CN112074273A - 包含阿立哌唑作为活性成分的辐射敏感性增强组合物 - Google Patents
包含阿立哌唑作为活性成分的辐射敏感性增强组合物 Download PDFInfo
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- CN112074273A CN112074273A CN201980029987.0A CN201980029987A CN112074273A CN 112074273 A CN112074273 A CN 112074273A CN 201980029987 A CN201980029987 A CN 201980029987A CN 112074273 A CN112074273 A CN 112074273A
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Abstract
本发明涉及包含阿立哌唑作为活性成分的辐射敏感性增强组合物，更具体地，涉及当与辐射疗法联合时可用作为辐射敏化剂的阿立哌唑来治疗癌症的辐射敏感性增强组合物。与辐射疗法联合给予有效量的本发明所述的阿立哌唑，具有优异的辐射敏感性增强效果，例如降低癌细胞生存力和诱导癌细胞死亡，因此可以有用地用作辐射敏感性增强剂。
Description
技术领域
本发明涉及包含阿立哌唑作为活性成分的用于增强辐射(radiation)敏感性的组合物，更具体地，涉及当将阿立哌唑与辐射联合时能够作为辐射敏化剂来治疗癌症的用于增强辐射敏感性的组合物。
背景技术
癌症疗法大致可分为手术、辐射疗法和化学疗法。随着世界范围内接受辐射疗法的癌症患者数量逐年增加，辐射疗法在癌症治疗中的重要性也在增加，但该疗法伴随着降低治疗效率的副作用，例如在大剂量辐射治疗过程中获得癌细胞的辐射抗性以及对正常组织的损害。为了减少辐射的副作用并克服其中的抗性，正在研究与辐射联合给予时增加辐射的抗癌效果的辐射敏化剂。
阿立哌唑(Aripiprazole)的化学名称为7-{4-[4-(2,3-二氯苯基)-1-哌嗪基]-丁氧基}-3,4-二氢喹诺酮或7-{4-[4-(2,3-二氯苯基)-1-哌嗪基]-丁氧基}-3,4-二氢-2(1H)-喹啉酮。阿立哌唑是多巴胺D2受体的强部分激动剂，已知作为抗精神病药可用于治疗精神分裂症、躁郁症和临床抑郁症。到目前为止，阿立哌唑对中枢神经系统和神经系统疾病的药理作用研究有限，其技术研究也只着眼于提高药物的溶解度和吸收率，并且阿立哌唑的辐射增敏效果目前还不清楚，也没有对此进行相关的研究。因此，迫切需要对阿立哌唑的辐射增敏效果进行研究和开发。
发明内容
技术问题
本发明的目的是提供用于增强辐射敏感性的组合物，所述组合物包含阿立哌唑或其药学上可接受的盐作为活性成分。
此外，本发明的目的是提供用于增强辐射敏感性的组合物，所述组合物包含：阿立哌唑或其药学上可接受的盐和多巴胺受体抑制剂作为活性成分。
技术手段
为了实现上述目的，本发明提供了用于增强辐射敏感性的组合物、用于癌症的辅助辐射疗法的药物组合物或用于癌症的辅助辐射疗法的保健功能性食品组合物，其包含阿立哌唑或其药学上可接受的盐作为活性成分。
此外，本发明提供了用于增强辐射敏感性的组合物、用于癌症的辅助辐射疗法的药物组合物或用于癌症的辅助辐射疗法的保健功能性食品组合物，其包含：阿立哌唑或其药学上可接受的盐和多巴胺受体抑制剂作为活性成分。
有益效果
本发明涉及包含阿立哌唑作为活性成分的用于增强辐射敏感性的组合物，更具体地，涉及当将阿立哌唑与辐射联合时能够作为辐射敏化剂来治疗癌症的增强辐射敏感性的组合物。通过与辐射辐照联合给予有效量的本发明所述的阿立哌唑，其具有优异的辐射敏感性增强效果，例如降低癌细胞生存力和诱导癌细胞死亡，因此可以有用地用作辐射敏感性增强剂。
附图说明
图1示出了在MCF-7细胞中通过321种药物单独或与辐射联合处理对细胞生存力(viability)的影响。
图2示出了在MCF-7细胞中用不同浓度阿立哌唑单独或与辐射联合处理对细胞生存力的影响。
图3示出了在MCF-7细胞中阿立哌唑单独或与辐射联合处理对细胞PARP分裂(cleavage)的影响。
图4示出了在MCF-7细胞或U251细胞中阿立哌唑单独或与辐射联合处理对DNA断裂(fragmentation)的影响。
图5示出了在MCF-7细胞中分别用硫利达嗪(thioridazine)或阿立哌唑与辐射联合处理、或者同时用硫利达嗪和阿立哌唑与辐射联合处理后评价PARP分裂的结果。
图6示出了在MCF-7细胞或BT-474细胞中分别用硫利达嗪或阿立哌唑与辐射联合处理、或者同时用硫利达嗪和阿立哌唑与辐射联合处理后评价DNA断裂的结果。
图7示出了在MCF-7细胞中分别用氟哌啶醇(haloperidol)或阿立哌唑与辐射联合处理、或者同时用氟哌啶醇和阿立哌唑与辐射联合处理后评价PARP分裂的结果。
图8示出了在MCF-7细胞或BT-474细胞中分别用氟哌啶醇或阿立哌唑与辐射联合处理、或者同时用氟哌啶醇和阿立哌唑与辐射联合处理后评价DNA断裂的结果。
具体实施方式
本发明提供了用于增强辐射敏感性的组合物，所述组合物包含阿立哌唑或其药学上可接受的盐作为活性成分。
此外，本发明提供了用于增强辐射敏感性的组合物，所述组合物包含：阿立哌唑或其药学上可接受的盐和多巴胺受体抑制剂作为活性成分。优选地，多巴胺受体抑制剂可以是硫利达嗪或氟哌啶醇，但不限于此。
优选地，所述组合物能够通过辐照诱导癌细胞的细胞凋亡，更优选地，所述组合物能够诱导癌细胞的PARP分裂或DNA断裂。
优选地，可在癌症治疗期间与辐照联合给予所述组合物。更优选地，所述癌症可以是乳腺癌、肺癌、骨癌、胰腺癌、皮肤癌、口腔癌、口咽癌、子宫癌、卵巢癌、直肠癌、胃癌、子宫内膜癌、宫颈癌、阴道癌、小肠癌、甲状腺癌、甲状旁腺癌、前列腺癌、慢性或急性白血病、淋巴细胞淋巴癌、膀胱癌、肾癌、肝癌、结肠癌或脑瘤，但不限于此。
此外，本发明提供了用于癌症的辅助辐射疗法(adjuvant radiation therapy)的药物组合物，所述药物组合物包含阿立哌唑或其药学上可接受的盐作为活性成分。
此外，本发明提供了用于癌症的辅助辐射疗法的药物组合物，所述药物组合物包含阿立哌唑或其药学上可接受的盐和多巴胺受体抑制剂作为活性成分。优选地，多巴胺受体抑制剂可以是硫利达嗪或氟哌啶醇，但不限于此。
此外，本发明提供了用于癌症的辅助辐射疗法的保健功能性食品组合物，所述保健功能性食品组合物包含阿立哌唑或其药学上可接受的盐作为活性成分。
此外，本发明提供了用于癌症的辅助辐射疗法的保健功能性食品组合物，所述保健功能性食品组合物包含阿立哌唑或其药学上可接受的盐和多巴胺受体抑制剂作为活性成分。优选地，多巴胺受体抑制剂可以是硫利达嗪或氟哌啶醇，但不限于此。
在本发明中，术语“药学上可接受的盐”是指具有适于人类给药的安全性和有效性特征的盐。具体而言，阿立哌唑的药学上可接受的盐的特定形式包括衍生自无机酸(例如盐酸、硝酸、磷酸、硫酸、氢溴酸、氢碘酸、亚磷酸以及它们的混合物)的盐以及衍生自有机酸(例如脂肪族单羧酸和脂肪族二羧酸、取代苯基链烷酸、羟基链烷酸、链烷双酸、芳香酸、脂肪族磺酸和芳香族磺酸)的盐，但不限于此。
在本发明中，术语“辐射敏感性”是指基于辐射剂量的存活细胞的数量。在本发明中，为了测量辐射敏感性，通过使用对按剂量辐照辐射后所形成的群落数量进行测量的方法来确认。
在本发明中，术语“增强”是指在特定辐射剂量下存活的细胞的数量的减少、致死剂量所需的辐射剂量的减少、或它们的组合，但也包括其它常规的增强手段。具体而言，在本发明中，辐射敏感性的增加是指当对按剂量辐射后所形成的群落数量进行测量时，群落数量根据辐射浓度而减少，或者所建立的线性模型的斜率值增加。
在本发明中，术语“辐照(irradiation)”是指损害恶性细胞的DNA的热治疗方法。正常细胞比肿瘤细胞具有更大的修复这种损伤的能力。辐照是指利用这些差异进行的治疗，并且它包括传统意义上使用辐射的处理方法。
由于辐照是局部疗法的形式，所以副作用一般局限于所治疗的区域。然而，存在作为常见的全身症状的疲劳。虽然确实在一些病人中许多遗传因素容易导致继发性癌症，但辐射也导致所涉及的风险增加。本发明所述的用于增加辐射敏感性的组合物可以通过减少所需的辐射量来减少这种副作用。此外，不仅可以在辐射敏感的癌细胞中提高辐射敏感性，而且可以在抗辐射的癌细胞中提高辐射敏感性。
在本发明中，术语“联合给药/给予”是指在治疗各种类型癌细胞的抗癌疗法中与辐射辐照一起进行给药/给予。具体而言，辐射辐照处理可与抗癌疗法联合，以用于治疗例如实体肿瘤(例如肺癌、乳腺癌、结肠癌、卵巢癌、头颈癌或脑癌)的癌细胞。
当本发明的组合物是药物组合物时，除了阿立哌唑以外，该药物组合物可包含药学上可接受的载体，该药学上可接受的载体是在药物制剂中通常使用的，并且包括乳糖、葡萄糖、蔗糖、山梨醇、甘露醇、淀粉、阿拉伯胶、磷酸钙、海藻酸盐、明胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、纤维素、水、糖浆、甲基纤维素、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石粉、硬脂酸镁、矿物油等，但不限于此。此外，所述药物组合物可进一步包含润滑剂、润湿剂、甜味剂、调味剂、乳化剂、悬浮剂、防腐剂等作为添加剂。
根据症状的程度来确定药物组合物的给予方法，并且通常优选局部给予方法。此外，药物组合物中活性成分的剂量可根据给予途径、疾病的严重程度、患者的年龄、性别和体重而变化，并且可每天给予一至几次。
可通过各种途径向哺乳动物(例如大鼠、小鼠、家畜和人类)给予药物组合物。可以预期任何给予方式，例如口服、直肠或者静脉、肌内、皮下、子宫内、硬脑膜或侧脑室注射。
药物组合物可通过使用药学上可接受的载体和/或赋形剂的制剂以单位剂型来制备，或可通过将其并入多剂量容器中来制备。在这种情况下，制剂可处于溶液剂、混悬剂或乳剂的形式，或者可处于酏剂(elixir)、提取物、散剂、颗粒剂、片剂、硬膏剂(plaster)、洗剂、软膏剂(ointment)等的形式。
此外，当本发明的组合物为保健功能性食品组合物时，所述保健功能性食品组合物可以以散剂、颗粒剂、片剂、胶囊剂、糖浆剂、饮料或丸剂的形式提供，并且所述保健功能性食品组合物与本发明所述的阿立哌唑(其为活性成分)以外的其它食品或食品添加剂一起使用，可根据常规方法适当使用。活性成分的混合量可根据使用目的(例如预防、保健或治疗处理)适当地确定。
保健功能性食品组合物中所含的阿立哌唑的有效剂量可根据药物组合物的有效剂量来使用，但在出于健康与卫生或健康控制目的而长期摄入的情况下，它可能小于上述范围，而且明显的是，由于在安全性方面没有问题，活性成分的使用量可以超过上述范围。
保健功能性食品的类型不受特别地限制，例如肉、香肠、面包、巧克力、糖果、零食、糕点、披萨、拉面、其它面条、口香糖、包括冰淇淋在内的乳制品、各种汤、饮料、茶、饮品、酒精饮料和维生素复合物等。
实施例
以下，将通过实施例对本发明进行更详细地说明。这些实施例仅旨在更详细地说明本发明，并且对于本领域技术人员显而易见的是，本发明的范围不受根据本发明主旨的这些实施例的限制。
<实施例1>乳腺癌细胞中的辐射敏感的试剂的检测
在抗辐射的乳腺癌细胞内的单次处理中未观察到细胞毒性，但在Enzo的药物库中检索到了与辐射治疗联合来增强辐射敏感性的辐射敏化剂候选药物。
将MCF-7细胞(人乳腺癌细胞系)调整到5000个细胞/孔的浓度，然后接种到96孔板中，预培养24小时。随后，去除培养基，以每种5mM的浓度单独或与辐射联合处理Enzo的药物库中的药物。96小时后，用Dogen’s EZ-Cytox细胞生存力测定试剂盒测定细胞存活率。
如图1所示，阿立哌唑被确定为辐射敏化剂，尽管单独的药物处理对细胞的存活率没有影响，当与辐射联合处理时，阿立哌唑降低了抗辐射的细胞的存活率。
<实施例2>阿立哌唑对癌细胞的辐射敏感性的影响
为了证实阿立哌唑对癌细胞中辐射敏感性的影响，如下采用MTT比色法对具有辐射抗性的乳腺癌细胞进行了细胞生存力测定实验。
将MCF-7细胞调整到5000个细胞/孔的浓度后，将其接种到96孔板中，预培养24小时。然后，去除培养基，单独或与辐射联合处理阿立哌唑(5μM、10μM、20μM)。96小时后，用Dogen’s EZ-Cytox细胞生存力测定试剂盒测定细胞存活率。
如图2所示，发现当与辐射联合处理时，生存率降低效果比单独用阿立哌唑处理更优异。发现阿立哌唑以浓度依赖的方式具有优异的辐射增敏效果。
<实施例3>阿立哌唑对癌细胞中辐射诱导的细胞凋亡的影响
最近有报道称阿立哌唑能够在癌细胞中诱导细胞凋亡，为了证实阿立哌唑对癌细胞中辐射诱导的细胞凋亡的影响，如下对癌细胞进行了PARP分裂和DNA断裂的测定。
用阿立哌唑(1μM、5μM、10μM、20μM)单独或与辐射联合处理MCF-7细胞。24小时后，用PBS洗涤后，从细胞中提取蛋白质，通过蛋白质印迹法确认PARP分裂的程度。
如图3所示，发现当与辐射联合处理时，PARP分裂诱导效果比阿立哌唑单独处理时更为优异。发现阿立哌唑以浓度依赖的方式在经辐射处理的癌细胞中诱导细胞凋亡。
将MCF-7细胞或U251细胞调整到5000个细胞/孔的浓度后，将它们接种到96孔板中，预培养24小时。此后，去除培养基，单独或与辐射联合处理阿立哌唑。24小时后，用罗氏(Roche)细胞死亡检测ELISA plus试剂盒检测DNA断裂的程度。
如图4所示，发现当阿立哌唑与辐射联合处理时，DNA断裂诱导效果优于各处理相加的效果。发现两种处理同时使用时，诱导细胞凋亡的效果比单一处理诱导DNA断裂的效果更优异。
<实施例4>多巴胺受体抑制剂硫利吡嗪和阿立哌唑对癌细胞中辐射诱导的细胞凋亡的影响
为了证实多巴胺受体抑制剂和阿立哌唑对癌细胞中辐射诱导的细胞凋亡的影响，在MCF-7细胞中与辐射联合分别处理硫利达嗪或阿立哌唑，或者与辐射联合处理硫利达嗪和阿立哌唑。24小时后，用PBS洗涤后，从细胞中提取蛋白质，通过蛋白质印迹法确认PARP分裂的程度。
如图5所示，与通过“硫利达嗪与辐射联合处理”或“阿立哌唑与辐射联合处理”的处理诱导PARP分裂的效果相比，发现硫利达嗪和阿立哌唑与辐射联合处理表现出更为优异的PARP分裂诱导效果。
将MCF-7细胞或BT-474细胞调整到5000个细胞/孔的浓度后，将它们接种到96孔板中，预培养24小时。然后，去除培养基，与辐射联合分别处理硫利达嗪或阿立哌唑，或者与辐射一起同时处理硫利达嗪和阿立哌唑。24小时后，用罗氏细胞死亡检测ELISA plus试剂盒确认DNA断裂的程度。
如图6所示，相较于各个硫利达嗪联合辐射处理或阿立哌唑联合辐射处理的相加效果，发现硫利达嗪和阿立哌唑与辐射的联合处理示出了更优异的DNA断裂诱导效果。
<实施例5>多巴胺受体抑制剂氟哌啶醇和阿立哌唑对癌细胞中辐射诱导的细胞凋亡的影响
为了证实多巴胺受体抑制剂和阿立哌唑对癌细胞中辐射诱导的细胞凋亡的影响，在MCF-7细胞中与辐射联合分别处理氟哌啶醇或阿立哌唑、或者与辐射联合处理氟哌啶醇和阿立哌唑。24小时后，用PBS洗涤后，从细胞中提取蛋白质，通过蛋白质印迹法确认PARP分裂的程度。
如图7所示，相较于通过“氟哌啶醇与辐射联合处理”或“阿立哌唑与辐射联合处理”的处理诱导PARP分裂的效果，发现氟哌啶醇和阿立哌唑与辐射的联合处理表现出更优异的PARP分裂诱导效果。
将MCF-7细胞或BT-474细胞调整到5000个细胞/孔的浓度后，将它们接种到96孔板中，预培养24小时。然后，去除培养基，与辐射联合分别处理氟哌啶醇或阿立哌唑，或者与辐射一起同时处理氟哌啶醇和阿立哌唑。24小时后，用罗氏细胞死亡检测ELISA plus试剂盒检测DNA断裂的程度。
如图8所示，相较于各个氟哌啶醇联合辐射处理或阿立哌唑联合辐射处理的相加效果，发现氟哌啶醇和阿立哌唑与辐射的联合处理示出了更优异的DNA断裂诱导效果。
虽然已经参照本发明的具体实施方式对本发明进行了具体描述，但是显而易见的是，该具体描述只是优选的实施方式，并且对于本领域技术人员而言，本发明的范围不限于此。即本发明的实际范围由所附权利要求及其等同物所限定。
Claims (11)
1.一种用于增强辐射敏感性的组合物，所述组合物包含阿立哌唑或其药学上可接受的盐作为活性成分。
2.一种用于增强辐射敏感性的组合物，所述组合物包含阿立哌唑或其药学上可接受的盐和多巴胺受体抑制剂作为活性成分。
3.如权利要求2所述的用于增强辐射敏感性的组合物，其中，所述多巴胺受体抑制剂是硫利达嗪或氟哌啶醇。
4.如权利要求1-3中任一项所述的用于增强辐射敏感性的组合物，其中，所述组合物通过用辐射辐照来诱导癌细胞的细胞凋亡。
5.如权利要求4所述的用于增强辐射敏感性的组合物，其中，所述组合物诱导癌细胞的PARP分裂或DNA断裂。
6.如权利要求1-3中任一项所述的用于增强辐射敏感性的组合物，其中，在癌症治疗期间，与辐射辐照联合给予所述组合物。
7.如权利要求6所述的用于增强辐射敏感性的组合物，其中，所述癌症是乳腺癌、肺癌、骨癌、胰腺癌、皮肤癌、口腔癌、口咽癌、子宫癌、卵巢癌、直肠癌、胃癌、子宫内膜癌、宫颈癌、阴道癌、小肠癌、甲状腺癌、甲状旁腺癌、前列腺癌、慢性或急性白血病、淋巴细胞淋巴癌、膀胱癌、肾癌、肝癌、结肠癌或脑瘤。
8.一种用于癌症的辅助辐射疗法的药物组合物，所述药物组合物包含阿立哌唑或其药学上可接受的盐作为活性成分。
9.一种用于癌症的辅助辐射疗法的药物组合物，所述药物组合物包含阿立哌唑或其药学上可接受的盐和多巴胺受体抑制剂作为活性成分。
10.一种用于癌症的辅助辐射疗法的保健功能性食品组合物，所述保健功能性食品组合物包含阿立哌唑或其药学上可接受的盐作为活性成分。
11.一种用于癌症的辅助辐射疗法的保健功能性食品组合物，所述保健功能性食品组合物包含阿立哌唑或其药学上可接受的盐和多巴胺受体抑制剂作为活性成分。
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