CN103585135B - 厚朴酚在制备治疗恶病质及癌症的药物中的应用 - Google Patents
厚朴酚在制备治疗恶病质及癌症的药物中的应用 Download PDFInfo
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Abstract
本发明公开了厚朴酚或其异构物或该等化合物的医药上可接受的盐类在制备治疗恶病质及癌症药物中的应用。所述恶病质可由选自以下所组成的群的疾病、状态或损伤所导致:癌症、免疫不全疾病、感染性疾病、自体免疫疾病、代谢性疾病以及慢性的肠道、肝脏、肾脏、肺脏及心脏疾病、厌食症、创伤、烧伤、营养吸收不良及贫血。在一具体实施例中,本发明的药物可投予可能产生恶病质的疾病的患者,例如,癌症等。本发明还提供了厚朴酚或其异构物或该等化合物的医药上可接受的盐类在制备治疗膀胱癌药物中的应用,特别是在抑制膀胱癌的肿瘤生长、癌细胞转移,并提高动物存活率中的应用。
Description
相关申请案的交叉参考
本申请案主张2012年8月14日申请的台湾临时专利申请案第101129398号的优先权,所述说明书是以其全文引用的方式并入本文中。
技术领域
本发明涉及厚朴酚或其异构物或该等化合物的医药上可接受的盐类在制备治疗恶病质及癌症药物中的应用。本发明的药物可施用于有需要的个体,如恶病质病患,以改善或减缓恶病质的病征。本发明也涉及厚朴酚在制备治疗膀胱癌的药物中应用,特别是抑制膀胱癌的肿瘤生长或癌细胞移转。
背景技术
恶病质(cachexia)是一种在疾病情况下所产生的复杂代谢性症候群,主要的临床病征为肌肉耗损及体重下降(Evans WJ et al.Clin Nutr.2008;27:793)。目前临床上诊断恶病质的标准为:患者有持续体重下降的情形,例如,一年内体重减轻原体重的5%,并伴随下列五项标准的其中三项:肌肉张力降低、疲劳、厌食、低无脂肪重量指数、及生化指数异常,例如,发炎因子上升(如,介素白-6(IL-6)、反应蛋白(CRP))、贫血(血红素浓度小于12g/dL)、血清白蛋白下降(小于3.2g/dL)(Evans WJ et al.,supra)等。恶病质的肌肉耗损病征无法单纯通过供给营养而回复,其与因饥饿、老化相关的肌肉质量流失、原发性忧郁症或内分泌异常而产生的病征并不相同。恶病质的病患即便增加进食量或提高营养的摄取,也无法预防或停止病患体重的持续下降。
恶病质可发生在许多慢性病或重症患者中,例如,癌症(如,膀胱癌、肝癌、乳癌、卵巢癌、胃癌、胰脏癌、大肠癌、骨癌、血癌等)、免疫不全疾病(如,艾滋病等)、感染性疾病(如,结核病、败血症等)、自体免疫疾病(如,风湿性关节炎等)、代谢性疾病(如,糖尿病等)以及慢性的肠道、肝脏、肾脏、肺脏或心脏疾病(如,肝硬化、肾衰竭、慢性阻塞性肺病(COPD)、慢性心脏衰竭等)、厌食症、创伤或烧伤、营养吸收不良、贫血等。恶病质一旦发生,几乎难以回复,患者各种生理功能会急速降低,使生活质量下降,最后身体因过度虚弱而无法承受各种治疗,加速患者死亡。
目前针对恶病质的治疗方向以改善患者生活质量、增加食欲、降低疲劳感、减少促发炎因子以及增加瘦体质量为主,其常用药物可分为四大类:(1)促蛋白合成剂,例如,癸酸诺龙(nandrolone decanoate)、胰岛素(insulin)、类固醇(corticosteroids)等;(2)食欲促进剂,例如,醋酸甲地孕酮(megestrol acetate)、甲孕酮(medroxyprogesterone)等;(3)细胞激素抑制剂,如沙利窦迈(thalidomide)、褪黑激素(melatonin)等;(4)抗发炎制剂,如,非类固醇抗发炎药物等。然而,这些药物虽可改善食欲或增加体重,但肌肉质量并未增加(Donohoe CL et al.,Gastroenterology research and practice.2011;2011:601434)。因此,仍需要提供另一种针对恶病质的有效治疗方案。
厚朴酚(magnolol)又称木兰酚,是来自木兰科植物厚朴(Magnolia officinalis)主要的活性成分之一。已知厚朴酚有抑制细菌生长、抗血小板凝集、抗氧化及抗发炎等作用,也有报导用于治疗肠胃道疾病、心血管和过敏症等疾病(Teng Yu et al.,Life science1990;47(13):1153-61.;Bang KH et al.,Arch Pharm Res2000;23(1):46-9)。近年来研究认为厚朴酚可经由抑制核酸复制、停滞细胞周期,促进细胞凋亡等,而达到抗癌的功效(Ikeda K et al.,Biol Pharm Bull2002;25(12):1546-9.;Lee SJ etal.,Biochem pharmacol2008;75(12):2289-300.;Fried LE et al.,Antioxid redox signal2009;11(5):1139-48)。然而,目前并无任何现有技术揭示厚朴酚可用以治疗恶病质。
发明内容
在一方面,本发明提供了厚朴酚或其异构物或该等化合物的医药上可接受的盐类在制备治疗恶病质的药物中的应用。本发明也提供了将厚朴酚或其异构物或该等化合物的医药上可接受的盐类投予有需要的个体以治疗恶病质的方法。在一具体实例中,本发明的治疗恶病质的药物可与一或多种抗癌药剂并用。
在另一方面,本发明提供了一种药物组合,其包括第一活性成分,所述第一活性成分包括对治疗恶病质有效量的厚朴酚或其异构物或该等化合物的医药上可接受的盐类;以及第二活性成分,所述第二活性成分是第一活性成分以外的活性成分,包括一或多种对治疗癌症有效量的抗癌药剂。具体而言,本发明的药物组合一方面可提供治疗癌症的效果,一方面可避免或推迟恶病质的发生或改善症状。在一具体实例中,本发明的药物组合中的第一活性成分及第二活性成分可共同存在于同一药物单元或分开存在于不同药物单元;两种活性成分可同时或分开投用。
此外,本发明也提供了一种癌症的新疗法,其包括对有需要的个体投予治疗癌症有效量的抗癌药剂及/或施予放射性疗法,并同时投予治疗恶病质有效量的厚朴酚或其异构物或该等化合物的医药上可接受的盐类。
在又一方面,本发明提供了厚朴酚或其异构物或该等化合物的医药上可接受的盐类在制备治疗膀胱癌的药物中的应用。特定而言,本发明的药物可有效抑制膀胱癌的肿瘤生长或癌细胞转移。本发明亦提供将厚朴酚或其异构物或该等化合物的医药上可接受的盐类投予有需要的个体以治疗膀胱癌或避免癌细胞转移的方法。
下文中将详细描述本发明的各种具体实施例。本发明的其他特征将通过下列有关各种具体实施例的详细说明以及权利要求而清楚呈现。
相信在本发明所属领域的技术人员在不需进一步说明的情况下可根据此处的描述利用本发明至其最广范围。因此,下列描述应被当作例证的目的而非以任何方式作为本发明的范围的限制。
附图说明
图1显示厚朴酚在恶病质动物模型中改善或减缓(A)体重及(B)进食量的下降。
图2显示厚朴酚在恶病质动物模型中改善或减缓肌肉耗损,其中(A)显示肌肉组织外观,(B)显示肌肉重量的测量结果,(C)显示肌肉细胞形态,以及(D)显示蛋白酶活性试验分析结果,包括胰凝乳蛋白酶、胰蛋白酶及半胱天冬酶。
图3显示厚朴酚在恶病质动物模型中减少促骨骼肌分解因子的表达,其中(A)显示免疫荧光染色分析结果,以及(B)显示Western Blotting分析结果。
图4显示厚朴酚在恶病质动物模型中抑制肌肉生长抑制素的表达(酵素免疫分析结果)。
图5显示厚朴酚在恶病质动物模型中有保护脏器避免细胞坏死的功效,(A)是动物的膀胱切片染色结果,(B)是动物的肾脏切片染色结果,(C)是动物的血浆肌酸肝(Creatinine),以及(D)是动物的尿素氮(BUN)生化值测量结果。
图6显示厚朴酚在恶病质动物模型中保护小肠黏膜组织及回复消化酶活性的功效,其中(A)显示小肠组织病理切片,(B)显示小肠病理损伤分级的分数,以及(C)、(D)及(E)分别显示亮氨酸肽酶、淀粉酶及脂解酶的活性分析结果。
图7显示厚朴酚在恶病质动物模型中减少发炎因子的表达,其中(A)显示包括TNF-α、IL-6、IL-1β及急性发炎蛋白CRP的Western Blotting的结果,以及(B)、(C)及(D)显示TNF-α、IL-6及IL-1β的酵素免疫分析法的结果。
图8显示厚朴酚在异种移植膀胱癌细胞的肿瘤小鼠模型中抑制肿瘤的生长,其中(A)显示取下的肿瘤外观,(B)显示取下的肿瘤重量,以及(C)处理期间测量的肿瘤体积,以及在膀胱癌细胞注射至裸鼠膀胱的小鼠模型中,(D)显示各组动物的膀胱重量。
图9显示厚朴酚抑制小鼠膀胱癌所诱发的肺脏肿瘤转移,其中(A)显示取下的肺脏肿瘤外观,(B)显示各组肺脏上癌组织的结节(nodules)数目,以及(C)显示小鼠存活率。
图10显示厚朴酚的聚合物包覆微粒的显微镜图,其中(A)是聚缩酮包覆厚朴酚微粒,平均粒径大小为3.2μm,以及(B)是PLGA包覆厚朴酚微粒,平均粒径大小为3.9μm。
具体实施方式
除非另有说明,否则此处使用之全部技术和科学名词与本发明所属技术领域技术人员通常所了解的意义相同。
此处所使用的冠词“一”是指该冠词的一或一个以上(即,至少一个)的文法受词。
在本发明中,非可预期地发现厚朴酚投予恶病质的小鼠可有效改善或减缓肌肉耗损情形。根据本发明的揭露,恶病质的小鼠经投予厚朴酚后,不但改善肌肉耗损情形,也有效减缓体重减轻及食欲不振,并减少小肠黏膜损伤及回复消化酵素活性。所以,厚朴酚可作为治疗恶病质的药物。
本发明使用的厚朴酚是一种酚类化合物,化学名称为4-丙烯基-2-(5-丙烯基-2-羟基-苯基)酚(4-Allyl-2-(5-allyl-2-hydroxy-phenyl)phenol),尚有别名5,5'-二丙烯基-2,2'-联苯二酚(5,5'-Diallyl-2,2'-biphenyldiol),分子式为C18H18O2,结构如下:
本发明也可使用厚朴酚的异构物,特别是具有与厚朴酚相同的分子式(C18H18O2)及相同官能基或取代基,但其结构式不同,如位置异构物。更特定而言,本发明使用的厚朴酚异构物具有一联苯主体结构,其中各个苯环具有一丙烯基取代(H2C=CH-CH2R,R是指与其连接的苯环)及一羟基取代。在一具体实例中,本发明使用的厚朴酚异构物是异厚朴酚,又称和厚朴酚(Honokiol),其化学名称为2-(4-羟基-3-丙-2-烯基-苯基)-4-丙-2-烯基-酚(2-(4-hydroxy-3-prop-2-enyl-phenyl)-4-prop-2-enyl-phenol),尚有别名5,3'-二丙烯基-2,4'-二羟基联苯(5,3'-diallyl-2,4'-dihydroxydiphenyl),结构如下:
本发明也可使用厚朴酚或其异构物的医药上可接受盐类。本文所使用的“医药上可接受盐类”是指对于人类或哺乳动物服用具安全性且有效的盐类化合物,具有其所需的生物活性。医药上可接受盐类为本领域技术人员所熟知的,包括但不限于本发明使用的活性化合物的酸性或碱性盐类,例如与盐酸、氢溴酸、碘酸、硝酸、硫酸、硫酸氢钠、磷酸、磷酸酯、醋酸、乳酸、水杨酸、柠檬酸、酒石酸、泛酸、重酒石酸、抗坏血酸、丁二酸、马来酸、富马酸、葡萄糖酸、甲酸、苯甲酸、谷氨酸、甲基磺酸、对甲苯磺酸合成的碱性盐;或与铝、钙、锂、镁、钾、钠、锌和二乙醇胺盐合成的碱性盐。
本发明使用的厚朴酚或其异构物或其医药上可接受盐类可由商业上获得,也可以已知方法由天然植物来源萃取分离取得(例如,来自木兰科植物厚朴的干燥干皮、根皮及枝皮)或以化学合成方法获得。
此处所使用的“个体”一词包括人类及非人类动物,例如,伴侣动物(如,狗、猫及类似者)、农场动物(如,牛、羊、猪、马及类似者)或实验动物(如,大鼠、小鼠、天竺鼠及类似者)。
此处所使用的“治疗”一词是指为了治愈、愈合、减轻、舒缓、改变、矫正、改善、改进或影响该疾病、该疾病的症状、该疾病引起的残疾或罹患该疾病的倾向的目的,而将包含一或多种活性剂的组合物施用或投与至患有该疾病、该疾病的症状或有罹患该疾病的倾向的个体。
此处所使用的“治疗上有效量”一词是指相较于未接受该量的对应个体,一药物或药剂可造成治疗目的的有效成分的含量。例如,治疗恶病质有效量为可防止、改善或减缓肌肉耗损的剂量,或可进一步防止、改善或减缓一或多种其他恶病质病征(如,体重下降、疲倦、厌食、无力、衰弱等)的剂量。该等病征可使用本领域已知方法并基于各种与病程相关的指标进行测定及评估,例如,与发炎相关的细胞激素及蛋白,如,IL-6、TNF-α、IL-1β及CRP,净体重(lean body mass,LBM),血红素,肌力测试,进食量,疲倦测试,衰弱等(可参见Malnutrition,fatigue,frailty,vulnerability,sarcopenia and cachexia:overlap of clinical features.Curr Opin Clin NutrMetab Care.2012May;15(3):213-9.;Anorexia,cachexia and fatigue.Clin Med.2010Oct;10(5):476.;Diagnostic criteria of cachexia and their assessment:decreased musclestrength and fatigue.Curr Opin Clin Nutr Metab Care.2008Jul;11(4):417-21.)。又例如,治疗癌症有效量可为减少肿瘤大小或癌细胞生长或转移能力等的剂量,亦可用本领域已知方式评估治疗效果。有效量可视各种因素而变动,例如,投药途径、接受该药剂的个体的体重及物种,以及投药目的。本领域技术人员可根据此处的揭示及已建立的方法依经验决定每一个别案例的剂量。具体而言,本发明的药物口服剂量可为每日1至500mg/kg,较特定为每日2.5至250mg/kg,更特定为每日5至100mg/kg的有效成分。在一特定实例中,依据本发明制得的药物可含有50-500毫克(mg),或25-250毫克(mg)的活性成分供适当的每次单一或二或更多的投药。在本文中,当剂量以一特定数值表示时,该数值包括其上下20%范围内的剂量。例如,以500mg的剂量为例,其表示400mg至600mg的剂量。
本发明的药物可用于治疗个体的恶病质。具体而言,本发明的药物可施用于具有产生恶病质风险或感受恶病质相关病征的个体,以避免恶病质的发生或改善或推迟恶病质的进展。
在部分具体实施例中,本发明的药物可施用于具有可导致恶病质的疾病、状态或损伤的个体,该等疾病、状态或损伤包括但不限于,癌症(如,膀胱癌、肝癌、乳癌、卵巢癌、胃癌、胰脏癌、大肠癌、骨癌、血癌等)、免疫不全疾病(如,艾滋病等)、感染性疾病(如,结核病、败血症等)、自体免疫疾病(如,风湿性关节炎)、代谢性疾病(如,糖尿病等)、慢性的肠道、肝脏、肾脏、肺脏或心脏疾病(如,肝硬化、肾衰竭、慢性阻塞性肺病(COPD)、慢性心脏衰竭等)、厌食症、创伤或烧伤、营养吸收不良、贫血等。
以癌症而言,当病程进入末期,有80%病患会出现恶病质症状,是造成病患死亡的主要原因。因此,本发明亦提供一种癌症疗法,其包括对有需要的个体在进行化疗及/或放射性疗法,并同时投予治疗恶病质有效量的厚朴酚,使得在治疗癌症的同时,避免恶病质的发生或改善或推迟恶病质的进展。厚朴酚的投予可与化疗及/或放射性疗法同时(同步)或依序进行。
因此,本发明也提供了一种药物组合,其包括第一活性成分,所述第一活性成分包括对治疗恶病质有效量的厚朴酚或其异构物或该等化合物的医药上可接受的盐类;以及第二活性成分,所述第二活性成分是指第一活性成分以外的活性成分,包括一或多种对治疗癌症有效量的抗癌药剂。具体而言,本发明的药物组合一方面可提供治疗癌症的效果,一方面可避免或推迟恶病质的发生或改善症状。在一具体实例中,本发明的药物组合中的第一活性成分及第二活性成分可共同存在于同一药物单元或分开存在于不同药物单元;两种活性成分可同时或分开投用。
此处所描述的“化疗”是对病患投予抗癌药剂以治疗癌症。抗癌药剂包括但不限于,烷化剂(alkylating agents),例如,爱斯达(fosfamide)、环磷酰胺(cyclophosphamide)及达喀尔巴嗪(dacarbazine);抗代谢药物(antimetabolites),例如,卡培他滨(capecitabine)、卡莫氟(carmofur)及健泽(gemcitabine);植物碱类药物(plant alkaloid agents),例如,抗癌妥(irinotecan)、太平洋紫杉醇(paclitaxel)及抗癌妥(irinotecan);抗生素类药物,例如,放线菌素D(actinomycin D)、莫力辛(bleomycin)及丝裂霉素C(mitomycin C);铂类药物,例如,奥沙利铂(oxaliplatin)、佳铂帝(carboplatin)、顺铂(cisplatin)及奈达铂(nedaplatin);荷尔蒙制剂(hormonalagents),例如,安美达锭(Anastrozole)、氯地孕酮(chlormadinone)及泰莫西芬(tamoxifen);分子标靶类药物(molecular target drugs),例如,替尼(Imatinib)、艾瑞莎(gefitinib)、吉妥单抗(gemtuzumab)及妥昔单抗(rituximab)等。抗癌药剂的投予方式依药物种类不同而异,可为口服或注射,如肌肉内或静脉注射。
此处所描述的“放射性疗法”是对病患投予放射线以治疗癌症。放射性疗法的施用方式包括但不限于体外放射治疗,例如,术中放射线疗法(intraoperativeradiotherapy)及预防式头部放射(prophylactic cranial irradiation,PC);体内放射治疗,例如,组织间质放射性治疗(interstitial radiation therapy)、腔内放射性治疗(intracavitary radiation therapy)及管道内放射性治疗(intraluminal radiationtherapy);全身性放射性治疗(systemic radiation therapy);立体定位放射手术(stereotactic(stereotaxic)radiosurgery);三度空间顺形放射治疗(three-dimensionalconformal radiotherapy,3D CRT);及强度调控放射治疗技术(Intensity ModulatedRadiation Therapy,IMRT)。放射性疗法的能量来源包括但不限于X射线、伽马射线、粒子束(particle beams)、质子束(proton beam)及高能光子射束(high-energy photonradiation)。
另一方面,亦发现厚朴酚本身对于膀胱癌有优异的治疗效果。因此,本发明提供一种厚朴酚或其异构物或该等化合物的医药上可接受的盐类在制备治疗膀胱癌的药物中的应用。特定而言,本发明的药物可抑制膀胱癌的肿瘤生长或癌细胞转移。在一具体实例中,本发明的药物可抑制膀胱癌的癌细胞转移至其他器官,例如,肝、肺、骨头等。
根据本发明,膀胱癌是指各种出自膀胱的恶性肿瘤,包括上皮性肿瘤,包括乳头状瘤、移行细胞癌、鳞状细胞癌及腺癌等,以及非上皮性肿瘤。在临床上,90%以上的膀胱癌属于移行性上皮细胞(Transitional cell carcinomas,TCCs),依据移行性上皮细胞癌侵入肌肉层组织程度可分为:Ta,乳突肿瘤于泌尿道上皮与计划朝向腔道发展;Tcis,平坦病变组织切片确认为泌尿道上皮;T1,乳突状肿瘤侵入上皮组织;T2,肿瘤往平滑肌肉层入侵;T3,肿瘤入侵脂肪层;及T4,肿瘤入侵前列腺、尿道、阴道、肾孟或腹部壁。
目前膀胱癌治疗包括外科疗法、免疫疗法、放射线治疗及化学药物治疗,表浅性膀胱癌可经由膀胱镜切除肿瘤合并术后给予化学药物治疗。顺铂为治疗膀胱癌常用的化学药物,但对肾脏具有毒性(Dos Santos NA et al.,Arch Toxicol.2012Aug;86(8):1233-50),因此多与健泽合并使用(Cohen MH et al.,Oncology.2001;19:1229-31)。然而,接受多重性疗法的膀胱癌患者,其局部及远程扩散后的五年存活率仍仅约五成(George L et al.,Urology.2004;64:488-93)。本发明提供针对膀胱癌的药物组合物,尤其可降低其移行或侵犯能力,可提供膀胱癌的有效治疗。
根据本发明,治疗有效量的有效成分可与医药上可接受载体调配成适当剂型的药物组合物,以达输送及吸收的目的。视投药模式而定,本发明的药物组合物较佳含有约0.1重量%至约100重量%的有效成份,重量百分比是以总组合物计。
此处“医药上可接受”是指该载体可与组合物内所含的有效成分兼容,其较佳为能稳定该活性成分并且对被治疗的个体无害。该载体可作为活性成分的稀释剂、载体、赋形剂或基质。一些适当赋形剂的实例包括乳糖、右旋糖、蔗糖、山梨糖、甘露糖、淀粉、阿拉伯胶、磷酸钙、褐藻酸盐、黄蓍树胶、明胶、硅酸钙、微晶纤维素、聚乙烯吡咯啶酮、纤维素、灭菌水、糖浆和甲基纤维素。组合物可另外包括润滑剂,例如,滑石粉、硬脂酸镁和矿物油;湿润剂;乳化和悬浮剂;保存剂,例如,羟基苯甲酸甲酯和丙酯;甜味剂;以及调味剂。本发明的组合物通过本领域已知的方法配制后,能在投与至病人后提供活性成分的快速、持续或延迟释放的效果。
在一具体实例中,医药上可接受载体可以是生物可降解的聚合物,包括但不限于聚乳酸(PLA)、聚乙醇酸(PGA)、乳酸乙醇酸共聚物、聚乳酸-羟基乙酸(PLGA)共聚物、聚羟基丁酸、聚缩酮(polyketal)、淀粉、纤维素、乙酰纤维素、羟丙基甲基纤维素、几丁质、葡聚糖、其混合物及其共聚物,较佳为聚乳酸-羟基乙酸(PLGA)及聚缩酮(polyketal)。该等聚合物的分子量没有特别限制,可视需要调整。在一具体实例中,该等聚合物的分子量可为500kDa或以上、1,000kDa或以上、1,500kDa或以上、2,000kDa或以上。在另一具体实例中,该等聚合物的分子量可为200,000kDa或以下、150,000kDa或以下、100,000kDa或以下、50,000kDa或以下。也可选择在上述范围以外的聚合物,只要可达到输送的目的即可。
在一具体实例中,本发明的活性成分可与生物可降解的聚合物依比例混合制成适当粒径的微粒。此处所描述的“微粒”可以是含有粒状物的固体或悬浮液形式的粒状系统。具体来说,所述粒状物可为微小球,其具有平均粒径(直径)为999微米(μm)或以下,特定为500微米或以下,更特定为250微米或以下,又特定为100微米或以下,再特定为50微米或以下,又再特定为25微米或以下,再更特定为10微米或以下。在一特定具体实例中,微粒的平均粒径可达奈米大小。粒状物的粒径大小可由此领域的习知技术测量而得,例如,雷射绕射或光学显微镜。
根据本发明该组合物的形式可为锭剂、药丸、粉末、糖锭、药包、药片、酏剂、悬浮液、乳剂、溶剂、糖浆、软和硬明胶胶囊、栓剂、灭菌注射液和包装粉末。
本发明的组合物可经由任何生理上可接受途径,例如,口服、肠道外(例如,肌肉、静脉、皮下、腹腔内)、经皮、直肠、吸入等方式予以输送。对于非经肠道的投药,最佳是以无菌水溶剂形式使用,其可含有其它物质,例如,足够的盐或葡萄糖以使此溶液与血液呈等渗压。水溶液需要时需被适当缓冲(较佳为pH值为3至9)。于无菌条件下制备适合的非经肠道组成物可通过本领域技术人员所熟知的标准药学技术方法完成,而不需要付出额外的创造性劳动。
现参考以下具体实施例更明确地描述本发明,其目的为用以说明而非作为限制。
实例
1.材料及方法
1.1厚朴酚(magnolol)
本发明使用的厚朴酚(magnolol)是来自台湾医药发展机构提供的标准品,纯度高于99%,溶于1%DMSO后作下述一系列完整的细胞及活体生物活性实验。
1.2细胞培养
膀胱癌细胞T24购自国家细胞库,源自人类女性膀胱移形性上皮细胞癌,生长特性为贴附型单层细胞。T24细胞培养于含有10%胎牛血清(Fetal Bovine Serum,FBS)、0.2%NaHCO3、100μ/ml青霉素(Penicillin)、100μg/ml链霉素(Streptomycin)的RPMI1640完全培养液。在含有5%CO2及饱和水蒸气的37℃培养箱中培养,每三天更换一次培养液并定期继代培养,培养期间定期以倒立式显微镜观察细胞形态的完整性与生长速度。
1.3动物试验
本研究使用的动物是六或八周龄的母BALB/c裸鼠,每只体重约为25克,购自国家动物中心。饲养在有12小时光照周期(AM7:00-PM7:00),并给予适当温度及湿度控管、充份供应饲料与饮水。
1.4建立恶病质动物模型
在第0天以软针将2×105/100μl的T24人类膀胱癌细胞原位注射到8周大的BALB/c裸鼠膀胱中。在肿瘤诱发后十天左右,将老鼠随机分组予以投药,其中顺铂(Cisplatin;75mg/m2予以腹腔注射)是以每周给予一次为一周期,施打两个周期休息一周期;健泽(Gemcitabine;1000mg/m2予以腹腔注射)是以每周给予两次为一周期,施打两个周期休息一周期(Hahn KA,Seminars in avian and exotic petmedicine2005:193–198);厚朴酚(每日10mg/kg,予以腹腔注射)连续投药30天。评估动物的体重及食欲变化,最后牺牲裸鼠,取下内脏及下肢肌肉等部位,进行后续分析。
1.5小肠酵素活性试验
将裸鼠牺牲后取下的小肠撷取片段刮除肠黏膜,取0.2克加入4℃0.9%NaCl溶液,其含有蛋白酶抑制剂1μM苯甲基磺酰化氟(phenylmethylsulfonylfluoride,PMSF)及2.2mM碘乙酸(iodoacetic acid),然后以均质机均质化离心后取上清液滴加于玻片(Fuji DRI-CHEM slides),并于分析仪(Fuji DRI-CHEM3030Analyzer(Fuji Photo Film Co.Ltd.,Tokyo,Japan)进行酵素活性测定。
1.6免疫化学染色分析(IHC)
将组织切片脱蜡后以TBS缓冲液(pH值7.5-7.6)清洗细胞。加入含30%H2O2的甲醇置室温下作用十分钟以去除内生性过氧化酵素。以TBS缓冲液清洗细胞,去除非特异性的结合,将3%胎牛血清(FBS)加入细胞培养片(coverslips)中使其足以覆盖表面,置室温下十分钟。移除胎牛血清,以TBS缓冲液清洗细胞后,加入一抗置于4℃过夜反应。移除一抗,以TBS缓冲液清洗细胞后,加入二抗于室温下反应一小时。移除二抗,以TBS缓冲液清洗细胞后,加入过氧化氢酵素共轭的链霉亲和素(peroxidase-conjugated streptavidin)于室温下反应二十分钟。移除过氧化氢酵素共轭的链霉亲和素,以TBS缓冲液清洗细胞后,加入二氨基联苯胺(diaminobenzidine,DAB)约两分钟作呈色反应。再以TBS缓冲液内清洗后,使用血毒素(hemotoxin)染细胞核,以TBS缓冲液冲洗后进行封片,封片后即可使用显微镜进行拍照。
1.7肿瘤生长分析
第0天在8周龄BALB/c裸鼠背部以皮下注射方式注入2×106/100μl的T24细胞,当肿瘤体积(0.52x主轴(mm)x副轴(mm)2)长到达100mm3时,将老鼠随机分组连续投药30天。厚朴酚以腹腔注射投药,一日一次,剂量为每日2mg/kg、5mg/kg或10mg/kg。利用光标尺每星期测量一次肿瘤大小的变化(n=5)。
1.8抗肿瘤转移试验
将4×106/100μl的T24人类膀胱癌细胞经尾静脉注射于8周大BALB/c裸鼠。在注入肿瘤细胞后十天,将老鼠随机分组投药30天或直至动物自然死亡为止。厚朴酚以腹腔注射投药,一日一次,剂量为每日2mg/kg或5mg/kg。在实验结束后将动物牺牲,取出肺脏利用人工计数的方式,计算肺脏表面上的所形成的肿瘤结节(nodule)数。同时,也进行存活试验,计算动物存活率。
1.9统计分析方法
本研究结果的图式皆以平均值±标准误差来表示,统计方法是根据原始实验数据,并以单因子变异数分析法(one-way ANOVA)比较各组之间是否有差异,若有统计上差异则以Student t-test检定法进行统计分析。若P<0.05则视为有显著差异。
2.结果
2.1改善体重减轻及食欲低下
本研究使用恶病质动物模型进行分析,其中各组动物处理方式如下:
注射T24细胞的肿瘤小鼠于第10天后以上述方式给药,每三天记录摄各组动物的食量及体重变化。
如图1(A)显示,控制组(肿瘤小鼠)的体重相较于正常组较低,而当给予健泽及顺铂两种化疗药物后(第3组),外观明显瘦弱许多,体重至少降低原体重5%以上,同时观察到小鼠行动力下降、衰弱而无法正常活动;相较之下,化疗药物合并给予厚朴酚的组别(第4组及第5组),体重皆有增加,以第5组改善最为明显,行动力亦有显著改善。此外,如图1(B)显示,给予健泽及顺铂两种化疗药物的动物(第3组),其平均摄食量相较于其他组为最低,但合并给予厚朴酚则可增加摄食量(第4组及第5组)。
这些结果显示厚朴酚可明显改善或减缓恶病质动物的体重减轻及食欲降低等病征。
2.2减少肌肉耗损
将裸鼠以二氧化碳处死后,将下肢肌肉取下观察。由外观可见肿瘤合并化疗药物组别的整体肌肉组织明显较小,而给予厚朴酚合并治疗后肌肉组织及外观显著增加及正常,参见图2(A),而肌肉重量的测量结果也显示出一致的结果,参见图2(B)。
此外,将各组别骨骼肌肉组织以石蜡包埋切片后进行苏木紫-伊红染色(H&Estatin),于显微镜下观察正常组别肌肉细胞型态。结果显示,正常组的肌肉细胞型态为排列整齐的椭圆形,而肿瘤组的肌肉细胞型态已产生变化,呈狭长及萎缩型态,当给予化疗药物后肌肉萎缩情形更加严重,而给予厚朴酚后肌肉细胞排列较为紧密,已接近正常肌肉组织的型态,尤以健泽+厚朴酚组改善最显著,参见图2(C)。
另外,也利用蛋白酶活性试验分析下肢肌肉的肌肉降解情况。如图2(D)显示,肿瘤合并化疗药物组别(第3组)的降解酶(胰凝乳蛋白酶、胰蛋白酶、半胱天冬酶)活性明显增加,代表肌肉降解增加;而给予厚朴酚合并治疗后降解酶均显著下降。
这些结果显示厚朴酚可显著改善或减缓恶病质动物的肌肉降解耗损。
2.3减少促骨骼肌分解因子的表达
肌肉细胞中泛素连接酶(ubiquitin ligase)Atrogin-1(MAFbx)及MuRF1活化时可促使肌肉的萎缩,这些因子可受到许多转录因子的调控,例如,FoxO。本研究将各组别骨骼肌肉组织以石蜡包埋切片后进行免疫荧光染色分析,观察泛素连接酶及相关转录因子的表达。结果显示当肿瘤合并化疗药物治疗时,泛素连接酶及相关转录因子皆大量表达,而合并给予厚朴酚后可抑制其表达,参见图3(A)。类似的泛素连接酶及相关转录因子的蛋白质表达变化也在Western Blotting结果中得到进一步证实,参见图3(B)。
2.4抑制肌肉生长抑制素的表达
肌肉生长抑制素(myostatin)于骨骼肌萎缩中也扮演重要角色。因此,本研究取部分肌肉组织进行酵素免疫分析法,结果显示在肿瘤小鼠中,肌肉生长抑制素的表达量高于正常组,再给予化疗药物后,其表现情形更加明显,而合并给予厚朴酚,可降低肌肉生长抑制素的表达,参见图4。在Western Blotting也进一步证实,与促进肌肉生长有关的AKT信息路径,在肿瘤组及合并给予化疗药物组的磷酸化AKT的表达都低于正常组,而磷酸化AKT的减少可促使FoxO的活化及肌肉分解,因此肌肉生长抑制素(myostatin)/ActRⅡB/FoxO为抑制肌肉生长的主要信息路径,肿瘤组及合并给予化疗药物组会促使肌肉生长抑制素的表现增加,而给予厚朴酚后不但可抑制肌肉生长抑制素及其接受器ActRⅡB的表现,同时也抑制转录因子FoxO的活性,参见图3(B)。
2.5保护脏器的作用
将小鼠以二氧化碳牺牲,取下膀胱及肾脏以石蜡包埋切片后进行苏木紫-伊红染色(H&E stain)。如图5(A)显示,于显微镜下观察发现肿瘤组的膀胱因肿瘤生长快速,已出现细胞坏死(necrosis)(箭号处),癌细胞也侵犯至髋部,再给予化疗药物后(第3组:健泽+顺铂)可减缓癌细胞侵犯程度,降至肌肉层,但细胞坏死的情形并无改善,然而合并厚朴酚后(第4组:健泽+顺铂+厚朴酚,TGCM)可抑制癌细胞生长速度使细胞坏死情况得到改善并影响肿瘤侵犯能力。
另,取小鼠肾脏进行肾脏病理染色切片图。如图5(B)显示,于显微镜下观察发现,控制组(肿瘤小鼠)组与正常组相比较,控制组(肿瘤小鼠)组其肾丝球已经出现基威二氏结(Kimmelstiel-Wilson nodules)的迹象,在同一平面的肾丝球分布也较正常组来得少,其肾丝球与正常组相比也较为不完整;而当给予健泽及顺铂两种化疗药物后(第3组)不仅基威二氏结的迹象越发严重外,发炎情况也明显增加。相较之下,化疗药物合并给予厚朴酚的组别(第4组),可看到在肾丝球分布和完整程度与给予健泽及顺铂两种化疗药物后(第3组)组相比,已有明显增加与改善,但肾丝球仍具有肥大的迹象。而在第5组肾丝球分布和完整程度不仅有明显增加与改善,且改善程度比第4组更为接近正常组。此外,也测量肾脏相关生化值,如图5(C)及5(D)显示,可发现给予健泽及顺铂两种化疗药物后(第3组)的相关血浆肌酸肝(Creatinine)及尿素氮(BUN)生化值都有显著升高,相较之下,化疗药物合并给予厚朴酚的组别(第4组及第5组)则明显下降。
这些结果显示厚朴酚有保护脏器免于破坏,特别是防止膀胱细胞坏死及保持肾脏组织完整及延缓肾功能恶化。
2.6保护小肠黏膜组织及回复消化酶活性
由于化疗药物抑癌的机转为针对癌细胞快速生长特性,作用于细胞周期,因此同样具有此特性的小肠黏膜细胞也会受到破坏,因此也针对小肠组织的损伤情形进行评估。将裸鼠的小肠组织做病理切片检查,发现相较于肿瘤组,健泽+顺铂组(第3组)对小肠黏膜的破坏更为严重,然而给予厚朴酚的动物则显著减少此破坏现象,肠道黏膜受到保护,小肠绒毛的形态也维持完整,参见图6(A)。另外,也由病理医师依病理损伤进行分级,依情况好至差,分为0至3分的分数(Cancer ChemotherPharmacol(2008)63:91–98),结果参见图6(B)。
化疗药物造成肠胃道黏膜细胞损伤,使得消化酶分泌及活性降低,导致消化动物的吸收功能不良。收集裸鼠的小肠萃取液,分析其酵素活性,结果显示健泽+顺铂组的三种主要消化酶(亮氨酸肽酶、淀粉酶及脂解酶)的活性都低于控制组,并远低于正常组,而给予厚朴酚合并治疗后三种酵素活性数值均明显增加,尤以健泽+厚朴酚组增加最多,参见图6(C)、6(D)及6(E)。
这些结果显示厚朴酚在恶病质动物有保护小肠黏膜组织及回复消化酶活性的作用,此与前述改善或减缓体重减轻及食欲低下的结果一致。
2.7减少发炎因子的表达
在肿瘤微环境中,癌细胞与宿主产生交互作用衍生出许多细胞激素,例如,TNF-α、IL-6、IL-1β,而造成体内产生发炎反应进而驱动恶病质的发生,血液中细胞激素的表达也为临床诊断恶病质标准之一。本研究以Western Blotting法及酵素免疫分析法分析动物实验中给予厚朴酚是否可抑制发炎因子的表达。
Western Blotting结果显示,于肿瘤组及肿瘤合并化疗药物组的动物中,肌肉组织中这些发炎因子表达量均高于正常组,而合并给予厚朴酚,则可明显减少TNF-α、IL-6、IL-1β及急性发炎蛋白CRP的表达,参见图7(A)。酵素免疫分析法结果也显示,于肿瘤组及肿瘤合并化疗药物组的动物的血清中,TNF-α、IL-6、IL-1β的含量均高于正常组,而合并给予厚朴酚,则显著减少其表达,参见图7(B)、7(C)及7(D)。
2.8抑制肿瘤生长
本研究亦在异种移植膀胱癌细胞的肿瘤小鼠进行抑制肿瘤生长分析试验。在小鼠背部皮肤植入T24人类膀胱移形性上皮细胞癌细胞株,当肿瘤体积长到固定大小时,以腹腔注射方式给予不同剂量的厚朴酚,连续投药30天,每星期测量肿瘤大小,为期四周,最后牺牲后将肿瘤取下秤重。
结果显示,对照组老鼠于转植肿瘤后四个星期,肿瘤大约可长到507.8±91.0mm3大,而给予厚朴酚治疗组的老鼠肿瘤体积分别为489.3±95.0mm3(2mg/kg/day)、132.5±23.4mm3(5mg/kg/day)及119.2±16.4mm3(10mg/kg/day),相较于对照组达到显著统计差异;此外在肿瘤重量比较上也显示类似的抑制效果,对照组老鼠肿瘤重量约为0.61±0.04g,而厚朴酚治疗组(10mg/kg/day)则为0.19±0.01g,相较于对照组也达到显著差异,参见图8(A)、8(B)及8(C)。
此外,在T24人类膀胱癌细胞原位注射到8周大的BALB/c裸鼠膀胱中,在肿瘤诱发后十天左右,将老鼠随机分组予以投药,测量各组小鼠的膀胱重量。如图8(D)显示,肿瘤组(第2组:控制组)重量最重,代表肿瘤生长最多;给予化疗药物后(第3组:健泽+顺铂)因可减缓癌细胞生长速度,因此重量与控制组相较下显著下降许多;尤其是合并厚朴酚后(第4组:健泽+顺铂+厚朴酚,TGCM)膀胱重量又更为下降,代表厚朴酚与化疗药物合并使用可降低肿瘤生长速度,具加乘作用。
此结果显示,厚朴酚亦具有抑制膀胱癌的肿瘤生长的作用,且与化疗药物并用有优异的加成效果。
2.9抗肿瘤转移
本研究在膀胱癌转移动物模式中分析癌细胞移转情形。将T24人类膀胱移形性上皮细胞癌细胞株,经尾静脉注射于小鼠,十日后,将小鼠分组投药或直至动物自然死亡为止。在实验结束后将动物牺牲,取出肺脏,计算肺脏表面形成的肿瘤结节数目,同时行存活试验,计算动物存活率。
结果显示,给予厚朴酚治疗组肿瘤结节数约为9.2±1.3(每日2mg/kg)及3.1±0.6(每日5mg/kg)相较于控制组肿瘤结节数约为16.9±1.4,皆达到统计显著意义,证实厚朴酚可明显减少膀胱癌细胞经血液循转移至肺脏的现象。此外,在存活试验中,也发现厚朴酚治疗组的动物存活天数分别约为78天(每日2mg/kg)及84天(每日5mg/kg),与控制组的64天相较存活率明显增加,证实给予厚朴酚治疗可减少肿瘤转移并增加癌症动物的存活率(请参阅图9A、9B及9C)。
3.结论
综合以上研究结果,我们在恶病质动物模型中已证实,厚朴酚可有效改善恶病质动物的肌肉耗损情形,以及厚朴酚有效减缓了动物的体重减轻、食欲不振、衰弱及肌肉无力,并减少小肠黏膜损伤、及回复消化酵素活性。此外,厚朴酚也证实具有治疗膀胱癌的效果,也可抑制膀胱癌的肿瘤生长、并减少肿瘤转移,提高动物的存活率。
4.厚朴酚的奈米及微米粒包埋制备
利用聚缩酮或PLGA(聚乳酸-羟基乙酸共聚物(poly(lactic-co-glycolic acid))与厚朴酚以特定比例混合,经搅拌、离心、喷雾造粒和冷却干燥等步骤,再包覆适当赋形剂如α-乳糖等,制成适当大小粒径的厚朴酚奈米粒、微米粒或微米包覆奈米粒,作为各类医疗用途的特定药物传输系统之用,如用于口鼻、肺或体液等药物传输。参见图10(A)及(B)。
本领域技术人员将了解上述具体实施例可被改变而仍不偏离其广义的发明概念。因此,应了解本发明非仅局限于所揭示的特定具体实施例,而应涵盖所附权利要求书所定义的发明的精神及范围内的变化。
从上述的说明,本领域技术人员可轻易地确认本发明的主要特征,以及在不偏离本发明的精神和范围的下可作出各种的改变和修饰,以适应各种的用途和状况。因此,其他具体实施例亦属于权利要求的范围内。
Claims (4)
1.厚朴酚或其异构物或该等化合物的医药上可接受的盐类在制备治疗癌症个体接受顺铂及健泽的化疗而引起的恶病质的药物中的应用。
2.如权利要求1所述的应用,其特征在于,其中所述药物可改善或减缓所述个体的肌肉耗损的恶病质病征。
3.如权利要求2所述的应用,其特征在于,其中所述药物可改善或减缓所述个体的体重降低、厌食、发炎、衰弱或肌肉无力的恶病质病征。
4.如权利要求1所述的应用,其特征在于,其中所述药物可使所述个体的小肠黏膜组织受到保护及消化酶活性予以回复。
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