能修复。人类可以遗传受损伤的DNA,这是一些遗传性癌的原因。人的DNA由于暴露于环境中的物质,如吸烟或暴露于生物危害如放射而受到损伤。
癌一般形成为肿瘤。一些癌,如白血病不形成肿瘤。替代地,这些癌细胞涉及血液及血液形成器官,并且循环到其它组织并在这些组织生长。癌细胞常常传播到身体的其它部分,在那里开始生长和替代正常组织。此过程称为转移,在癌细胞进入我们身体的血流或淋巴管时发生。当来自癌,如乳腺癌的细胞扩散到另一器官如肝时,此癌仍称为乳腺癌,而不是肝癌。不是所有肿瘤都是癌性的。良性(非癌性)肿瘤不扩散到身体的其它部分(转移)并且,除了非常罕见的例外,不威胁生命。
任一个体都处于患癌症的危险中。癌症的发生在生命中随衰老而增加(“终生危险”)。例如,在美国,男人具有二分之一的患癌症的终生危险,女人具有三分之一的危险。认为其它危险因素包括遗传、饮食和环境接触(例如,接触诱变性化学品、辐射、转化病毒等等)。世界卫生组织估计目前世界上每年大约有1000万新的癌症病例发生。到2015年该数字将预计达到1500万,这些新病例的三分之二发生于发展中国家(World Health48:22,1995)。例如,据估计每年全世界有大约600000个新的肺癌病例;每年接近100万的乳腺癌新病例;对于头颈癌(全世界第六大最频繁发生的癌症),每年有500,000个新病例发生。美国国立癌症研究所(the NationalInstitute of the United States)估计用于癌症的全部年度费用为1070亿美元。治疗费用占大约400亿美元。
当开发了新的治疗剂并测试其针对肿瘤的功效时,许多目前可用的癌症治疗是相对无效的。据报道,化学疗法仅在4%所治疗的患者中产生持久反应,且基本上延长了仅仅3%晚期癌症患者的生命(Smith等人,1993,J.Natl.Cancer Inst.85:1460-1474)。许多目前的抗癌药物是费用高昂的,并且呈现出严重的毒性。关于后者并依赖于所用的药物或药物组合,全身化学疗法可导致一种或多种毒性,包括血液的、脉管的、神经的、胃肠的、肾脏的、肺的、耳的和致死的毒性。例如,已将三苯氧胺用于妇女以限制乳腺癌复发长达25年。1992年开始的试验显示,三苯氧胺不仅作为治疗剂是有效的,而且在癌症预防中具有非常重要的益处(乳腺癌预防剂)。然而,在该项研究中,三苯氧胺的使用在健康妇女中显示出不利作用,即患子宫癌或产生肺部血块的危险增加(Science News,1998,153:228)。
植物是用于发现和开发用于治疗癌症的新的、自然来源的活性剂的宝贵资源。目前癌症治疗中所用的药物经设计用来干扰微管缩短(解聚)或延长(聚合)(Compton,D.A.等人,(1999)Science 286:913-914)。中心体-细胞的主要微管组织中心(MOTC)由称为中心粒旁物质(PCM)包围的两个中心粒组成,所述中心粒旁物质由复杂的细丝网络和两套附器组成(Paintrand,M.(1992)J Struct Biol 108:107-128)。中心体的主要功能是微管的成核现象和两极纺锤体的形成(Tanaka,T.等人,(1999)Cancer Res 58(17):3974-85)。中心体及其相关联的微管指导有丝分裂过程中的事件并控制动物细胞结构的组织和分裂间期的运动。恶性肿瘤通常显示出异常的中心体外形,特征为中心体大小和数量的增加、不规则的分配、异常的结构、异常的蛋白质磷酸化、以及与正常组织的中心体相比增强的微管成核能力(Lingle,W.L.等人,(1998)Proc Natl Acad Sci USA 95(6):2950-5;Sato.N.,等人,(1999)Clin Cancer Res 5(5):963-70;Pihan,G.A.等人,(1998)Cancer Res 58(17):3974-85;Carroll,P.E.,等人,(1999)Oncogene 18(11):1935-44;Xu,X.,等人,(1999)Mol Cell 3(3):389-95;Brinkley,B.R.,等人,(1998)Cell Motil Cytoskeleton 41(4):281-8;Doxsey,S.(1998)Nat Genet20(2):104-6;Kuo,K.K.,等人,(2000)Hepatology 31(1):59-64)。在这些异常中,发现中心体超扩增在多种肿瘤类型中是更加频繁的(Carroll,P.E.等人,(1999)Oncogene 18;18(11):1935-44;Hinchcliffe,E.H.等人,(1999)Science 283(5403):851-4;Xu,X.等人,(1999)Mol Cell 3(3):389-95;Weber,R.G.等人,(1998)Cytogenet Cell Genet 83:266-269)。0当前在癌症治疗中使用的多种药物设计为干扰微管聚合(如紫杉醇、多西他赛、依托泊苷、长春新碱、长春碱及长春烯碱)。它们具有结合组成微管的分子微管蛋白的共同作用机制(Compton,D.A.等人,(1999)Science286:913-914)。至少六种植物来源的抗癌剂得到FDA批准(例如,紫杉醇、长春碱、长春新碱、拓扑替康、依托泊苷、替尼泊苷)。在临床试验中正在评估其它治疗剂(例如,喜树碱、9AC和伊立替康)。
例如,最初分离自太平洋紫杉短叶红豆杉(Taxus brevifolia)的树皮的二萜类化合物紫杉醇是强有力的抗有丝分裂剂,其通过促进微管蛋白组装成稳定聚集的结构来起作用。(参见综述Kington,D.G.I.TrendsBiotechnol.1994,12,222;Schiff,P.B.;Fant,J.;Horwitz,S.B.Nature,1979,277,665)。紫杉醇显示出作为抗癌化合物的巨大潜能。实际上,目前将其用于治疗顽固性卵巢癌,并且临床试验鼓励用于治疗乳腺、肺、头和颈癌。(Rowinsky,E.K.;Cazenave,L.A.;Donehower,R.C.J.Nat.Cancer Inst.1990,82,1247;McGuire,W.P.;Rowinsky,E.K.;Rosenshein,N.B.;Grumbine,F.C.;Ettinger,D.S.;Armstrong,D.K.;Donehower,R.C.Ann.Int.Med.1989,11,273;Forastiere,A.A.,Semin.Oncol.Suppl.3.1993,20,56)。
10]正在研究化学预防剂在吸烟者和曾吸烟者的肺中降低癌前期细胞数量的能力,所述化学预防剂包括ACAPHA,其是在中国已经几个世纪以来用于疾病预防的六种植物性药材的组合(越南槐(Sophora tonkinensis)、圆穗蓼(Polygonum bistorta)、夏枯草(Prunella vulgaris)、Sonchus brachyotus、白鲜(Dictamnus dasycarpus)和黄独(Dioscorea bulbifera)。在US NationalCancer Institute许可下,British Columbia Cancer Agency(加拿大)正在领导国际协会开展ACAPHA的二期临床试验。
需要预防肿瘤的相对有成本效益的和高效的方法,所述方法额外减轻一般与全身化学治疗和放射治疗相关的毒性。
沙棘(Hippophae rhamnoides)提取物用于多种用途。例如,用沙棘种子油的不饱和脂肪酸调节血脂、抵抗血管硬化和放射、抑制肿瘤细胞、增强免疫力和滋养皮肤(CN1207920 Zou(1999));声称来自沙棘果实的油用于化妆品、药品和食品(DE4431393 Lorber和Heilscher(1996));护肤产品的沙棘油提取物(RU2106859 Senjavina等人(1998));化妆护肤霜中的沙棘油(RU2134570 Bencharov(1999));沙棘的软膏(0.5-1.5%)用于抑制发炎和过敏性皮肤损伤患者中caragenin诱导的水肿和被动皮肤过敏反应(RU2132183 Prokof等人(1999));含有沙棘油的软膏用于治疗烧伤和感染损伤(RU2129423 Frolov(1999));含有沙棘油的化妆护肤霜用于在冬天保护面部皮肤(RU2120272 Detsina和Selivanov(1998));含有沙棘油的护肤霜显示出抗过敏、杀细菌、抗炎和再生活性(RU2123320 Chistjakov(1998))。
发明概述
本发明提供了包含沙棘提取物的新组合物、提取物和化合物和它们的生产和制备方法。也提供了此类组合物在预防和治疗疾病状态(诸如癌症)期间的应用和用于制备和配制所述组合物的方法以及用本发明的组合物进行治疗的方法。一些实施方案还包含沙棘与有效量的至少一种化学治疗剂。
以前已证实了沙棘的一般抗氧化和免疫调节性质。本发明涉及用沙棘的抗氧化、免疫增强和其它性质减轻癌症治疗中的化学治疗和放射治疗的毒性作用。本发明也涉及鉴定显示显著较高抗氧化活性的沙棘的来源。本发明也鉴定了沙棘形式,诸如叶和浆果之间的差异。还公开了产生出乎意料的高质量沙棘组合物的提取和干燥方法。要求保护这些方法一般用于制备沙棘提取物和制剂。
在2003年9月8日提交的美国临时申请号60/501,456中公开了向其它植物提取物中加入沙棘的协同作用,将该临时申请在此引用作为参考。本发明提供了含有沙棘的组合物在癌症治疗中的应用并且其基于沙棘降低化学治疗药物的毒性的所公开的能力。
在一个实施方案中,本发明的组合物包含有效量的灵芝(Ganodermalucidum)、半枝莲(Scutellaria barbata)、丹参(Salvia miltiorrhiza)和沙棘提取物,所述有效量的提取物通过显示一种或多种性质而用于抑制原始癌细胞的进一步生长,所述一种或多种性质为(i)增强免疫系统,(ii)减小对细胞和组织的氧化性损伤,(iii)减轻炎症,(iv)阻止细胞周期特定阶段中细胞的增殖,(v)抗氧化活性,和(vi)针对进一步暴露至致癌剂和诱变剂的抗诱变效应。
本发明的组合物包含有效量的沙棘叶、浆果和/或种子提取物,所述提取物自身或组合优先抑制COX-2酶的活性强于抑制COX-1的活性。在优选的实施方案中,有效量的沙棘提取物抑制COX-2比抑制COX-1更有效1.5倍、2倍、3倍、5倍或10倍。在一些实施方案中,有效量的沙棘提取物抑制COX-2活性及增强COX-1活性。
本发明和本发明的其它目的、特征及优点将在在下面的发明详述和附图和实施方案中变得更显而易见。
附图简述
图1显示植物提取物的提取平台。
20]图2显示用热水的提取步骤。
图3显示用80%乙醇的提取步骤。
图4显示用氯仿/甲醇的提取步骤。
图5A显示沙棘浆果的抗氧化组分。图5B显示沙棘叶的抗氧化组分。
图6显示灵芝、丹参和半枝莲(3H)粉末掺和物的剂量效应曲线。
图7为灵芝、丹参和半枝莲(3H)及3H加沙棘(4H)粉末掺和物的剂量效应曲线。
图8显示3H及4H粉末掺和物的组合指数曲线。
图9显示3H及4H热水提取掺和物的剂量效应曲线。
图10显示用于3H及4H热水提取掺和物的组合指数曲线。
图11A显示沙棘和其它浆果的维生素C含量。图11B显示沙棘果和其它浆果的维生素E含量。
30]图12A显示沙棘和其它浆果的栎精含量。图12B显示沙棘和其它浆果的黄酮醇含量。
图13显示在不同干燥条件下沙棘浆果的抗氧化剂含量。
图14显示植物掺和物的抗氧化活性。
图15显示植物对抗氧化活性的相对贡献(GL=灵芝;SB=半枝莲;SL=丹参;SBTL=沙棘叶)。
图16显示与抗癌药物施用的植物提取物的协同作用。
图17A显示沙棘叶及沙棘浆果的不同提取物(脂类提取物/溶剂级分(LE/SF);脂类提取物/水级分(LE/WF);80%乙醇(EtOH);和热水(HW))对COX-2酶活性的抑制。图17B显示沙棘叶及沙棘浆果的不同提取物对COX-1酶活性的抑制。
发明详述
本发明提供了用于预防和治疗个体中癌症的新方法及用作抗癌剂的组合物。本发明涉及新发现:基于植物提取物的组合物向个体施用时可以有效抑制肿瘤生长并且基本上无毒性。组合物包含灵芝、半枝莲、丹参及任选地,沙棘的两种或多种提取物。
在一个实施方案中,此方法包括向荷瘤个体(哺乳动物;在优选的实施方案中,人)施用治疗有效量的组合物。在另一实施方案中,此方法包括向个体施用预防有效量的组合物以预防肿瘤发展(例如,在发生肿瘤的高度危险的个体中;或在减轻但有复发危险的个体中)。
因此,本发明的首要目的是提供通过施用治疗有效量的组合物治疗荷瘤个体的方法,所述组合物在向所述荷瘤个体施用时具有抑制肿瘤生长的性质。
本发明的另一目的是提供通过施用预防有效量的组合物防止具有肿瘤发生危险的个体中肿瘤发生的方法,所述组合物在向所述个体施用时具有抑制肿瘤生长的特性。
40]本发明的另一目的是提供用治疗有效量的组合物治疗荷瘤个体、或具有发展肿瘤危险个体的方法,所述组合物在向个体施用时具有抑制肿瘤生长及基本上无毒性的特性。“基本上无毒性”表示组合物缺乏一般与全身化学治疗相关的毒性;即缺乏可检测的毒性,包括血液学、血管、神经、胃肠、肾、肺、耳科学及免疫抑制(可导致致死性感染)毒性。
本发明的又一目的是提供治疗肿瘤负荷实质性降低但仍有复发危险的个体的方法,其中该方法包括向个体施用预防有效量的组合物,所述组合物具有向所述个体施用时抑制肿瘤生长和基本上无毒性的性质。
定义
对于本说明书和权利要求,文中使用的“肿瘤”表示导管上皮细胞来源的实体非淋巴原发性肿瘤,包括但不限于,源自乳腺、前列腺、结肠、肺、胰腺、肝脏、胃、膀胱或生殖道(子宫颈、卵巢、子宫内膜等等)、脑和骨髓的肿瘤;黑素瘤或淋巴瘤。
对于本说明书和权利要求,文中使用的“抑制肿瘤生长”表示减慢肿瘤生长、阻止肿瘤生长、引起肿瘤减小或退化、抑制肿瘤侵入、引起肿瘤细胞死亡和引起转移降低或退化的一种或多种。
对于本说明书和权利要求,文中使用的“防止肿瘤发展”指抑制肿瘤生长;更特别地,在防止肿瘤块形成中引起肿瘤细胞死亡。
文中使用的术语“植物”是指用于所描述目的的种子、叶、茎、花、根、浆果、茎皮或任意其它植物部分。对于某些用途,优选植物的地下部分,如利用根和根茎。叶、茎、种子、花、浆果、茎皮或其它植物部分也具有医疗作用并且可以用于制备茶和其它饮料、乳膏和食物制品。
“协同作用”可以通过组合指数(CI)测定。组合指数方法由Chou和Talalay描述。(Chou,T.-C.The median-effect principle and thecombination index for quantitation of synergism and antagonism,p.61-102.In T.-C.Chou和D.C.Rideout(ed.),Synergism and antagonism inchemotherapy.Academic Press,San Diego,Calif.(1991);Chou,T.-C.,和P.Talalay.Quantitative analysis of dose-effect relationships:the combinedeffects of multiple drugs on enzyme inhibitors.Adv.Enzyme Regul.22:27-55(1984))。将0.90或更低的CI值认为是协同的,0.85的值是中等协同的,且低于0.70的值为显著协同的。将0.90至1.10的CI值视为几乎是累加的,而更高值则为拮抗的。
表1.作为CI值函数的协同/拮抗作用
CI值 | 解释 |
>10 | 非常强的拮抗作用 |
3.3-10 | 强拮抗作用 |
1.45-3.3 | 拮抗作用 |
1.2-1.45 | 中等拮抗作用 |
1.1-1.2 | 轻微拮抗作用 |
0.9-1.1 | 累加的 |
0.85-0.9 | 轻微协同作用 |
0.7-0.85 | 中等协同作用 |
0.3-0.7 | 协同作用 |
0.1-0.3 | 强协同作用 |
<0.1 | 非常强协同作用 |
4值得注意的是协同的确定可受到生物变异性、剂量、实验条件(温度、pH、氧张力等等)、治疗时间表和组合比率的影响。
沙棘
在俄罗斯和中国医学中沙棘油广泛用作健康油或用作药物(Li,T.S.C.;Schroeder,W.R.Sea buckthorn(Hippophae rhamnoides L.):Amultipurpose plant.HorTech.1996,6,370-380.)。报道它防止肝损伤、急性和慢性肝炎(Xiaoping,T.;Qiaohong,S.;Xiaolan,C.;Jun,C.;Yulan,L.;Qingning,L.Study of biochemical pharmacology of sea buckthorn fruitoil and its compound health products.Proc.Int.Workshop on Seabuckthorn,1995,Beijing,China,(published)1996,pp 161-164);对化学灼伤具有治疗作用(Nikulin,A.A.;Iakusheva,E.N.;Zakharova,N.M.Acomparative pharmacological evaluation of sea buckthorn,rose andplantain oils in experimental eye burns.Eksp.Klin.Farmakol.1992,55,64-66.);和具有抗诱变性质(Nersesian,A.K.;Zil’fian,V.N.;Kumkumadzhian,V.A.;Proshian,N.V.Antimutagenic properties of seabuckthorn oil.Genetika 1990,26,378-380)。
沙棘种子油含有高含量的两种必需脂肪酸——亚油酸和α-亚麻酸,其为其它多不饱和脂肪酸例如花生四烯酸和二十碳五烯酸的前体。来自沙棘浆果的果肉/果皮的油富含棕榈油酸和油酸(Chen等人″Chemicalcomposition and characteristics of seabuckthorn fruit and its oil.″Chem.Ind.Forest Prod.(中国)10(3),163-175)。在血浆脂类中α-亚麻酸水平的升高表明对遗传过敏性皮炎症状的明显改善的效果(Yang,B.,等人“Effect ofdietary supplementation with sea buckthorn(Hippophae rhamnoides)seedand pulp oils on the fatty acid composition of skin glycerophospholipids ofpatients with atopic dermatitis.”J Nutr Biochem.2000 Jun 1;11(6):338-340)。已将α-亚麻酸的这些效果归因于类花生酸组成的变化和独立于类花生酸合成的其它机制(Kelley 1992,α-linolenic acid and immuneresponse.Nutrition,8(3),215-2)。
沙棘(Hippophae rhamnoides L.)是含水和亲脂的抗氧化剂以及多不饱和脂肪酸的丰富来源。已报道了抗氧化剂丰富的果汁(沙棘)对人中的冠心病危险因子的作用(Eccleston等人J Nutr Biochem.2002 Jun;13(6):346-354.)。沙棘对肝硬化患者的作用进行了研究并报道缩短了转氨酶正常化的持续时间。(Gao ZL.等人,World J Gastroenterol.2003Jul;9(7):1615-1617)。证实沙棘整个浆果的乙醇提取物RH-3在小鼠对全身致死性照射存活方面提供放射保护活性(Goel HC,等人Phytother Res.2003Mar;17(3):222-226)。
利用淋巴细胞作为模型系统已证实沙棘(Hippophae rhamnoides)的抗氧化剂和免疫调节性质(Geetha等人,J Ethnopharmacol 2002Mar;79(3):373-8)。也报道了沙棘油的细胞保护活性(Geetha等人,Biomed.Pharmacother.2002,56:463-467.)。还阐明了沙棘的己烷提取物的抗溃疡效果(Suleyman H等人,Phytother Res 2001Nov;15(7):625-7)。沙棘浆果的植物制剂(30mg/kg小鼠体重)在小鼠中对全身致命辐射的辐射保护提示了自由基清除,干细胞增殖加速和免疫刺激剂特性。(Goel HC等人,Phytomedicine 2002 Jan;9(1):15-25)。已报道来自沙棘的总黄酮的血小板凝集抑制作用。(Cheng等人,Life Sciences 2003,72:2263-2271)。沙棘整个浆果的有机提取物对大鼠血液中烟碱诱导的氧化应激的有益作用与维生素E进行了比较(Suleyman H等人,Biol.Pharm.Bull.25:1133-1136;2002)。
一个研究发现抗坏血酸是沙棘汁的主要抗氧化剂(大约75%)。(RoschD.等人,J Agric Food Chem.2003 Jul 16;51(15):4233-4239.)。已报道来自沙棘Indian Summer变种(Hippophae rhamnoides L.Cv.IndianSummer)的沙棘汁组合物的加工作用(Beveridge T.等人,J Agric FoodChem.2002 Jan 2;50(1):113-116)。
沙棘提取物对编程性细胞死亡和细胞增殖的作用不清楚,可能取决于使用的提取物和量。用30mg/kg体重的沙棘浆果提取物处理小鼠增加淋巴细胞、多形核白细胞和单核细胞的增殖。(Goel HC等人,Phytomedicine9:15-25;2002)。在辐射前向小鼠施用沙棘浆果提取物降低空肠中隐窝和绒毛的细胞损失和降低此类细胞中编程性细胞死亡的频率。(Goel HC等人,Phytotherapy Research 17:222-226;2003)。然而,相同研究者也发现沙棘提取物可以在简单化学系统中产生活性氧类别和在经处理的胸腺细胞中产生DNA-蛋白质交联。他们的研究显示了沙棘的差别作用:在没有辐射时用低浓度提取物处理的细胞产生氧自由基而用高浓度提取物处理细胞能清除通过辐射产生的自由基。(Goel HC等人,Molecular and CellularBiochemistry 245:57-67;2003)。以依赖于浓度的方式,达100μg/ml的沙棘浆果提取物在先体外后体内条件下在胸腺细胞中诱导编程性细胞死亡。然而,在此剂量之外,编程性细胞死亡的诱导受到抑制。沙棘浆果提取物的30mg/kg体重的放射保护剂量(参见以上Goel,Phytomedicine 9:15-25;2002)也在胸腺细胞中诱导显著的DNA断裂。(Goel HC等人,Journal ofEnvironmental Toxicology and Oncology 23:123-137;2004)。
本发明涉及用沙棘提取物预防癌症。沙棘的抗氧化性质用于保护细胞免受环境对染色体和基因的损伤和因此降低癌相关基因中突变的可能性。
本发明还涉及用沙棘提取物治疗癌症。通过与化学治疗剂共同施用使用沙棘的抗氧化性质。沙棘降低了此类治疗剂的毒性副作用,允许(i)增加化学治疗剂的剂量和/或(ii)减轻施用化学治疗剂的症状。
由于沙棘对放射治疗和化学治疗的保护作用,它在治疗癌症中是有益的。另一方面,沙棘的强抗氧化性质可以抵消防止癌细胞增殖的活性剂的细胞毒性作用。通过调节沙棘提取物的浓度对本发明的组合物进行制备以优化有益作用。
组合物
本发明的组合物可以为任意有效的形式,包括,但不限于干粉、研磨物(grounds)、乳剂、提取物和其它常规的组合物。为提取或浓缩组合物的有效成分,通常用适当的溶剂例如水、乙醇、甲醇或其它溶剂或混合溶剂接触植物部分。溶剂的选择可常规地完成,例如,基于将通过溶剂提取或浓缩的活性成分的特性。组合物优选的活性成分包括但不限于维生素C和E、α-亚麻酸、phenolocs、酚酯、黄酮醇、花色素苷、蛋白质、栎精等。这些成分可以同样的步骤来提取,例如,利用醇溶剂、或者单独提取它们,每次利用对从植物中提取特定目的成分特别有效的溶剂。在特定的实施方案中,可通过下列方法来进行提取:将所选的部分,优选叶子研磨成粉末。可将粉末在目的溶剂中浸泡一段时间以从该组合物中有效提取活性剂。可将溶液过滤并浓缩以产生含有高浓度的溶剂提取成分的糊剂。在一些情况下,可将糊剂干燥来产生组合物的粉末提取物。提取物中活性成分的含量可利用HPLC、UV和其它光谱测定方法来测定。
本发明的组合物可以任意形式通过任何有效的途径施用,施用途径包括例如,经口、肠道外的、肠的、腹膜内的、局部的、经皮的(例如利用任何标准贴剂)、眼的、鼻的、局部的、非口服的、例如气溶胶的、吸入、皮下的、肌内的、口腔的、含服、直肠的、阴道的、动脉内的、和鞘内途径等等。它可单独或与任意活性或非活性成分包括在药用形式中或者作为食物或饮料添加剂施用。
在本发明优选的实施方案中,将组合物以任意适当的形式经口施用,所述形式包括,例如,整个植物、粉末化或研磨的植物材料、提取物、丸剂、胶囊剂、粒剂、片剂或混悬剂。
可将组合物与任何药物学上可接受的载体组合。短语“药物学上可接受的载体”表示任何药物载体,例如Remington′s Pharmaceutical Science,第18版,Mack Publishing company,1990中所描述的标准载体。合适载体的实例在本领域是众所周知的,可包括但不限于任何标准药物载体,例如磷酸缓冲盐溶液,含有Polysorb 80的磷酸缓冲盐溶液、水、乳剂例如油/水乳剂和多种类型的润湿剂。其它载体还可包括无菌溶液、片剂、包衣片剂药物和胶囊剂。通常此类载体含有赋形剂,例如淀粉、奶、糖、某些类型的粘土、明胶、硬脂酸或其盐、硬脂酸镁或钙、滑石、植物脂肪或油、树胶、二元醇。此类载体还可包括风味或颜色添加剂或其它成分。通过众所周知的常规方法配制包含此类载体的组合物。通常与组合物一起配制的赋形剂适合于经口施用并且不与其或其它活性成分有害地反应。合适的药物学上可接受的载体包括但不限于水、盐溶液、醇、阿拉伯树胶、植物油、苯甲醇、明胶、糖,例如乳糖、直链淀粉或淀粉、硬脂酸镁、滑石、硅酸、粘性石蜡、芳香油、脂肪酸甘油单酯和甘油二酯、季戊四醇脂肪酸酯、羟基甲基纤维素等等。其它添加剂包括,例如,抗氧化剂和防腐剂,着色剂、调味剂和稀释剂,乳化剂和悬浮剂,例如,阿拉伯树胶、琼脂、藻酸、藻酸钠、皂土、卡波姆、角叉藻聚糖、羧甲基纤维素、纤维素、胆固醇、明胶、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、甲基纤维素、辛苯昔醇-9(octoxynol 9)、油醇、聚维酮、一硬脂酸丙二醇酯、十二烷基硫酸钠、山梨聚糖酯、硬脂醇、黄蓍胶、黄原胶,及其衍生物,溶剂和混杂成分,例如微晶纤维素、柠檬酸、糊精、葡萄糖、液体葡萄糖、乳酸、乳糖、氯化镁、偏磷酸钾、淀粉等等。
组合物可与其它活性成分配制,所述活性成分为例如抗氧化剂、维生素(A、C、抗坏血酸、B族、例如B1、硫胺素、B6、吡哆醇、B复合物、生物素、胆碱、烟酸、泛酸、B12、维生素B12、和/或B2、D、D2、D3、麦角钙化醇、E、例如生育酚、核黄素、K、K1、K2)。优选的化合物,包括,例如一水合肌酸、丙酮酸盐、L-肉碱、α-硫辛酸、植酸钙镁或植酸、辅酶Q10、NADH、NAD、D-核糖、氨基酸例如L-谷氨酰胺、赖氨酸、白杨素、前激素,例如4-雄烯二酮、5-雄烯二酮、4(或5-)雄烯二醇、19-去甲-4(或5-)-雄烯二酮、19-去甲-4(或5-)-雄烯二醇、β-蜕皮甾酮、5-甲基-7-甲氧基异黄酮。优选的活性成分包括,例如,松花粉、枸杞子(Fructus Lycii)、沙棘、当归(ligusticum)、刺五加(Acanthopanax)、距骨(astragalus)、麻黄(ephedra)、党参(Codonopsis)、远志(polygola tenuifolia Willd)、百合(Lilium)黑三棱(Sparganium)、人参、panax notogiseng、藤黄(Garcinia)、Guggle、葡萄种子提取物或粉末、和/或无心银杏(Ginkgo Biloba)。
可与本发明的组合物配制的其它植物和植物药材包括多种教科书和出版物,例如ES Ayensu,Medicinal Plants of West Africa,ReferencePublications,Algonac,Mich.(1978);L.Boulos,Medicinal Plants of NorthAfrica,Reference Publications Inc.,Algonac,Mich.(1983);和N.C.Shah,Botanical Folk Medicines in Northern India,J.Ethnopharm,6:294-295(1982)中所提及的那些。
其它活性成分包括,例如,抗氧化剂、抗癌剂、抗炎剂、激素、和激素拮抗剂、抗生素(例如,羟氨苄青霉素)和其它细菌制剂,以及其它医药上有用的药物,例如那些在例如Remington′s Pharmaceutical Sciences,第18版,Mack Publishing Company,1990中所鉴定的药物。本发明优选的组合物包含大约1%-100%,优选地大约20-70%的植物提取物;以及,任选地,药物学上可接受的赋形剂。
本发明涉及施用组合物的方法,例如,用以提供抗氧化剂效果、保护免受氧化、提供抗癌效果、促进DNA修复、提供抗辐射效果、保护免受辐射、减轻炎症、及如此处所述的其它病症和疾病。
术语“施用”意指以这样的方式将组合物递送给宿主,所述方式可以实现预期的目的。如所提到的,可通过有效的途径例如经口、局部地、直肠地等等途径来施用组合物。组合物可施用给需要治疗的任意宿主,例如脊椎动物,例如哺乳动物,包括人、男人、女人、灵长类、宠物,例如猫和狗、家畜,例如牛、马、鸟、鸡等等。
将有效量的组合物施用于此类宿主。有效量是这样的量,其可用于实现预期效果,优选地如上所述的有益或治疗性效果。所述量可常规地来确定,例如,通过进行剂量反应实验,其中对细胞、组织、动物模型施用不同剂量以确定获得目的效果的有效量。量的选择基于多种因素,包括组合物所施用的环境(例如,癌症患者、动物模型、组织培养细胞,等等)、所要处理的细胞的位置、所要治疗的患者或动物的年龄、健康、性别和重量,等等。有用量包括每剂量不同形式的组合物1-100、5-500、10-1000μg/mL、10毫克-100克,优选例如,100毫克-10克、250毫克-2.5克、1克、2克、3克、500毫克-1.25克或更高,所述组合物为例如植物粉剂、植物提取物糊剂或粉剂、制备成含有组合物有效成分的茶和饮料,以及注射剂,这取决于受者的需要和制备方法。
治疗性沙棘组合物
本发明涉及包含沙棘提取物的组合物,所述组合物通过显示一种或多种性质而在“早期”癌和前癌病症中起作用,所述一种或多种性质为(i)增强免疫系统,(ii)降低对细胞和组织的氧化损伤和(iii)抗炎活性,诸如COX-2抑制作用。在典型的组合物中包括沙棘提取物和其它抗癌化合物,诸如化学治疗剂。
适合用于本发明的组合物和方法中的化学治疗剂可为任意已知的药学上可接受的治疗剂,这至少部分取决于因其抗癌活性而干扰细胞结构和/或代谢。常规的化学治疗剂的实例包括但不限于,铂化合物,例如顺铂、卡波铂和它们的类似物及衍生物;烷化剂例如苯丁酸氮芥、氮芥、氧氮芥、环磷酰胺、4-过氧羟基环磷酰胺、醛磷酰胺(aldophosphamide)的2-己烯基吡喃糖苷(2-hexenopyranoside)、苯丙氨酸氮芥、BCNU、CCNU、甲基-CCNU、尿嘧啶芥、甘露氮芥、三亚胺嗪(triethylenemelamine)、氯脲霉素、ACNU、GANU、MCNU、TA-77、六甲密胺、二溴甘露醇、哌泊溴烷、双环氧哌啶、环氧哌嗪、ethoglucide、pippsulfan、dimethylmilelane、bubulfan、inprocuon、threnimone、噻替哌和氮替哌;抗代谢物例如5-氟尿嘧啶、叶酸、氨甲喋呤(MTX)、6-巯基嘌呤、氨基蝶呤、8-氮鸟嘌呤、咪唑硫嘌呤、尿嘧啶、阿糖胞苷、重氮丝氨酸、喃氟啶、BHAC、SM108、阿糖胞苷、cispuracham、diazamycine、HCFU、5′DFUR、TK-177和cyclotidine;抗生素,例如博来霉素、柔红霉素、四环素、放线菌素D、丝裂霉素C、carzinophylin、macrocinomycin、neothramycin、大分子霉素、nogaromycin、cromomycin、7-o-methylnogallol-4′-表柔比星、4-去甲氧基柔红霉素、链脲佐菌素DON和米托蒽醌;二-氯乙基化治疗剂,例如麦磺磷芥、氮芥、nornitrogen mustard、苯丙氨酸氮芥、苯丁酸氮芥;激素类例如雌激素类;生物还原剂,例如丝裂霉素C、和其它的治疗剂,例如米托蒽醌、甲基苄肼、多柔比星、表柔比星、松龙苯芥、异环磷酰胺、P-糖蛋白抑制剂,例如thaliblastine,以及蛋白激酶抑制剂,例如蛋白激酶C抑制剂(依莫佛新)。化学治疗剂特别指抗微管剂或微管蛋白靶定剂,包括长春花生物碱;长春花生物碱例如依托泊苷、鬼臼毒素、长春新碱和长春花碱;紫杉烷类(紫杉醇、多西他赛)和前体紫杉烷(10-脱乙酰基浆果赤霉素III)、砷盐、秋水仙素、硫代秋水仙素、秋水仙酰胺、秋水仙碱水杨酸盐和其它colchium盐;表鬼臼毒素(依托泊苷)、细胞松弛素(例如A-E,H,J)、冈田酸(okadaic acid)、胺甲萘及其代谢物,例如萘酚或萘基化合物,包括1-萘酚、2-萘酚、磷酸1-萘基酯、丙二酸、洛可达唑(甲基-(5-[2-噻吩基-羰基]-1H-苯并咪唑-2-基)氨基甲酸酯)、cryptophycin(CP)及其类似物例如CP-52、渥曼青霉素、12-O-十四烷酰佛波醇-13-乙酸酯(TPA)、14-3-3sigma及其同系物(例如rad24和rad25)、Ustiloxin F、野百合碱,例如野百合碱吡咯(MCTP)、雌氮芥、以及腺苷的抑制剂。这些化学治疗剂既可单独使用也可组合使用。优选地,将一种抗代谢物和一种抗微管剂相组合,且更优选地将具有不同肿瘤杀伤机制的紫杉醇、顺铂、苯丁酸氮芥、环磷酰胺、博来霉素或5-氟尿嘧啶相组合。干扰细胞骨架的含有砷化合物、秋水仙素、秋水仙碱、秋水仙酰胺、秋水仙碱水杨酸盐、colchium salts、长春花碱、紫杉醇及相关化合物的组合是最优选的。由于新的化学治疗剂和药物得以鉴定并且可被本领域利用,所以可将它们直接应用于本发明的实践中。
在优选的实施方案中,除了灵芝、半枝莲、丹参的一种或更多种外,所有天然组合物还包含与植物组分组合的沙棘提取物,所述植物组分为例如环磷酰胺、4-过氧羟基环磷酰胺、噻替哌、紫杉醇和相关化合物,阿霉素、柔红霉素和新制癌菌素。
目前用于癌症治疗及设计用于干扰微管缩短(解聚)或延长(聚合)的药物例如紫杉醇、多西他赛、依托泊苷、长春新碱、长春花碱和长春烯碱是沙棘组合物的成分。这些药物结合到微管蛋白——组成微管的分子上,并通过抑制纺锤体组装来抑制有丝分裂中的细胞(Compton,D.A.等人,(1999)Science 286:313-314)。
除施用治疗有效量的组合物外,根据本发明利用沙棘组合物进行抗癌治疗的方法还包含施用治疗有效量的一种或多种标准抗癌治疗(例如,一种或多种放射疗法、化学疗法、外科手术、免疫疗法和光动力疗法)。在此备选的优选实施方案中,除施用治疗有效量的组合物外,所述方法还包含施用治疗有效量的一种或多种标准化学治疗药物。治疗有效量的一种或多种标准化学治疗药物和治疗有效量的沙棘组合物的组合由于沙棘减轻了化学治疗剂的毒副作用而允许使用更大剂量的该化学治疗剂。
本发明还涉及包含沙棘提取物的组合物,所述提取物由于显示一种或多种性质而可以治疗“晚期”癌症,所述一种或多种性质为(i)加强免疫系统,(ii)降低对细胞和组织的氧化损伤,和(iii)增加对标准治疗的耐受性。在优选的实施方案中,使用了沙棘的热水提取物。提取物,特别是沙棘的热水提取物显示出显著的抗氧化性质和对标准化学治疗和放射治疗的增强的耐受性。
实施例
相信本领域的技术人员不用进一步的详细阐明就可以利用前面的描述在最大程度上利用本发明。下面的实例仅仅是例证性的,并且无论如何不限制该公开的剩余内容。
除了沙棘外,所有实施例中使用以下植物的提取物:西洋参(PanaxQuinquefolium)、灵芝、半枝莲、丹参和大叶茶(Camellia sinensis)(绿茶)。
常常将利用这些组合或单独提取物所获得的结果与ACAPHA——六种植物的组合(越南槐(Sophora tonkinensis)、圆穗蓼(Polygonum bistorta)、夏枯草(Prunella vulgaris)、Sonchus brachyotus、白鲜(Dictamnus dasycarpus)和黄独(Dioscorea bulbifera)相比较。
实施例1:制备植物提取物的方法
本发明的组合物可以作为干燥植物施用。植物制剂含有植物化学物质,它们中的一些在水性介质中是可溶的,而其它的在有机(醇、脂类)介质中是相对更可溶的。使用了不同的提取方法并测试了从植物中提取有效成分的能力。提取方法包括:热水提取、有机(脂类或溶剂级分)提取、有机(水性级分)提取、和乙醇提取。
7通过图1中显示的一般提取平台用不同溶剂从植物制备产物。用溶剂(热水、80%乙醇或氯仿/甲醇)回流30-60分钟对植物或植物掺和物进行提取,通过过滤以获得滤液来分离,并风干用于进一步分析。在测定活性前将滤液合并、稀释或浓缩。优选地,将提取重复一次以上,但在第三次提取后回收率趋低。
用热水、80%乙醇和氯仿/甲醇的提取步骤分别在图2、3和4中图示。一般地,植物的热水提取物具有最高浓度的酚类化合物、酚酯、黄酮醇和花色素苷。沙棘浆果和叶具有高浓度的此类成分。在一个实施方案中连续热水提取后用乙醇提取最合适用于提取黄酮类化合物。
实施例2:沙棘叶和浆果提取物的性质
浆果和种子的重量、大小和产量在沙棘的品种中显著不同,此类不同也随季节而明显。沙棘的理化特征依赖于品种,甚至在一个位置生长时也如此。依赖于品种,汁液的产量为73%至91%并且可溶性固体为7.7至15.2糖度。类似地,汁液中的抗坏血酸含量和总类胡萝卜素含量也分别为31至754mg/100g和7至19mg/100g果实。也观察到在品种之间汁液的抗氧化效率(AE)为9.5%至88%的显著差异。
取决于品种,用己烷提取的种子油含量为9.1%至15.5%,果实果肉油含量为29%至49%。生育酚分析结果显示维生素E含量也依赖于品种,种子油为106至161mg/100g,果实果肉油为76至227mg/100g。
通过单阶段热气干燥箱(air oven)方法(60℃/24h)确定了完整浆果样本的含湿量。将充分混合的汁液样品于5000转/分钟离心15分钟,取来自每个样品的澄清汁液级分的等分试样,用阿贝数字折光仪(Abbe digitalrefractometer)(Mark II型)确定汁液的可溶性固体含量。
来自种子的油用己烷(1∶5重量/体积研磨的种子/己烷)提取3小时,重量分析挥发的己烷和油含量。通过15000转/分钟4℃离心15分钟从汁液获得浆状物,然后-25℃保存2小时。上层用作浆状物。通过用己烷(1∶1w/v)匀浆浆状物回收油和进行重量分析测定。
用已知方法通过HPLC测定生育酚。(Bourgeois,C.1992.Determination of Vitamin E:Tocopherols and Tocotrienols.ElsevierApplied Science,London and New York)。通过β胡萝卜素方法确定定义为样品与丁化羟基甲苯(BHT)相比相对活性百分率的抗氧化效率(AE)。(Velloglu YS,Mazza G,Gao L和Oomah BD,Antioxidant activity andtotal phenolics in selected fruits,vegetables and grain products.J AgricFood Chem 46:4113-4117(1998))。
用扫描UV-可见光分光光度计(Beckman DU-600)确定果汁、种子油和浆状物油的总类胡萝卜素的含量。
根据Acar和Gokman(1996)描述的改进方法(Gokman,V和Acar,JASimple HPLC method for determination of total vitamin C in fruit juicesand drinks.Fruit Processing 5:198-201)通过HPLC测定来自不同品种的汁液样品的抗坏血酸含量。
抗氧化活性的确定基于适合微量培养板的ABTS自由基正离子脱色作用测定。提取物样品溶液用蒸馏水制备使浓度范围为0-100mg/L。该方法基于含有黄酮类化合物和酚类化合物的提取物的相对自由基清除的能力的测量,所述黄酮类化合物和酚类化合物通过它们作为电子或质子供体的性质而具有自由基清除能力。(Pellegrini,N.;Re,R.;Yang,M.;Rice-Evans,C.1999.Meth.Enzym.299,379-389.)。一旦抗氧化剂与ABTS(2,2’-连氮-双(3-乙基苯并噻唑啉-6-磺酸))自由基相互作用,自由基被还原并且它的绿色在时间尺度上受到一定程度的抑制。自由基的还原率测定为在734nm吸光度的降低。在存在Trolox或栎精标准时测定相对抗氧化能力并表示为每克干重植物存在的trolox(或栎精)当量抗氧化剂。
在一个实施方案中,通过混合5ml 7mM ABTS[2,2’-连氮-双(3-乙基苯并噻唑啉-6-磺酸)]与88μl 140mM K2S2O8制备ABTS贮存液。贮存液用乙醇稀释使734nm的吸光度为0.7±0.05(Pellegrini等人,1999)。沙棘提取物(20mg/ml,100μl)与1ml ABTS试剂混合,在室温30分钟后于734nm进行测定。水和酚(无抗坏血酸)提取物之间吸光度的差异对应于抗坏血酸。将Trolox用作标准,自由基清除的能力表示为trolox当量mg/g抗氧化能力。
沙棘叶和浆果提取物为维生素A、C、E、K和泛酸的重要来源。维生素K影响白细胞介素1和6的合成;维生素C降低幽门螺旋杆菌(Helicobacter pylori)感染的患病率,因此降低消化性溃疡和胃癌的危险。吸烟降低血清维生素C水平,建议吸烟者补充维生素C摄取量。维生素A、C和E为保护人体免受氧化损伤的抗氧化剂,氧化损伤导致的癌、心脏病和衰老。
如图5A和5B中显示地,叶和浆果具有抗氧化活性地显著不同分布图。β-胡萝卜素、维生素C和E(生育酚)对浆果的抗氧化活性贡献显著而酚类化合物的作用较小。由于高含量的酚类化合物和生育酚和中等水平的维生素C,叶子显示显著(高于5x)的抗氧化活性,类胡萝卜素具有较小作用。
实施例3:沙棘和植物提取物活性的协同作用
测试包含灵芝、丹参和半枝莲(3H)和任选沙棘浆果和/或叶(4H)的植物提取物的掺和物的抗氧化性质。如以上描述地以trolox和栎精当量测定抗氧化活性。此外,通过将总酚浓度除以它的ED50值来测量酚抗氧化指数(PAOXI),其是对抗氧化剂的质量和数量的组合测量(Vinson等人,J.Agric.Food Chem.46:3630-3634(1998))。在提取前混合植物增加了3H和4H提取物的PAOXI值。4H掺和物的热水(HW)和脂类提取物/水级分(LE/WF)的PAOXI值高于3H混合物的。
trolox当量抗氧化能力(TEAC)测定表明丹参是对HW和LE.WF提取物的抗氧化活性的主要贡献者。脂类/溶剂级分(LE/SF)中丹参对3H提取物的抗氧化潜力贡献最小,半枝莲(59%)和灵芝(27%)对3H提取物的抗氧化潜力贡献显著。在4H提取物的两个测定系统中,发现沙棘叶负责整个混合物的大约50%的抗氧化活性。
用CalcuSyn for Windows软件统计分析不同浓度3H和4H提取物的抗氧化活性数据(T-C Chou和P.Talalay(Trends Pharmacol.Sci.4,450-454))以确定植物组合为累加的、协同的,或者还是拮抗的。剂量降低指数(DRI)测定在给定效应水平下,与单独施用每种植物相比,协同组合中植物的剂量降低多少。组合指数(CI)为按照效应的给定点的累加效应(CI=1)、协同作用(CI<1)或拮抗作用(CI>1),相互作用程度的定量测定。
测定了个别植物和3H和4H粉剂掺和物的不同浓度的热水提取物的自由基清除活性(%抑制)。如图6中显示的,单种植物的曲线斜率为0.855至1.584,表明它们具有相似作用方式。灵芝的极低活性可以反映在热水中的低溶解性。图7显示在特定剂量,4H(与沙棘)掺和物的作用显著高于3H掺和物。
如图8中显示地,在ED50或更高剂量3H和4H粉末混合物显示协同作用,CI值在0.3-0.7之间,即观察到的抗氧化活性高于预计的抗氧化活性。
与粉末掺和物不同,热水提取物的剂量降低指数表明灵芝是组合物有效所必需的。与粉末掺和物相似,3H和4H热水提取物均显示协同作用,CI值在0.2和0.6之间(图9和10)。如图10显示地,4H掺和物(具有沙棘)的协同作用高于3H掺和物。
实施例4:沙棘与其它浆果的比较
图11和12中显示了沙棘中某些生物活性剂的水平与其它浆果的比较。图11A-B表明与其它浆果比较,沙棘中维生素C和E的水平最高。图12A-B表明沙棘具有显著水平的栎精和黄酮醇。
实施例5:沙棘叶和浆果的最佳干燥条件
沙棘叶中的总酚类化合物、类胡萝卜素、维生素E、抗坏血酸含量和抗氧化活性在不同干燥条件下不同。在所有干燥条件下,来自雌树的叶子由于较高的酚含量而比来自雄树的叶子具有更高抗氧化活性。在60℃烘干或冷冻干燥是保存抗氧化性质的最佳条件。冷冻干燥可以进一步阻止抗氧化化合物的酶降解而60℃高温可以灭活此类酶。在相同干燥条件下,雌叶与雄叶之间的抗氧化剂/酚类化合物比率不同,表明在雄叶和雌叶中酚类化合物之间的质的差异。
图13显示通过不同干燥条件接受的沙棘果实的多种抗氧化化合物的水平。除维生素C外,干燥增加所有抗氧化剂的水平。看起来冷冻干燥条件对维持抗氧化活性是最佳的。
实施例5:沙棘与植物提取物组合的抗氧化活性
检测包含沙棘浆果、沙棘叶、西洋参(Pq)、灵芝、丹参和半枝莲的植物提取物的两种或多种的掺和物的抗氧化活性。检测包含沙棘(Hr)浆果、Hr叶、Pq、灵芝、丹参和半枝莲的两种或多种的热水提取物的掺和物的抗氧化活性。
比较的标准为Trolox(维生素E的水溶性类似物),提取物的相对抗氧化活性定义为Trolox当量(TE)。在另一方法中,比较的标准为栎精(黄酮类化合物),相对抗氧化活性定义为栎精当量。
图14显示在不同提取步骤下植物混合物的抗氧化活性。3H代表灵芝、丹参和半枝莲,4H还包括沙棘。在所有提取条件下观察到沙棘对抗氧化水平的显著贡献。如图15中显示地,发现在两个测定系统下,沙棘叶负责整个混合物的大约50%的抗氧化活性。
实施例6:与抗癌药物施用的植物提取物的协同作用
共同待决的美国申请系列号___(代理人诉讼卷号544302000100;此公开此处全部引用)涉及丹参(#14)、灵芝(#9)和半枝莲(#15)的三种植物提取物的所有组合,所述组合协同抑制人癌细胞,诸如肺癌细胞、乳腺癌细胞、前列腺癌细胞和结肠癌细胞的增殖。检测单独植物灵芝、丹参、半枝莲提取物的1∶1∶1混合物(“AneustatTM”;图16中的条目#9、14和15)对抗癌药物抑制癌细胞生长功效的协同增强。如在图16的上图中显示的,在HeLa和A549肺癌细胞系中测定了每种植物提取物、ACAPHA、沙棘(#3050)和抗癌药物阿霉素、Epo B、氨甲蝶呤和长春烯碱单独和组合的IC50。
协同作用作为组合指数(CI)值测定,其中认为0.7或更低的值为协同作用的显著水平。图16的中间图显示了用固定浓度的三种植物提取物和不同浓度的阿霉素、Epo B、氨甲蝶呤和长春烯碱所得结果的平均数。三种植物提取物与化学治疗剂的组合也称为AneutoxTM。图16的下图显示固定量浓度的三种植物提取物和阿霉素、Epo B、氨甲蝶呤和长春烯碱所得结果的平均数。将混合物进行2x、4x、8x等等连续稀释以确定平均值。
在一个实施方案中,本发明的组合物包含有效量的灵芝、半枝莲、丹参和沙棘提取物,所述提取物由于显示一种或多种性质而显示抑制细胞效应以用于抑制原始癌细胞的进一步生长,所述一种或多种性质为(i)增强免疫系统,(ii)减小对细胞和组织的氧化性损伤,(iii)减轻炎症,(iv)阻止细胞周期特定阶段中细胞的增殖,(v)抗氧化活性,和(vi)针对进一步暴露至致癌剂和诱变剂的抗诱变效应。
实施例7:沙棘提取物对Cox-2/Cox-1的抑制
环加氧酶(Cox)是我们体内天然存在的酶。Cox-2是引起疼痛所必需的酶。非类固醇抗炎药物(NSAIDs)由于它们的镇痛和抗炎活性而广泛应用于治疗疼痛及关节炎的病征和症状。公认常见的NSAIDs通过阻断环加氧酶(COX)的活性而起作用,环加氧酶也称为前列腺素G/H合酶(PGHS),该酶将花生四烯酸转变成前列腺素类。最近,鉴定了两种形式的COX:组成型同工型(COX-1)和诱导型同工型(COX-2),其在炎症位置的表达受到上调(Vane,J.R.;Mitchell,J.A.;Appleton,I.;Tomlinson,A.;Bishop-Bailey,D.;Croxtoll,J.;Willoughby,D.A.Proc.Natnl.Acad.Sci.USA,1994,91,2046)。认为COX-1发挥生理学作用并负责胃肠和肾脏保护。另一方面,COX-2似乎发挥病理学作用并且是存在于炎症状态下的主要同工型。Cox2酶是炎症特异性的,C0x2抑制剂(例如Celebrex、Vioxx)最近通过了FDA批准。
大量的证据表明环加氧酶-2(COX-2)在胃肠癌中是重要的。与邻近的非肿瘤组织相比胰腺癌中COX-2mRNA的水平增加大于60倍。(Tucker等人,Cancer Res.1999 Mar 1;59(5):987-990.)环加氧酶-2(COX-2)在头和颈的鳞状细胞癌(HNSCC)中过表达,但在来自健康受试者的正常口腔粘膜中未检测到表达。(Chan等人,Cancer Res.1999 Mar 1;59(5):991-994)。目前有越来越多的证据表明COX-2的组成型表达在恶性上皮肿瘤的发生和发展中发挥作用。(Denkert等人,Cancer Res.2001 Jan 1;61(1):303-308.)。这些结果一起提示COX-2可成为癌症预防或治疗的靶标。利用前列腺素内过氧化物H合酶-1和-2同工酶(PGHS-1和-2),基于它们将花生四烯酸转变为前列腺素(PGs)的能力,进行了COX-2抑制活性的抗炎试验。本实验中使用的阳性对照是阿司匹林和西乐葆。优选的COX-2抑制剂将显示出对COX-2比对COX-1更强的抑制,COX-1负责胃肠和肾脏的保护。
通过COX-1和COX-2 ELISA测定试剂盒(Cayman Chemical Co.,Ann Arbor,MI)测定了抑制作用。商品化抗炎药物阿司匹林抑制COX-158%,抑制COX-242%,而西乐葆抑制COX-146%,抑制COX-285%。图17A显示通过沙棘叶和浆果的不同提取物以2mg/ml浓度抑制COX-2的效力。图17B显示通过沙棘叶和浆果的不同提取物以2mg/ml浓度对COX-1的抑制。对沙棘叶和浆果提取物分别测定。沙棘浆果的80%乙醇(EtOH)和热水(HW)提取物显示出与西乐葆(COX-2)和阿司匹林(COX-1)相当的强COX-2和COX-1抑制活性。沙棘浆果的脂类提取物/水级分(LE/WF)和脂类提取物/溶剂级分(LE/SF)显示出非常弱的COX-1抑制而仍显示出对COX-2活性的显著抑制。沙棘叶的LE/WF和EtOH提取物显示出对COX-1和COX-2的强效抑制,而沙棘叶的HW和LE/WF提取物显示出较小但是相对于COX-1对COX-2的优先抑制。叶和浆果的LE/SF提取物显示出对COX-2的低至中等(低于30%)的抑制而显示出对COX-1活性的一定活化。
此说明书中所引用的所有出版物和专利申请在此处引用作为参考,如同将每个单独的出版物或专利申请特别地并单独地指出引用作为参考一样。
尽管为了清楚理解已通过举例说明和实施例的方式详细地描述了前面的发明,但是本领域技术人员依据本发明的教导显而易见的是,可以对本发明进行一定修改和修饰而不背离所附权利要求的精神或范围。
Claims (46)
1.减轻人的癌症状况的方法,其包括:
向处于发展癌症危险中的个体施用预防有效量的包含沙棘提取物的组合物。
2.根据权利要求1的方法,其中所述组合物包含沙棘叶的提取物。
3.根据权利要求1的方法,其中所述组合物包含沙棘浆果的提取物。
4.根据权利要求1的方法,其中在提取之前干燥沙棘。
5.根据权利要求4的方法,其中通过(a)冷冻干燥,或(b)在60℃烘干干燥沙棘。
6.抑制COX-2酶活性的方法,其包括:
施用有效量的包含沙棘提取物的组合物用于抑制COX-2。
7.根据权利要求6的方法,其中所述组合物对COX-2活性的抑制显著高于对COX-1活性的抑制。
8.根据权利要求7的方法,其中所述组合物对COX-2活性的抑制比对COX-1活性的抑制高1.5倍。
9.根据权利要求6的方法,其中COX-2活性受到抑制并且COX-1活性得到增强。
10.根据权利要求6的方法,其中所述组合物包含沙棘浆果、沙棘浆果或沙棘种子的一种或多种提取物。
11.根据权利要求10的方法,其中在提取之前干燥沙棘。
12.根据权利要求10的方法,其中提取物为有机提取物的含水级分。
13.根据权利要求10的方法,其中提取物为有机提取物的溶剂级分。
14.根据权利要求10的方法,其中提取物为沙棘浆果的乙醇或热水提取物。
15.根据权利要求1的方法,其还包含大叶茶(绿茶)提取物。
16.根据权利要求1的方法,其还包含灵芝提取物、丹参提取物和半枝莲提取物的一种或多种。
17.减轻人癌症状况的方法,其包括向癌症早期的个体施用:
(a)治疗有效量的包含沙棘提取物的组合物;和
(b)灵芝、半枝莲和丹参的一种或多种提取物。
18.根据权利要求17的方法,其中所述组合物还包含(c)治疗有效量的至少一种化学治疗剂。
19.根据权利要求17的方法,其中所述组合物包含沙棘叶的提取物。
20.根据权利要求17的方法,其中所述组合物包含沙棘浆果的提取物。
21.根据权利要求17的方法,其中在提取之前干燥沙棘。
22.根据权利要求21的方法,其中通过(a)冷冻干燥,或(b)在60℃烘干干燥沙棘。
23.根据权利要求17的方法,其中提取物为热水提取物。
24.根据权利要求17的方法,其中提取物为醇提取物。
25.根据权利要求17的方法,其中提取物为有机提取物。
26.根据权利要求25的方法,其中提取物为有机提取物的脂类级分。
27.根据权利要求25的方法,其中提取物为有机提取物的含水级分。
28.根据权利要求17的方法,其还包括对个体施用治疗有效量的一种或多种抗癌治疗,所述治疗选自放射治疗、化学治疗、手术、免疫治疗、光动力学治疗和它们的组合。
29.根据权利要求17的方法,其中所述癌症选自肺癌、乳腺癌、子宫颈癌和前列腺癌。
30.根据权利要求18的方法,其中所述化学治疗剂干扰微管聚合。
31.根据权利要求30的方法,其中所述化学治疗剂选自紫杉醇、多西他赛、依托泊苷、长春新碱、长春碱和长春烯碱。
32.根据权利要求18的方法,其中所述化学治疗剂选自环磷酰胺、4-氢过氧环磷酰胺、噻替哌、紫杉醇、阿霉素、柔红霉素和新制癌菌素。
33.抗癌组合物,其包含灵芝、半枝莲和丹参的一种或多种提取物和治疗有效量的沙棘提取物。
34.根据权利要求33的组合物,其还包含治疗有效量的至少一种化学治疗剂。
35.根据权利要求34的组合物,其中所述化学治疗剂干扰微管聚合。
36.根据权利要求34的组合物,其中所述化学治疗剂选自紫杉醇、多西他赛、依托泊苷、长春新碱、长春碱和长春烯碱。
37.根据权利要求34的组合物,其中所述化学治疗剂选自环磷酰胺、4-氢过氧环磷酰胺、噻替哌、紫杉醇、阿霉素、柔红霉素和新制癌菌素。
38.根据权利要求33的组合物,其中所述组合物包含沙棘叶、浆果和种子的一种或多种提取物。
39.根据权利要求33的组合物,其中在提取之前干燥沙棘。
40.抑制COX-2酶活性的组合物,其包含有效抑制COX-2的沙棘提取物的量。
41.根据权利要求40的组合物,其中所述组合物对COX-2活性的抑制显著高于对COX-1活性的抑制。
42.根据权利要求41的组合物,其中所述组合物对COX-2活性的抑制比对COX-1活性的抑制高1.5倍。
43.根据权利要求41的组合物,其中COX-2活性受到抑制并且COX-1活性得到增强。
44.根据权利要求40的组合物,其中所述提取物为有机提取物的含水级分。
45.根据权利要求40的组合物,其中所述提取物为有机提取物的溶剂级分。
46.根据权利要求40的组合物,其中所述提取物为沙棘浆果的乙醇或热水提取物。
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US50505303P | 2003-09-22 | 2003-09-22 | |
US60/505,053 | 2003-09-22 |
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US (1) | US20050214394A1 (zh) |
EP (1) | EP1667528A4 (zh) |
JP (1) | JP2007505934A (zh) |
CN (1) | CN1878471A (zh) |
AU (1) | AU2004275885A1 (zh) |
CA (1) | CA2539534A1 (zh) |
RU (1) | RU2006113703A (zh) |
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CN106942737A (zh) * | 2017-03-13 | 2017-07-14 | 浙江大学 | 沙棘黄酮及其应用 |
CN107550952A (zh) * | 2017-09-14 | 2018-01-09 | 广东瑞普生物科技有限公司 | 一种治疗乳腺浸润性导管癌的植物提取物及其制备方法 |
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- 2004-09-22 US US10/948,580 patent/US20050214394A1/en not_active Abandoned
- 2004-09-22 WO PCT/US2004/031986 patent/WO2005029963A1/en active Application Filing
- 2004-09-22 EP EP04789256A patent/EP1667528A4/en not_active Withdrawn
- 2004-09-22 CA CA002539534A patent/CA2539534A1/en not_active Abandoned
- 2004-09-22 CN CNA2004800332660A patent/CN1878471A/zh active Pending
- 2004-09-22 AU AU2004275885A patent/AU2004275885A1/en not_active Abandoned
- 2004-09-22 RU RU2006113703/15A patent/RU2006113703A/ru not_active Application Discontinuation
- 2004-09-22 JP JP2006527168A patent/JP2007505934A/ja active Pending
- 2004-09-22 SG SG200809496-3A patent/SG149053A1/en unknown
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
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CN105636647A (zh) * | 2013-06-03 | 2016-06-01 | 盖尼奥斯生物医学国际公司 | 使用植物组合物和多西紫杉醇治疗前列腺癌的联合疗法 |
CN106942737A (zh) * | 2017-03-13 | 2017-07-14 | 浙江大学 | 沙棘黄酮及其应用 |
CN107550952A (zh) * | 2017-09-14 | 2018-01-09 | 广东瑞普生物科技有限公司 | 一种治疗乳腺浸润性导管癌的植物提取物及其制备方法 |
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AU2004275885A1 (en) | 2005-04-07 |
CA2539534A1 (en) | 2005-04-07 |
JP2007505934A (ja) | 2007-03-15 |
SG149053A1 (en) | 2009-01-29 |
US20050214394A1 (en) | 2005-09-29 |
RU2006113703A (ru) | 2007-11-10 |
EP1667528A4 (en) | 2007-10-24 |
WO2005029963A1 (en) | 2005-04-07 |
EP1667528A1 (en) | 2006-06-14 |
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