CN1893939A - 用于预防和治疗肝癌的组合物 - Google Patents
用于预防和治疗肝癌的组合物 Download PDFInfo
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- CN1893939A CN1893939A CNA2004800343881A CN200480034388A CN1893939A CN 1893939 A CN1893939 A CN 1893939A CN A2004800343881 A CNA2004800343881 A CN A2004800343881A CN 200480034388 A CN200480034388 A CN 200480034388A CN 1893939 A CN1893939 A CN 1893939A
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Abstract
本发明提供用于预防和治疗肝癌的组合物,本发明提供特征为含有以具有肝癌增殖抑制作用的化合物肠内酯(ENL)或其植物木脂体前体作为有效成分的用于预防和治疗肝癌的组合物、特征为由具有肝癌增殖抑制作用的化合物肠内酯(ENL)或其植物木脂体前体以及药理学上容许的载体成分构成的肝癌预防和治疗用药物,和特征为以具有肝癌增殖抑制作用的化合物肠内酯(ENL)或其植物木脂体前体作为功能性成分配合在食品原料的功能性食品原料。
Description
技术领域
本发明涉及新型用于预防和治疗肝癌的组合物,更详细讲,涉及含有肠内酯(ENL)或其植物木脂体前体作为有效成分的肝癌预防和治疗用药物以及含有这些成分作为功能性成分的功能性食品。本发明可在肝癌的预防和治疗用医药品以及与之有关的功能性食品的技术领域中,用于提供利用广泛存在于植物的根、叶、茎、种子、果实等的木脂体的在哺乳动物体内的主要代谢产物肠内酯(ENL)的很强肝癌增殖抑制作用的新型肝癌预防和治疗用药物、治癌剂、以及新功能性食品等。
背景技术
木脂体(lignan)是由苯丙醇单位构成的酚化合物,这些化合物虽然量少,但却分布于植物的根、叶、茎、种子、果实的所有部分。木脂体与雌激素同样,进行肝肠循环,在尿中作为葡萄糖苷酸缀合物或硫酸盐缀合物释放(非专利文献1)。据报道含有很多木脂体的亚麻或亚麻子的木脂体〔secoisolariciresinol diglycoside(SDG)〕可阻止二甲基苯蒽(DMBA)导致的大鼠乳癌细胞的恶化(非专利文献2、3、4、5),另外,也有报道称摄取含有木脂体的黑麦可早期预防前列腺癌(非专利文献6、7)。不过,有关木脂体对肝癌的作用到目前为止还没有研究报告例。
非专利文献1:Axelson M,Setchell KD,The excretion oflignans in rats--evidence for an intestinal bacterial sourcefor this new group of compounds.FEBS Lett.1981 Jan26;123(2):337-42.
非专利文献2:Serraino M,Thompson LU.The effect of flaxseedsupplementation on early risk markers for mammarycarcinogenesis.Cancer Lett.1991 Nov;60(2):135-42.
非专利文献3:Serraino M,Thompson Lu.The effect of flaxseedsupplementation on the initiation and promotional stages ofmammary tumorigenesis.Nutr Cancer.1992;17(2):153-9.
非专利文献4:Thompson LU,Seidl MM,Rickard SE,OrchesonLJ,Fong HH.Antitumorigenic effect of a mammalian lignanprecursor from flaxseed.Nutr Cancer.1996;26(2):159-65.
非专利文献5:Thompson LU,Rickard SE,Orcheson LJ,SeidlMM.Flaxseed and its lignan and oil components reduce mammarytumor growth at a late stage of carcinogenesis.Carcinogenesis.1996 Jun;17(6):1373-6.
非专利文献6:Landstrom M,Zhang JX,Hallmans G,Aman P,Bergh A,Damber JE,Mazur W,Wahala K,Adlercreutz H.Inhibitoryeffects of soy and rye diets on the development of Dunning R3327prostate adenocarcinoma in rats.Prostate.1998 Aug1;36(3):151-61.
非专利文献7:Zhang JX,Hallmans G,Landstrom M,Bergh A,Damber JE,Aman P,Adlercreutz H.Soy and rye diets inhibit thedevelopment of Dunning R3327 prostatic adenocarcinoma in rats.Cancer Lett.1997 Mar 19;114(1-2):313-4.
发明内容
发明要解决的课题
在这样的状况下,本发明人借鉴上述以往技术,就木脂体及其代谢产物的各种化合物对肝癌的作用不断进行各种研究,结果发现来自松树的木脂体,即羟罗汉松脂素(HMR)在哺乳动物体内的主要代谢产物肠内酯(ENL)具有很强的肝癌增殖抑制作用,再进一步进行研究,直至完成本发明。本发明的目的在于提供新型用于预防和治疗肝癌的组合物、肝癌预防以及治疗用药物和功能性食品。
用于解决课题的手段
用于解决上述课题的本发明由以下的技术手段构成。
(1)肝癌预防及其治疗用组合物,其特征是:作为有效成分含有具有肝癌增殖抑制作用的化合物肠内酯(ENL)或其植物木脂体前体。
(2)肝癌预防及其治疗用药物,其特征是:由具有肝癌增殖抑制作用的化合物肠内酯(ENL)或其植物木脂体前体以及药理学上容许的载体成分构成。
(3)功能性食品原料,其特征是:将具有肝癌增殖抑制作用的化合物肠内酯(ENL)或其植物木脂体前体作为功能性成分配合在食品原料中。
(4)功能性食品,其特征是:作为功能性成分含有具有肝癌增殖抑制作用的化合物肠内酯(ENL)或其植物木脂体前体。
(5)上述(4)所述的功能性食品,其中上述食品是营养辅助食品、营养剂、治疗用食品、营养辅助食品或健康食品。
以下对本发明进行更详细的说明。
本发明涉及到特征为含有肠内酯(ENL)或其植物木脂体前体作为有效成分的用于预防和治疗肝癌的组合物,特别是肝癌预防和治疗用药物、以及功能性食品。在本发明作为有效成分使用的肠内酯(enterolactone,ENL)是植物木脂体代谢产物,其为一种已知的哺乳动物木脂体(mammalian lignans),例如:作为来自松树的植物木脂体羟罗汉松脂素(hydroxymatairesinol,HMR)的主要代谢产物已为人们所知。在本发明中虽然优选使用这个肠内酯,但并不受此限制,可以使用它的植物木脂体前体。
在本发明中,作为上述植物木脂体前体,可以使用肠二醇(enterodiol,END)、罗汉松脂素(matairesinol,MR)、开环异落叶松树脂酚(secoisolariciresinol,SECO)、 开环异落叶松树脂酚双糖甙(secoisolarisiresinoldiglycoside,SDG)、丁香树脂醇(syringaresinol)、牛蒡配基(arctigenin)、落叶松树脂醇(lariciresinol)、松脂酚(pinoresinol)、芝麻素(sesamin)。这些植物木脂体前体通过肠内细菌经过所定代谢途径,转换为其代谢产物肠内酯,发挥肠内酯具有的肝癌增殖抑制作用。
植物木脂体前体在生体内通过肠内细菌被转换为其代谢产物肠内酯。例如在代谢过程中,SDG被糖捕获,变成SECO,该SECO经由END转换为ENL。MR直接转换为ENL。通过将以前已知的来自松树的木脂体羟罗汉松脂素给予人,以使人血清中的肠内酯或羟罗汉松脂素的其它的代谢产物浓度增加的方法,来预防人的癌症、某种非癌性激素依赖性疾病和/或心脏疾病的方法等已有报道(特表2002-541158号公报)。
不过,以往实际研究的,例如癌,只限于乳癌、前列腺癌和结肠癌,关于肝癌还没有研究。即,以往通过将羟罗汉松脂素给予人,以使人血清中的肠内酯或羟罗汉松脂素的其它的代谢产物浓度增加的方法是否具有肝癌增殖抑制作用尚且未知。
可在本发明使用的上述肠内酯(ENL)及其植物木脂体前体无论那一个都是众所周知的化合物,例如:有关肠内酯(ENL)可以使用市售品,也可以用众所周知的方法合成。本发明除了将有效成分肠内酯(ENL)直接给予人的方法之外,也包含将作为有效成分的肠内酯的植物木脂体前体直接给予人的方法,在本发明中,适合这些方法的医药组合物也包含在本发明的范围内。作为本发明的组合物,例如可例举由将有效量的上述有效成分浓缩的液体或固体材料构成的组合物。在本发明的医药组合物中,除了这些有效成分之外,也可以配合例如药理学上容许的载体等任意成分后再进行制剂,对其方法和药剂的形态等没有特别限制。另外,在本发明中,作为功能性成分添加所定量上述有效成分后,可以制造例如食品添加物、营养辅助食品、营养剂、治疗用食品、营养补给食品、健康食品等任意种类及形态的功能性食品原料、功能性食品。
在本发明中,例如可例举作为配合在医药组合物的有效量的肠内酯(ENL)为1~10mg/kg体重,但不受此限制。另外,配合在功能性食品中的上述有效成分的配合量等可以根据目的食品的种类等任意设计。而且,对来自天然的体内代谢产物肠内酯(ENL)、或其前体的植物木脂体对于生物体的安全性等,到目前为止已在多篇论文中得到确认。
以往,报道了通过使人血清中的肠内酯或羟罗汉松脂素的其它的代谢产物浓度增加的方法,来预防人的癌症、非癌性激素依赖性疾病和/或心脏疾病的预防方法等,实际上研究的癌,只限于乳癌、前列腺癌以及结肠癌的特定癌,对于其它癌的有效性完全不知。在本发明中,实际上进行了以往未研究的肠内酯等对肝癌的影响的试验,结果证实了其有效性,肠内酯等对肝癌的有效性是通过本发明人实施的特别实验首次证实的。在本技术领域,某一成分即使对于例如乳癌、前列腺癌、结肠癌有效,但该成分不一定同样对肝癌也有效,为了阐明这一问题,实际上需要进行特别的实验,在没有证实肠内酯等对肝癌的有效性的状况下,预期肠内酯等具有肝癌增殖抑制作用是困难的。本发明无疑是构成以往的一部分人类癌症预防方法的选择发明。
发明的效果
通过本发明(1)可以提供具有肝癌增殖抑制作用的新型用于预防和治疗肝癌的组合物、肝癌预防和治疗用医药组合物以及功能性食品;(2)可以提供以来自植物木脂体的代谢产物肠内酯作为有效成分的新的治癌剂等;(3)该化合物在低用量下具有高的肝癌增殖抑制作用;(4)该化合物也能够达到改善肝癌性脂类代谢异常的效果。
附图说明
图1表示肠内酯对细胞周期影响的分析结果。
图2表示肠内酯对凋亡影响的分析结果。
图3表示对实体瘤大小进行经时比较的结果。
图4表示血清中的胆固醇浓度。
图5表示粪中的中性固醇以及胆汁酸的排泄。
具体实施方式
以下,根据实施例对本发明进行具体说明,但本发明并不局限于以下的实施例。
实施例1
在本实施例中,为了分析ENL对肝癌细胞的增殖和侵袭的作用(体外/离体),使用ENL对AH109A细胞的抗肿瘤作用进行了研究。
1.材料和方法
(1)材料
在本实施例使用的ENL的化学结构式如式1所示。
(2)肝癌细胞的培养
大鼠腹水肝癌AH109A细胞(东北大学老龄医学研究所(仙台))通过连续移植到Donryu系雄性大鼠(NRC榛名、群马)的腹腔内进行维持。在大鼠腹水充分蓄积时,由腹水纯化AH109A细胞。通过将腹水在1000rpm(190×g)、4℃下离心分离10分钟后,除去上清,加等量溶血缓冲液〔0.16M NH4Cl∶0.17M Tris(三羟基甲基氨基甲烷)=9∶1、pH 7.2(全部由和光纯药公司,大阪,日本购入)〕,吹打悬浮后,于冰中放置约20分钟,破坏红血球进行纯化。
再进行2次于1000rpm(190×g)、4℃下进行10分钟离心分离后,除去上清,去除血细胞的操作,用磷酸缓冲液〔在1L MQ水中溶解了(磷酸缓冲盐溶液(-)(PBS(-))NaCl 8g、KCl 0.2g、KH2PO4 0.2g、Na2HPO4·12H2O2.9g(全部从和光纯药公司,大阪,日本购入),调整到pH 7.4〕洗涤2次。纯化的AH109A细胞用含有10%牛血清(CS,JRHBIOSCIENCES,Lenexa,KS,USA)的 Eagle MEM培养基(NISSUIPHARMACEUTICAL公司,东京,日本),按照1×106个接种到用子细胞培养的6cm平皿(NUNC、Roskilde,Denmark)中,进行培养。使用的CS是在使用前于56℃下放置30分钟,在水浴中进行了灭活的CS。
(3)肝癌细胞的增殖活性测定
通过测定整合到DNA的〔3H〕胸苷(20Ci/mmol,New EnglandNuclear,Boston,USA)的放射活性(Yagasaki K.,Tanabe T.,Ishihara K.,and Funabiki R.,(1992)Modulation of theproliferation of cultured hepatoma cells by urea cycle-relatedamino acids.In:Murakami,H.,Shirahata S.,and TachibananaH.,(ed.)Animal Cell Technology:Basic and Applied Aspects.Vol.4(pp.257-263).Kluwer Academic Publisher,Dordrecht/Boston London)评价AH109A细胞的增殖活性。
即,按照每1孔2.5×104个将AH109A细胞接种到组织培养用48孔板(Nunc)中,加各实验培养基,至最终每孔为400μl,培养20小时后,按照0.15μCi/well向各孔添加〔3H〕胸苷,于CO2培养箱内再培养4小时。然后,按照50μl/孔添加1M抗坏血酸(和光纯药公司),将各孔的培养基分别回收到Maruemu管(Maruemu Corporation Co.,Ltd.),用PBS(-)将48孔板洗涤2次,将该洗涤液也回收到Maruemu管中。于1500rpm(400×g)在4℃下离心分离5分钟,抽滤除去上清。
将板用400μl的10%TCA洗涤2次,将该洗涤液回收到Maruemu管,再次于3000rpm(1500×g)、4℃下离心分离5分钟,除去上清。留在48孔板、Maruemu管的细胞分别添加150μl、50μl的0.2N NaOH/0.1%SDS,于37℃的培养箱内放置30分钟,将细胞完全溶解。将48孔板、Maruemu管的细胞溶解液两者合并,移到小管式瓶中,添加5ml NT闪光剂〔甲苯700ml、nonion 300ml、DPO 4g〕,再添加150μl的1N HCl,充分振荡混合,确认液体变得透明,使用液体闪烁扫描计数器(LS 6500;Beckman、Fullerton、CA、USA)测定放射活性。求以对照值为100时的比例(%),将该值作为增殖活性的指标。
(4)肝癌细胞的侵袭活性测定
侵袭活性测定法是对Akedo等人的体外侵袭分析法(Akedo H,Shinkai K,Mukai M,Mori Y,Tateishi R,Tanaka K,Yamamoto R,Morishita T.Interaction of rat ascites hepatoma cells withcultured mesothelial cell layers:a model for tumor invasion.Cancer Res.1986 May;46(5):2416-22)进行了部分改变的方法(Miura Y.,Shiomi H.,Sakai F.,and Yagasaki K.1997 Assaysystems for screening food components that haveanti-proliferative and anti-invasive activity to rat asciteshepatoma cells:Invitro and exvivo effects of green tea extract.Cytotechnology 23:127-132)。
培养7~10天直至原代培养的来自大鼠肠系膜的间皮细胞(M-cell)形成汇合单层后,更换成各实验培养基3ml,将AH109A细胞按照2.4×104个置于间皮细胞上,安静地搅拌后,于CO2培养箱内进行培养。24小时后用PBS(-)洗涤,将细胞用0.25%戊二醛/PBS(-)固定。对于每枚平皿中任意选择出的10个2mm四方形区域内的潜入到间皮细胞层下的AH109A细胞的细胞数以及集落数的进行计数,以将其换算成每1cm2的数的平均值作为侵袭活性的指标。
(5)对来自肠系膜的间皮细胞(M-cell)的纯化
对于Donryu系雄性大鼠(4~10周龄)按照5mg/0.1ml/100g体重腹腔内注射戊巴比妥麻醉后,切断颈动脉,采取血液。然后用洗必泰液消毒后,在净化台内开腹,将肠系膜逐片切下,用PBS(-)洗涤,回收到15ml的PBS(-)中。加等量的0.5%胰蛋白酶/PBS(-),于37℃下搅拌20分钟。然后,加5ml 10%CS/MEM培养基,使胰蛋白酶反应终止,用Komagome移液管充分吹打后,用金属筛过滤。滤液于1500rpm(440×g)、4℃下离心分离10分钟,用PBS(-)进行洗涤。获取的细胞按照1.5~2.0×105个接种到带有网格的(2mm四方)6cm平皿中。培养基使用10%CS/MEM,在获取的第二天和之后每隔1天更换培养基。
(6)M-cell的增殖活性测定
M-cell培养至达到近汇合状态前后,用PBS(-)洗涤,添加1ml的0.1%胰蛋白酶,使细胞分散后,用10%CS/MEM使胰蛋白酶反应终止,回收细胞,按照1.25×105cell/400μl/孔接种到48孔板中,培养24小时。确认细胞充分附着之后,除去培养基,添加样品,于37℃下培养20小时。加各实验培养基,最终每孔至400μl,培养20小时后,按照0.15μCi/孔向各孔添加〔3H〕胸苷(NEN,Boston,MA,USA),于CO2培养箱内再培养4小时。然后根据上述(3)进行增殖活性的测定。
(7)肝癌细胞的细胞周期分析
对于6.25μM和12.5μM的ENL对AH109A细胞的细胞周期的影响进行经时分析。按照每孔2.5×105个细胞向用于细胞胞培养的6孔板(NUNC)中接种AH109A细胞,于37℃、CO2培养箱内中培养0、24和48小时。将在各个处理条件培养的AH109A细胞回收到2ml样品管(日本Genetex、东京)中,于1000rpm(190×g)、4℃下离心分离5分钟,用PBS(-)洗涤2次。然后,加300μl的PI溶液[1mg二碘化丙啶(SIGMA)/20ml 0.1%Triton X-100、0.1%柠檬酸钠(和光纯药公司)],避光下于冰中静置30分钟,进行染色。用流式细胞仪(EPICS ELITEESP;Beckman-Coulter,Hialeah,FL,USA)进行细胞周期的分析。
(8)通过使用Annexin V/PI双重染色法的流式细胞术进行AH109A细胞的凋亡分析
使用ANNEXIN V VFITC试剂盒(IMMUNOTECH、马赛、法国)进行分析。向用于细胞培养的的6cm平皿(NUNC)中添加3ml实验培养基,接种AH109A细胞至1×106个,于37℃、CO2培养箱内培养0、3、6小时。回收于各个处理条件下培养的AH109A细胞,于1000rpm(90×g)、4℃下离心分离5分钟,用PBS(-)洗涤1次。然后加490μl结合缓冲液,再加5μl PI溶液和5μl annexin V FITC,平稳混合。避光下于冰中静置10分钟,进行染色,用流式细胞仪(EPICS ELITEESP;Beckman-Coulter,Hialeah,FL,USA)进行凋亡的分析。
(8)统计处理
统计处理采用在单因素分析后进行Tukey-Kramer多重比较检验。
2.试验结果
(1)关于ENL对AH109A细胞以及正常细胞的作用
ENL表现出浓度依赖性地抑制AH109A细胞侵袭的作用。不过,ENL的浓度如果在25μM以上,对于侵袭活性测定系中使用的M-cell表现出细胞毒性,由于不能进行侵袭活性的分析,所以在不超过12.5μM的浓度下进行分析。另外,由于ENL也强烈抑制癌细胞AH109A细胞的增殖,所以使用M-cell作为正常细胞,也进行了对于正常细胞增殖影响的研究,并进行了比较。其结果表明在体外ENL浓度依赖性地抑制M-cell的增殖,而对于AH109A细胞,比正常细胞表现出更强的效果,在浓度50μM下,AH109A细胞的增殖几乎被完全抑制。因此,为了阐明该细胞增殖抑制是引起细胞分裂停止、细胞凋亡或坏死的细胞增殖抑制机制,通过PI染色的细胞周期的分析和通过annexin V FITC/PI的凋亡诱导性的观察,研究了ENL抑制AH109A细胞增殖的机制。
(2)对于细胞周期的分析
图1显示了分析结果。根据ENL处理0小时的曲线图A可以看出各浓度的ENL处理对AH109A细胞的细胞周期没有影响。不过,由ENL处理24小时的曲线图B看到,与0μM处理的对照比较,进行了ENL处理的细胞G1期的比例增加,S期的比例减少。
(3)关于凋亡
分析结果如图2所示。对浓度6.25μM和12.5μM的ENL是否引起AH109A细胞凋亡诱导进行了经时研究。在用0μM的ENL进行了3小时处理的AH109A细胞中,第3象限为90.7%、第4象限为6.2%、第2象限为2.5%,而用6.25μM的ENL处理了3小时处理的AH109A细胞中,第3象限为88.1%、第4象限为8.4%、第2象限为2.8%,另外在用12.5μM的ENL进行了3小时处理的AH109A细胞中,第3象限为86.1%、第4象限为11.4%、第2象限为2.3%,通过进行ENL处理,活细胞的比例浓度依赖性地减少,凋亡初期细胞的比例增加。而进行了6小时处理的AH109A细胞也大致表现出同样的结果,而且二次坏死细胞的比例也稍有增加。
实施例2
在本实施例中,为了对ENL对肝癌移植时的癌增殖、转移、高脂血症的作用进行分析(体内),实际上使大鼠摄取ENL,在荷癌大鼠模型上对癌的增殖、转移、癌性恶病质的效果进行研究。
1.材料和方法
(1)动物饲养
购入4周龄Donryu系雄性大鼠(NRC榛名、群马)后,5连笼,照明期8:00~20:00、室温22±1℃、相对湿度60±5%的环境控制室内,进行6天预备饲养。最初3天将固体饲料(CE-2;CLEA日本,东京)加到玻璃容器,接下来的3天,将含有20%奶酪蛋白的基本饲料(20C)(表1)加入到玻璃容器中,与自来水一起供它们自由摄取。预备饲养结束后,按照使各组的体重相等分成3组(11只/组),将悬浮于PBS(-)的AH109A细胞按照每1只大鼠1.0×107个移植到所有大鼠的背部皮下。对于各个实验组,从刚移植后开始使它们摄取如表2所示的饲料。
实验期间,测定每天的体重和摄食量以及实体瘤的大小(长、宽、高的长度)。于处死当天9:00断掉饲料,4小时后进行处死。而在这期间也可以使它们自由摄取水。从颈动脉放血,在采取血液样品的同时,摘取肝脏和实体瘤。采取的血液于室温下放置约2小时后,在3000rpm(1750×g)、4℃下离心分离10分钟,制备血清,于-20℃下冷冻保存。肝脏和实体瘤用冰冷生理盐水洗涤后,用滤纸擦干,测定总重量。另外为了测定类固醇排泄量,收集移植后第19~21天的粪,于-20℃下冷冻保存。
表1实验食物组成
成分(g/kg) | 对照(20C) |
玉米淀粉a酪蛋白bα-玉米淀粉a蔗糖c大豆油d纤维素粉末b矿物质混合物(AIN-93G)a,e维生素混合物(AIN-93)a,fL-半胱氨酸gCholine bitartrateh | 397.5200.0132.0100.070.050.035.010.03.02.5 |
aNihon Nosan Kogyo公司,横滨,日本
bOriental Yeast公司,东京,日本
cMitsui Sugar公司,东京,日本
dMiyazawa Yakuhin公司,东京,日本
eAIN-93G组合物
fAIN-93组合物
gAjinomoto公司,东京,日本
h和光纯药,大阪,日本
表2实验食物组成
成分(g/kg) | 对照(20c) | 肠内酯(10ppm) | 肠内酯(100ppm) |
肠内酯玉米淀粉a酪蛋白bα-玉米淀粉a蔗糖c大豆油d纤维素粉末b矿物质混合物(AIN-9 3G)A,E维生素混合物(AIN-9 3)A,FL-半胱氨酸GCholine BitartrateH | -397.50200.00132.00100.0070.0050.0035.0010.003.002.50 | 0.01397.49200.00132.00100.0070.0050.0035.0010.003.002.50 | 0.10397.40200.00132.00100.0070.0050.0035.0010.003.002.50 |
aNihon Nosan Kogyo公司,横滨,日本
bOriental Yeast公司,东京,日本
cMitsui Sugar公司,东京,日本
dMiyazawa Yakuhin公司,东京,日本
eAIN-93G组合物
fAIN-93组合物
gAjinomoto公司,东京,日本
h和光纯药,大阪,日本
(2)实体瘤经时变化的测定
测定长、宽、高的长度,使用测定值的总和作为实体瘤的大小。
(3)血清脂类水平的测定
对血中胆固醇(Ch)和甘油三酯(TG)的浓度进行测定。针对总胆固醇(T-Ch)水平、使用磷钨酸沉淀法使极低密度脂蛋白+低密度脂蛋白〔(VLDL+LDL)-Ch〕沉淀的上清级分高密度脂蛋白(HDL-Ch)水平以及TG水平进行测定。(VLDL+LDL)-Ch水平为T-Ch水平与HDL-Ch水平的差。而作为致动脉硬化指数,算出致动脉粥样硬化指数〔AI:(VLDL+LDL)-Ch/HDL-Ch〕。
(4)血清过氧化脂类水平的测定
LPO水平通过使用过氧化脂类检测Wako(和光纯药公司)的八木荧光法测定硫代巴比妥酸反应物质(TBARS)求出。
(5)肝脏中脂类水平的测定
1)总脂类的提取
为了测定脂类水平,通过Folch等人的方法(FOLCH J,LEES M,SLOANE-STANLEY GH,Asimple method for the isolation andpurification of total lipides from animal tissues.J.Biol.Chem.226:497-509,1957)从肝脏提取总脂类。精确秤量约0.5g肝脏后,与5ml甲醇一起在Polytron匀浆器(Type PT10/35、Kinematica、Switzerland)中进行匀浆,加10ml氯仿进行搅拌,放置过夜后,过滤,将残渣再用氯仿-甲醇(2∶1)混合液洗涤后,将两者合并有25ml,作为脂类抽出液。
2)总胆固醇水平的测定
通过Zak法(Zak B.,Simple rapid microtechnic for serumtotal cholesterol.Am.J.Clin.Path.27,583-588,1957)测定Ch含量。将脂类提取液(2ml)加到螺纹口试管,干燥、加50%(w/V)氢氧化钾-乙醇溶液3ml,于45℃下进行1小时皂化。添加3ml蒸馏水稀释后,添加3ml正己烷进行振荡,提取Ch。将己烷层2ml装入试管,干燥后、加0.08%氯化铁-醋酸溶液(将氯化铁1.33g溶解在醋酸中,调整到1L)2ml、硫酸2ml,进行搅拌,放置冷却后以Ch作为标准测定560nm的吸光度。
3)甘油三酯水平的测定
通过Van Handel法(VAN HANDEL E.Suggested modifications ofthe micro determination of triglycerides.Clin.Chem.7:249-51,1961)测定TG水平。将脂类提取液加入到螺纹口试管,干燥后,加沸石(和光纯药公司)0.5g、氯仿10ml进行振荡,除去磷脂(PL)。然后进行过滤,将滤液2ml加入到带有螺纹的试管,干燥。加0.4%(w/v)氢氧化钾-乙醇溶液0.5ml,于65℃下进行20分钟皂化,加0.2N硫酸0.5ml终止反应。在沸腾水浴中除去乙醇后,添加0.5%甲烷过碘酸钠0.005ml进行氧化分解,10分后添加5%亚硫酸氢钠0.05ml终止反应。然后加5ml变色酸-硫酸溶液[将变色酸二水合物(DOJINDO,Kumamoto)2.24g溶解于蒸馏水中,调到200ml后,边冰冷边添加24N硫酸900ml],于沸腾水浴中加热30分钟,冷却后以三棕榈酸甘油酯作为标准测定570nm的吸光度。
(6)粪中类固醇的测定
针对中性固醇(NS)以及胆酸(BA)进行粪中类固醇排泄量的测定。使粪在60℃下干燥,测定干燥重量后,使用粉碎机和乳钵进行粉碎,精确称量约100mg后,加入到螺纹口试管,添加4N氢氧化钾1.5ml、乙醇1ml后,于70℃下进行1小时皂化。添加正己烷3ml,进行振荡,于3000rpm(1750×g)下离心分离10分钟,通过将正己烷层转移到试管,提取NS。同样操作进行3次。然后,添加蒸馏水2.5ml,将氢氧化钾浓度稀释到1.2N,于121℃下进行3小时高压处理(高压灭菌),使缀合BA脱缀合。
放置冷却后,添加盐酸0.8ml后,将溶液的pH调整到1,添加二乙醚3ml后进行振荡,于3000rpm(1750×g)下离心分离10分钟,通过将二乙醚层移至试管,提取BA。该操作也进行3次。正己烷抽出液干燥后,添加异丙醇0.4ml、10%Triton X-100 1.6ml,溶解NS,取其中的0.24ml样品,使用胆固醇C检测Wako,进行测定。二乙醚抽出液干燥后,添加甲醇2ml,溶解BA,取其中的0.02ml,使用总胆汁酸检测Wako,通过使用3α-羟类固醇脱氢酶的酶法进行测定。以最后2天里排出的总量表示。
(7)统计处理
在单因素方差分析后,通过Tukey-Kramer多重比较检验进行统计处理。
2.试验结果
图3给出了对实体瘤的大小进行经时比较的结果。实体瘤的形成于肝癌移植后第5天开始可目测看到。与对照取食组相比,摄取ENL的组,特别在摄取100ppm组,肝癌移植后第7、8日,以及第18日目以后,实体瘤的成长被有意义地抑制。就象下述表3所示,在将癌移植到背部皮下后,对在21天里转移的肿瘤进行比较,在对照取食组中的11只中有3只发生癌转移,癌转移的大鼠的比例为27.3%,而在ENL取食组中,没有观察到转移。
另外对于摄食量、肝脏重量、过氧化脂类以及肝脏中的脂类,在各组间无显著性差别,在体重增加量方面,在ENL 100ppm摄取组有意义增加,在摄取ENL的两个组中,实体瘤重量有意义地降低(表4)。
表3肠内酯对转移的效果
对照(20C) | 肠内酯(10ppm) | 肠内酯(100ppm) | |
转移的大鼠/组总转移数/组 | 3/11(27.3%)4(1,2,1) | 0/11(0%)0 | 0/11(0%)0 |
表4荷肝癌大鼠的食物摄取、体重增加、肝和肝肿瘤重量、血清和肝脂水平以及粪中固醇排泄量
测量 | 对照(20C) | 肠内酯(10ppm) | 肠内酯(100ppm) |
食物摄取(g/21天)体重增加(g/21天)肝重量(g/大鼠)肝肿瘤重量(g/大鼠)血清脂水平总胆固醇(mmol/L)HDL-胆固醇(mmol/L)(A)(VLDL+LDL)-胆固醇(mmol/L)(B)AI(B/A)甘油三酯TBARS(nmol/ml)肝脂水平(μmol/g肝)甘油三酯总胆固醇固醇排泄量粪干重(g/2天)中性固醇(μmol/2天)胆酸(μmol/2天) | 424±1914 6±8a11.6±0.89.6±2a2.52±0.091.39±0.091.13±0.16a1.00±0.291.28±0.248.53±0.7338.2±3.615.13±0.412.57±0.1320.2±2.3a14.8±1.07a | 433±14158±8a10.1±0.53.4±1b2.13±0.141.45±0.070.68±0.12b0.48±0.090.98±0.067.31±0.3743.8±3.835.15±0.432.87±0.1829.5±2.7b18.7±1.49ab | 472±9171±4b11.3±4.01.1±0.2b2.30±0.121.63±0.060.67±0.08b0.41±0.050.93±0.066.87±0.5142.8±7.055.47±0.402.99±0.1430.9±2.18b20.8±1.89b |
每个值代表11只大鼠的平均值±SEM,未标有共同字母的值表示通过Tukey-Kramer多重比较检验为有意义差别P<0.05。
下述图4中将血清中胆固醇浓度以图形形式表示。ENL取食组与对照取食组相比虽然并不显著,但可看到血清中HDL-Ch的上升趋势。反之,(VLDL+LDL)-Ch在ENL取食组,浓度依赖性地有意义地降低,其结果表明作为HDL-Ch与(VLDL+LDL)-Ch的比的AI值也表现出降低趋势。粪中的中性固醇和胆汁酸排泄如图5所示。与对照取食组相比,在ENL取食组,中性固醇与胆汁酸的排泄量用量依赖性地有意义增加。
实施例3
将肠内酯(ENL)作为有效成分与药理学上容许的载体成分按所定量配合,然后通过将它们进行制剂,制造用于预防和治疗肝癌的组合物。
实施例4
将肠内酯(ENL)作为有效成分,另外配合营养成分,制造具有肝癌增殖抑制作用的功能性食品。
产业上的可利用性
就象以上详述那样,本发明涉及用于预防和治疗肝癌的组合物,根据本发明可以提供利用肠内酯肝癌增殖抑制作用的新的肝癌预防和治疗用医药组合物以及功能性食品等。根据本发明,除了肝癌预防和治疗用药物之外,还可以提供例如发挥肝癌增殖抑制效果的食品添加物、营养辅助食品、营养剂、治疗用食品、营养辅助食品、健康食品等功能性食品原料、功能性食品。
Claims (5)
1.肝癌预防及其治疗用组合物,其特征是:含有具有肝癌增殖抑制作用的化合物肠内酯(ENL)或其植物木脂体前体作为有效成分。
2.用于预防及其治疗肝癌的药剂,其特征是:由具有肝癌增殖抑制作用的化合物肠内酯(ENL)或其植物木脂体前体以及药理学上容许的载体成分构成。
3.功能性食品原料,其特征是:将具有肝癌增殖抑制作用的化合物肠内酯(ENL)或其植物木脂体前体作为功能性成分配合在食品原料中。
4.功能性食品,其特征是:作为功能性成分含有具有肝癌增殖抑制作用的化合物肠内酯(ENL)或其植物木脂体前体。
5.权利要求4所述的功能性食品,其中上述食品是营养辅助食品、营养剂、治疗用食品、营养辅助食品或健康食品。
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Cited By (6)
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US8367124B2 (en) | 2008-06-18 | 2013-02-05 | Shiseido Company, Ltd. | Lymphatic vessel stabilizer |
CN104523721A (zh) * | 2014-11-11 | 2015-04-22 | 济南星懿医药技术有限公司 | 一种抗肿瘤的药物组合物 |
CN106265610A (zh) * | 2015-06-23 | 2017-01-04 | 香港浸会大学 | 抑制在有需要的主体内的食道癌生长的方法及木脂素化合物作为制备治疗食道癌药物的应用 |
CN109602759A (zh) * | 2019-01-17 | 2019-04-12 | 广西医科大学 | 罗汉松实多糖的用途 |
CN112386596A (zh) * | 2020-11-30 | 2021-02-23 | 哈尔滨医科大学 | 一种抗肿瘤联合用药物组合物及其应用 |
CN113181223A (zh) * | 2021-04-25 | 2021-07-30 | 广西医科大学 | 一种具有抗鼻咽癌作用的组合物 |
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US6451849B1 (en) * | 1999-03-30 | 2002-09-17 | Hormos Nutraceutical Oy Ltd. | Use of hydroxymatairesinol for prevention of cancers, non-cancer, hormone dependent diseases and cardiovascular diseases by hydroxymatairesinol, and a pharmaceutical preparation, food additive and food product comprising hydroxymatairesinol |
FI20106293A0 (fi) * | 2010-12-06 | 2010-12-06 | Emilia Peuhu | Uudet farmaseuttiset koostumukset |
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JPH01228928A (ja) * | 1988-03-09 | 1989-09-12 | Tsumura & Co | リグナン類およびリグナン類を有効成分とする抗腫瘍剤 |
US6261565B1 (en) * | 1996-03-13 | 2001-07-17 | Archer Daniels Midland Company | Method of preparing and using isoflavones |
US6008260A (en) * | 1998-01-09 | 1999-12-28 | Pharmascience | Cancer chemopreventative composition and method |
US6451849B1 (en) * | 1999-03-30 | 2002-09-17 | Hormos Nutraceutical Oy Ltd. | Use of hydroxymatairesinol for prevention of cancers, non-cancer, hormone dependent diseases and cardiovascular diseases by hydroxymatairesinol, and a pharmaceutical preparation, food additive and food product comprising hydroxymatairesinol |
US6689809B2 (en) * | 1999-03-30 | 2004-02-10 | Hormos Nutraceutical Oy Ltd. | Food additive or product or a pharmaceutical preparation, comprising hydroxymatairesinol |
JP2003063971A (ja) * | 2001-08-23 | 2003-03-05 | Tama Seikagaku Kk | 連翹葉及びその抽出物とそれらの用途 |
US6649650B2 (en) * | 2001-12-07 | 2003-11-18 | Council Of Scientific And Industrial Research | Herbal chemical composition for the treatment of cancer |
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2004
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Cited By (9)
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US8367124B2 (en) | 2008-06-18 | 2013-02-05 | Shiseido Company, Ltd. | Lymphatic vessel stabilizer |
CN102056630B (zh) * | 2008-06-18 | 2013-03-13 | 株式会社资生堂 | 淋巴管的稳定剂 |
CN104523721A (zh) * | 2014-11-11 | 2015-04-22 | 济南星懿医药技术有限公司 | 一种抗肿瘤的药物组合物 |
CN106265610A (zh) * | 2015-06-23 | 2017-01-04 | 香港浸会大学 | 抑制在有需要的主体内的食道癌生长的方法及木脂素化合物作为制备治疗食道癌药物的应用 |
CN106265610B (zh) * | 2015-06-23 | 2019-04-02 | 香港浸会大学 | 抑制在有需要的主体内的食道癌生长的方法及木脂素化合物作为制备治疗食道癌药物的应用 |
CN109602759A (zh) * | 2019-01-17 | 2019-04-12 | 广西医科大学 | 罗汉松实多糖的用途 |
CN112386596A (zh) * | 2020-11-30 | 2021-02-23 | 哈尔滨医科大学 | 一种抗肿瘤联合用药物组合物及其应用 |
CN112386596B (zh) * | 2020-11-30 | 2022-02-15 | 哈尔滨医科大学 | 一种抗肿瘤联合用药物组合物及其应用 |
CN113181223A (zh) * | 2021-04-25 | 2021-07-30 | 广西医科大学 | 一种具有抗鼻咽癌作用的组合物 |
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