CN102083426B - 与非大麻素化学治疗剂(例如血清或者烷基化剂)相组合的大麻素 - Google Patents
与非大麻素化学治疗剂(例如血清或者烷基化剂)相组合的大麻素 Download PDFInfo
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Abstract
本发明涉及一种或多种大麻素,特别是THC和/或者CBD,与非大麻素化学治疗剂的组合在制造用于治疗癌症的药物中的用途。具体而言,所治疗的癌症是脑瘤,更具体的是胶质瘤,仍然更具体的是多形性胶质母细胞瘤(GBM)。该非大麻素化学治疗剂可以是选择性雌激素受体调节剂或者是烷基化剂。
Description
本发明涉及与非大麻素化学治疗剂组合的一种或多种大麻素在制造用于治疗癌症的药物中的用途。具体的,所治疗的癌症是脑瘤,更具体的是胶质瘤,仍然更具体的是多形性胶质母细胞瘤(GBM),并且优选的大麻素是四氢大麻酚(THC),大麻二酚(CBD)或者其组合。
背景技术
癌症是这样一种疾病,在其中细胞组表现出不受控生长的特征。这意味着细胞的生长和分裂超出了正常的限度水平。该细胞还能够侵袭和破坏周围的组织。另外,癌症细胞有时候还会转移,这意味着它们经由血液或者淋巴液扩散到身体的其他部位。
大部分癌症是由于细胞的基因材料的畸变引起的。这些畸变可以归因于致癌物质的作用。其他促癌作用的基因畸变可以是通过DNA复制中的错误随机获取的,或者是遗传的,并因此从出生就存在于全部细胞中。
在癌症中发现的基因畸变典型地影响两种常规种类的基因。促癌作用的致癌基因经常是在癌症细胞中激活的,赋予这些细胞新的性质,例如过度活跃的生长和分裂,防止细胞程序性死亡,正常组织边界的损失,以及在不同的组织环境中移植生长的能力。
肿瘤抑制基因通常在癌症细胞中失活,导致了在这些细胞中正常功能的丧失,例如精确的DNA复制、对细胞周期的控制、在组织中的定向和粘附力,以及与免疫系统的保护细胞的相互作用。
存在许多不同类型的癌症,并且癌症通常是根据其发生的组织的类型来分类的。
癌症通常是用下面的一种或多种方法来治疗的:外科手术法、化疗法、放射治疗、免疫治疗和单克隆抗体治疗。治疗的类型取决于肿瘤的位置和类别以及疾病的阶段。
治疗的目标是完全消除癌症,而不损害身体的其他部分。有时候这可以通过外科手术来实现,但是癌症侵袭相邻组织或者通过微观转移扩散到较远部位的倾向经常限制其效力。化疗法的效力经常受限于对于身体其他组织的毒性。放射也可能损害正常的组织。
已知的是癌症影响身体的许多区域,最常见类型的癌症包括:胆管癌、膀胱癌、骨癌、肠癌(包括结肠癌和直肠癌)、脑癌、乳腺癌、神经内分泌系统癌(通常称作类癌瘤)、子宫颈癌、眼癌、食道癌、头颈癌(该组包括在构成口、鼻、咽喉、耳朵或覆盖舌头的表面层的内膜(lining)的细胞中发生的癌症)、卡普西肉瘤、肾癌、喉癌、白血病、肝癌、肺癌、淋巴结癌、霍奇金淋巴瘤、非霍奇金淋巴瘤、黑素瘤、间皮瘤、骨髓瘤、卵巢癌、胰腺癌、阴茎癌、前列腺癌、皮肤癌、软组织肉瘤、脊髓癌、胃癌、睾丸癌、甲状腺癌、阴道癌、阴户癌和子宫癌。
在大脑中形成的肿瘤能够通过引起炎症而破坏或者损害脑细胞,压迫大脑的其他部分,引起脑水肿(脑肿胀),并且能够引起颅内压力升高(头骨中的压力)。
每年,英国有大约4300人被诊断为脑瘤。原发性脑瘤是由于脑内细胞的生长或者不受控的增殖所产生的物质。恶性的原发性脑瘤最有可能通过扩散到包围它们的正常脑组织中和产生压力以及损害脑周围的区域而引起问题。这些肿瘤很少扩散到脑外的身体其他部分中。但是,当癌症细胞从身体的其他部分例如肺或者胸部扩散到脑时,出现转移性脑瘤。
外科手术是治疗许多脑瘤的可选项。一些脑瘤能够完全切除,但是深入或者渗透到脑组织中的那些肿瘤可以减积而非切除。
根据所涉及的肿瘤类型,可以推荐放射治疗和化疗法。
胶质瘤细胞肿瘤可能经常是致命的。胶质瘤特有的扩散渗透性肿瘤生长经常使得外科手术不可能除去它们,这明显使得这些患者的临床治疗复杂化。
多形性胶质母细胞瘤(GBM)是最常见的且最严重类型的原发性脑瘤,并且占全部原发性脑瘤病例的52%和全部颅内肿瘤的20%。
已经研究了不同的方案,来改善诊断为胶质瘤的患者的死亡率。这些方案包括目标是胶质瘤细胞,但使正常细胞不受损的治疗,限制癌症细胞扩散的方法和阻断肿瘤生命维持分子的治疗。
一个这样的研究领域涉及使用大麻素作为抗肿瘤剂。
大麻素是大麻植物的活性成分,并且已经发现它们表现出诸多的药学性能。
例如EP1177790(Guzman等人)描述了施用天然或合成大麻素,特别是THC,来治疗脑肿瘤。它声称特定受体的活化导致了转化细胞的选择性凋亡。
最近大麻素CBD已经显示出具有抗肿瘤性能(Massi等人,2004)。该论文所述的工作描述了通过皮下注入到裸鼠体内,在生物体外使用U87和U373人类胶质瘤细胞系以及在生物体内使用U87人类胶质瘤细胞二者来获得抗增殖性作用。
Biochemical Pharmacology 2000,第6卷第1807-1813页将大麻素(包括THC和CBD)与雌激素受体调节剂他莫昔芬的作用进行了比较,并且得出这样的结论,即,大麻素的作用是适度的,并且在大麻素和他莫昔芬之间没有显著的相互作用。
恶性胶质瘤是高渗透性和增殖性的肿瘤,其符合生长的特征图。胶质瘤细胞侵袭了相邻的正常脑结构和周围的大血管。
另外,本申请人更早的专利EP1802274描述了使用大麻素CBD,来阻止癌症细胞从它们的原发肿瘤位置迁移到转移部位的发展。
本申请人的共同未决申请GB0810195.8(申请日2008年6月4日)描述了大麻素的组合在癌症治疗中的用途。
发明内容
根据本发明,提供了与非大麻素化学治疗剂结合的一种或多种大麻素在制造用于治疗癌症的药物中的用途。
优选地,该一种或多种大麻素选自:四氢大麻酚(THC);和大麻二酚(CBD)。
在一种实施方案中,使用单种的,或者主要为单种的大麻素。该单种大麻素是THC或者CBD。
或者,以及优选地,可以使用大麻素的组合。
该组合的大麻素优选是THC和CBD。
优选该THC和CBD的比例是20:1~1:20。
更优选该THC和CBD的比例是5:1~1:5。
仍然更优选该THC和CBD的比例是2:1~1:2,更优选是大约1:1。
每种大麻素是以治疗有效量来提供的。THC和CBD的剂量范围可以通过参考大麻素含量来确定,其优选全部大麻素为5~100mg。在使用多种大麻素时,各种大麻素可以以这样的量使用,即,如果其单独使用时,这样的量被认为是次优的。
在一种实施方案中,该非大麻素化学治疗剂是选择性雌激素受体调节剂。
选择性雌激素受体调节剂是作用于雌激素受体的一类药物。它们的作用在不同的组织中是不同的,由此获得在不同的组织中选择性抑制或者促进类雌激素效应的可能性。
选择性雌激素受体调节剂包括:阿非昔芬(4-羟基他莫昔芬)、阿佐昔芬、巴多昔芬、氯米芬、拉索昔芬、奥美昔芬、奥美昔芬、雷洛昔芬、他莫昔芬或者托瑞米芬,并且它们用于多种医学指征。
一些用作抗肿瘤剂的选择性雌激素受体调节剂包括雷洛昔芬,他莫昔芬或者托瑞米芬。它们优选用于本发明中。
在一种替代实施方案中,该非大麻素化学治疗剂可以是烷基化剂。
烷基化剂是一种类型的抗肿瘤剂,其通过以许多方式干扰DNA而起作用。
将额外的分子(称作烷基)加入到DNA中,当细胞试图取代它们时,其使得它分裂开。烷基化剂还干扰了DNA链之间的结合,阻止它们分离,这是DNA复制所需的一个步骤。通过取代碱(DNA的重要组分),烷基化剂还产生了失配,这是阻止DNA适当复制的另一种方式。
当细胞准备分裂时发生了全部的这些变化,并且它们造成的永久性损伤导致了分裂停止和细胞死亡。
优选该烷基化剂选自:磺酸烷基酯、白消安、吖丙啶和甲基三聚氰胺、六甲基三聚氰胺、六甲蜜胺、硫化三(环氮丙基)磷、氮芥类(nitrogen mustards)、环磷酰胺、二氯甲基二乙胺、氮芥(mustine)、尿嘧啶氮芥、尿嘧啶芥、美法仑、苯丁酸氮芥、异环磷酰胺、亚硝基脲、亚硝基脲氮芥、顺铂、链脲霉素、三氮烯、氮烯咪胺、咪唑四嗪和替莫唑胺。
用作抗肿瘤剂的烷基化剂包括:顺铂,替莫唑胺和亚硝基脲氮芥,并且它们在本发明的实践中是优选的。
所治疗的癌症可以是脑瘤。
脑瘤通常是根据肿瘤位置和形成癌症的细胞的类型来分类的。
例如不同类型的脑瘤包括:听神经瘤、星形细胞瘤、CNS淋巴瘤、室管膜瘤、成血管细胞瘤、髓母细胞瘤、脑膜瘤、胶质瘤、混合型胶质瘤、少突胶质细胞瘤、松果体区肿瘤和垂体瘤。
胶质瘤是胶质细胞的肿瘤;这些细胞支持和保护大脑中的神经细胞。胶质瘤占全部原发性脑瘤的接近一半,并且占全部原发性脊髓肿瘤的五分之一。
本发明的结合治疗对于脑瘤是胶质瘤,更具体的是多形性胶质母细胞瘤(GBM)的情况是特别有用的。
该一种或多种大麻素可以是作为植物提取物,作为纯化合物或者二者的组合而存在的。
植物提取物定义为来自植物材料的提取物,如下面的文献所述:Guidance for Industry Botanical Drug Products Draft Guidance,2000年8月,US Department of Health and Human Services,Food and Drug Administration Centre for Drug Evaluation and Research。
植物材料定义为植物或者植物的部分(例如树皮、木材、叶子、茎、根、花、果实、种子、浆果或者其部分)以及分泌液。
更优选该植物提取物是植物药物质形式的。
植物药物质定义如下。来自于大麻植物的植物药物质包括通过以下方法制得的主要提取物:例如泡软,浸透,用溶剂例如C1-C5醇(例如乙醇)、诺氟烷(HFA134a)、HFA227、液体二氧化碳在压力下萃取,以及使用热气萃取。该主要的提取物可以通过超临界或者亚临界萃取、蒸发和色谱法来进一步净化。当使用溶剂例如上述的这些溶剂时,所得到的提取物可以包含非特异性脂质可溶性材料。这可以通过多种方法除去,包括冬化,其包括激冷到-20℃,随后过滤除去蜡状渣子,用液体二氧化碳以及通过蒸馏进行提取。
植物药物质被配制成植物性药品,其在Guidance for Industry Botanical Drug Products Draft Guidance,2000年8月,US Department of Health and Human Services,Food and Drug Administration Centre for Drug Evaluation and Research中定义为:“一种植物性产品,其目的是用作药物;由植物药物质制成的药品”。
该一种或多种大麻素可以与非大麻素抗肿瘤剂分开、依次或者同时给药。
该一种或多种大麻素可以与非大麻素化学治疗剂一起以试剂盒的形式共同存在,具有或者不具有它们的使用说明。
本发明的某些方面是参考仅仅作为例举的附图来进一步描述的,其中:
图1是一种条形图,表示在用THC、CBD或者组合的THC和CBD治疗之后,与对照例相比,人类 U87 MG星形细胞瘤细胞的细胞活力;
图2a和2b是条形图,表示在两种细胞系U87MG(图2a)和T98G(图2b)上,在不同的浓度时在生物体内的细胞活力数据;
图3a、3b和3c提供数据,提示对于U87MG细胞的组合作用机理;
图4是条形图,表示在用示例性的大麻素THC或者组合的示例性大麻素THC和示例性的非大麻素抗肿瘤剂他莫昔芬治疗之后,与对照例相比,人类 U87 MG星形细胞瘤细胞的细胞活力;和
图5是条形图,表示在用示例性大麻素THC,或者组合的示例性大麻素 THC和示例性非大麻素抗肿瘤剂顺铂治疗之后,与对照例相比,人类U87 MG星形细胞瘤细胞的细胞活力。
具体实施方式
下面的实施例1-5说明了在生物体外和生物体内二者中,一种或多种大麻素如何有效地治疗癌症细胞。
实施例6继续证实了使用出于说明性目的单种大麻素,与非大麻素抗肿瘤剂组合的一种或多种大麻素如何能够优于单独使用该非大麻素抗肿瘤剂。
实施例1:THC和CBD对于抑制生物体外的癌症细胞生长的作用。
将大麻植物提取物形式的四氢大麻酚(THC)和大麻二酚(CBD)溶解在乙醇中,达到100mM的浓度,在需要之前,将其在-20℃存储。
在使用前,将该大麻植物提取物进一步稀释到期望的浓度,确保乙醇的浓度低于0.001%。
在该整个试验中都使用U87人类胶质瘤细胞。将细胞保持在37℃的具有5%CO2和95%空气的潮湿气氛中。
细胞是在75cm2培养瓶中,在Dulbecco’s Modified Eagle Medium(DMEM)中培养的,其已经补充了4mM的L-谷氨酰胺、100单位/ml青霉素、100mg/ml链霉素、1%丙酮酸钠、1%非必需氨基酸和10%热失活的胎牛血清。
在不同的大麻素浓度下测量人类U87 MG星形细胞瘤细胞的活力。将THC和CBD提取物与纯THC和纯CBD进行比较。
结果:
表1:培养中的人类U87 MG星形细胞瘤细胞的细胞活力
。
从上表1中可见,当将该提取物中大麻素的量调整为等量的纯化合物时,THC和CBD提取物在活性方面比它们相应的纯化合物要有利得多。
这表明THC和CBD以及它们的提取物有效抑制胶质瘤细胞生长。
实施例2:组合的THC和CBD提取物在抑制生物体外癌症细胞生长方面的作用。
该试验测试了组合的THC和CBD提取物是否如单独的提取物那样有效的抑制细胞生长。
所用方法如上面的实施例1所述。
结果:
图1详细表示了条形图,描述了相对于单独的THC和CBD提取物以及其彼此组合的人类U87 MG星形细胞瘤细胞的细胞活力。
可以看出,与单独使用THC或者CBD治疗后的细胞活力相比,当THC和CBD组合使用时细胞活力显著降低。
该数据表明大麻素THC和CBD在联用时,在治疗肿瘤方面更有效。
实施例3:组合的THC和CBD在生物体内抑制癌症细胞生长的作用。
该试验测试组合的THC和CBD提取物是否在生物体内同样有效。
将人类U87 MG星形细胞瘤细胞异种移植到裸鼠体内,将试验化合物以15mg/kg/天的浓度进行瘤周注射。
结果:
表2:在15天的治疗之后,与起始时间相比的肿瘤体积
。
从上表2中可以观察到,在用THC和CBD提取物的1:1组合治疗之后,肿瘤体积显著优于用单独的纯THC或者THC提取物治疗之后的肿瘤体积。
该数据表明大麻素THC和CBD在联用时,在治疗肿瘤方面更有效。
实施例4:大麻素浓度对于两种不同的细胞系中的细胞活力的作用。
研究了THC、CBD和1:1比例混合的THC和CBD在不同的浓度下,对于两种细胞系U87MG和T98G的作用。细胞活力数据在图2a和2b中给出。
参考图2a,可以看到在0.1μg/ml和0.25μg/ml的THC和CBD低效率/次优剂量(大于90%细胞活力)没有获得组合使用那样的令人满意的细胞活力的显著降低(SAT),该数据表明了剂量与提高浓度之间的依赖关系(在0.25μg/ml具有更大的细胞毒性)。
用细胞系T98G(一种替代的人类胶质瘤细胞系)获得了如图2b所示的类似结果。
实施例5:作用机理研究。
已知的是THC使用包括基因ATGl和pan-caspase的信令路由而引起细胞死亡。针对S6磷酰化,LC3脂质化以及ATGl和pan-caspase抑制剂的作用的调查结果分别表示在图3a、3b和3c中。
从图3a中可见,THC:CBD组合(与对照物C相比):
·抑制mTORCl活性(通过S6磷酰化程度来确定);和
·促进脂质化形式LC3(自噬的检验标记)的聚集。
图3b表示压制了基本的自噬基因ATGl,并且与用对照物siC感染的细胞相比,选择性(siATGlO)siRNA抑制剂降低了诱导的细胞死亡。
最后,图3c表明用pan-capase抑制剂Z-VAD处理的细胞也防止了诱导的细胞死亡。
实施例6:与示例性非大麻素抗肿瘤剂相组合的示例性大麻素提取物对于抑制生物体外的癌症细胞生长的作用。
该试验测试了含有大麻素的药品与非大麻素抗肿瘤剂的组合是否有用。
细胞活力测试是如上面的实施例1所述来进行的。
结果:
图4和5是详细的条形图,其说明与对照物处理相比,当用THC、抗肿瘤剂或者二者组合来处理时,人类U87 MG星形细胞瘤细胞的细胞活力。
从这些图中可见,所测试的两种示例性抗肿瘤剂他莫昔芬和顺铂当与示例性大麻素THC组合使用时,在降低细胞活力方面更有效。从实施例1-5显而易见的是,用CBD和组合的THC和CBD将获得类似的益处。
实施例1-6一起证实了与非大麻素抗肿瘤药相组合的一种或多种大麻素产生了比单独使用该非大麻素抗肿瘤药更有益的效果。
Claims (12)
1.一种组合物,其含大麻植物提取物形式的大麻素四氢大麻酚、大麻素大麻二酚和非大麻素化学治疗剂,其中大麻素四氢大麻酚和大麻素大麻二酚的比例是5:1~1:5,该组合物用于治疗脑瘤,其中所述非大麻素化学治疗剂选自烷基化剂和选择性雌激素受体调节剂。
2.权利要求1所述的组合物,其中所述非大麻素化学治疗剂是烷基化剂。
3.权利要求1所述的组合物,其中所述非大麻素化学治疗剂是选择性雌激素受体调节剂。
4.权利要求2所述的组合物,其中所述烷基化剂是顺铂。
5.权利要求3所述的组合物,其中所述选择性雌激素受体调节剂是他莫昔芬。
6.前述权利要求任一项所述的组合物,其中脑瘤的治疗是降低细胞活性、抑制细胞生长或减少肿瘤体积。
7.权利要求1所述的组合物,其中大麻素四氢大麻酚和大麻素大麻二酚的比例是约1:1。
8.前述权利要求任一项所述的组合物,其中全部大麻素含量是5~100mg。
9.前述权利要求任一项所述的组合物,其中所述脑瘤是胶质瘤。
10.权利要求9所述的组合物,其中所述胶质瘤是多形性胶质母细胞瘤。
11.前述权利要求任一项所述的组合物,其中所述植物提取物为植物药物质的形式。
12.前述权利要求中任一项所述的组合物,其中所述大麻素植物提取物是与非大麻素抗肿瘤剂分开、依次或者同时给药的。
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