CN113825528A - 用于预防或治疗抗治疗性癌症的药物组合物 - Google Patents
用于预防或治疗抗治疗性癌症的药物组合物 Download PDFInfo
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Abstract
本发明提供了一种通过光动力疗法PDT治疗或预防耐药癌症的药物组合物,其包含5‑氨基乙酰丙酸(ALA)或其衍生物或其盐,以及使用该药物组合物治疗或预防耐药癌症的方法。
Description
相关申请的交叉引用
本申请要求于2019年4月26日向日本专利局(作为受理局)提交的第PCT/JP2019/017995号国际申请的优先权,所述申请通过引用全部并入本文。
技术领域
本发明涉及一种包括5-氨基乙酰丙酸的药物组合物,所述药物组合物用于治疗或预防耐药癌症。
背景技术
5-氨基乙酰丙酸(5-ALA)是一种口服吸收物质,在细胞内线粒体血红素生物合成过程中代谢为原卟啉IX(PpIX)。PpIX是一种光敏物质,当在特定吸收带(称为Soret带(410nm)或Q带(500-650nm))中用光线辐照时,其产生活性氧物种。因此,可以通过用具有吸收带波长的光辐照聚积了PpIX的细胞来诱导细胞死亡(非专利文献1)。基于这种细胞杀伤作用原理的治疗方法称为光动力疗法(PDT),并且利用5-ALA的PDT有望在未来临床应用(专利文献1和2)。
根据日本厚生劳动省发布的“2016年人口动态统计摘要”,日本恶性肿瘤死亡率占所有死亡人数的28.5%,是死亡原因列表中的第一位。对于早期癌症,手术全切除肿瘤是主要的治疗方法,并且响应比例高。另一方面,对于晚期癌症,通常使用抗癌药物进行治疗。
然而,已知抗癌药物从治疗开始就可能无效,并且即使在药物有响应的情况下,抗癌药物的效果也往往是短暂的,并且在治疗过程中抗癌药物的效果会进一步降低,同时,癌症可能获得对具有不同作用机制和结构的抗癌药物的耐药性(非专利文献2和3)。这些耐药癌细胞(包括癌干细胞)可能对化疗响应不佳,当细胞重新生长时,可能导致转移和复发。
耐药癌细胞的存在仍然是当今癌症整体治疗中阻碍临床疗效改善的主要因素之一。尽管癌细胞获得耐药性的机制复杂多样,但在每个临床治疗算法中都将对抗癌药物没有表现出足够敏感性的癌症患者进行明确的分类,并将疾病状态与抗癌药物敏感性癌症区分开来,并且所采取的治疗政策将不同于针对抗癌药物敏感癌症的治疗政策(非专利文献4)。
上述肿瘤细胞获得对具有不同作用机制和结构的抗癌药物的交叉耐药性同样适用于PDT。一般而言,在PDT(包括5-ALA的使用)中,有许多报告表明PDT对抗肿瘤药物耐药的癌症通常无效,并且无论是抗肿瘤耐药性还是PDT耐药性都是交叉获得的(非专利文献5)。这意味着PDT对抗癌药物耐药的癌细胞不一定具有细胞杀伤作用,并且PDT对各种抗癌药物耐药癌症的疗效不容易预测。
此外,如非专利文献5所示,一些光敏剂在杀死对同一种抗癌药物耐药的癌细胞有效,而另一些则无效。因此,即使使用特定光敏剂的PDT对耐药癌症有效,本领域技术人员也不容易预测使用另一种光敏剂的PDT是否也有效。这不仅对耐药癌症是自然现象,例如,一份报告显示,使用金丝桃素或光敏素的PDT显示出抗肿瘤效果,而使用TPPS4或5-ALA的PDT没有显示出这种效果(非专利文献6)。
专利文献3公开了一种用于具有抗治疗癌细胞的抗治疗癌症的预防或治疗组合物,所述组合物用于光动力学治疗,其中所述组合物包含5-ALA或其盐。然而,该文献仅公开了,通过发现酪氨酸激酶抑制剂抑制参与PpIX外排的ABCG2,抑制ABCG2可增强细胞内PpIX的积累,并增强5-ALA/PDT对治疗耐药癌细胞的作用。该文献既没有公开5-ALA/PDT对酪氨酸激酶抑制剂耐药的癌症有效,也没有表明5-ALA/PDT对其它药物耐药的癌症有效。
上述专利文献3公开了一种用于具有抗治疗癌细胞的抗治疗癌症的预防或治疗组合物,所述组合物用于光动力治疗,其中所述组合物包含5-ALA或其盐。专利文献3中的抗治疗癌症优选为恶性肿瘤,但对治疗有抵抗力的癌症的类型不受限制。抗治疗癌症的例子包括原发性或转移性、侵袭性或非侵袭性癌症或肉瘤,如脑瘤、脊髓瘤、上颌窦癌、胰腺导管腺癌、牙龈癌、舌癌、唇癌、鼻咽癌、口咽癌、下咽癌、喉癌、甲状腺癌、甲状旁腺癌、肺癌、胸膜癌、癌性腹膜炎、癌性胸膜炎、食管癌、胃癌、结肠癌、胆管癌、胆囊癌、胰腺癌、肝癌、肾癌、膀胱癌、前列腺癌、阴茎癌、睾丸肿瘤、肾上腺癌、宫颈癌、子宫癌、阴道癌、外阴癌、卵巢癌、骨肿瘤、乳腺癌、皮肤癌、黑色素瘤、基底细胞癌、淋巴瘤、霍奇金病、浆细胞瘤、骨肉瘤、软骨肉瘤、脂肪肉瘤、横纹肌肉瘤和纤维肉瘤。抗治疗癌症特别优选脑瘤。此外,抗治疗癌症优选为实体癌。因此,专利文献3未表明5-ALA对实体癌以外的治疗耐药癌症(如白血病和血癌疾病)的疗效。此外,专利文献3实际上仅公开了PDT对脑瘤细胞和宫颈癌细胞的应用。
来那度胺是一种抗造血系统恶性肿瘤药物,用于治疗多发性骨髓瘤和其它恶性肿瘤。莫利珠单抗是一种抗肿瘤药物,用于治疗T细胞淋巴瘤和其它恶性肿瘤。维甲酸(全反式维甲酸,ATRA)是一种白血病治疗剂,用于治疗急性早幼粒细胞白血病和其它疾病。伊马替尼是一种抗肿瘤药物,用于治疗慢性粒细胞白血病和其它恶性肿瘤。
本文引用的所有参考文献全部通过引用合并。如果通过引用并入的材料与本说明书不一致,本说明书将取代任何此类材料。
现有技术
专利文献
专利文献1:JP 2005-132766 A
专利文献2:JP 2017-513952 A
专利文献3:WO 2015/125732 A
非专利文献
非专利文献1:T Namikawa等人,World J Gastroenterol.21(29):8769-8775,2015。
非专利文献2:Ueda K等人,Proc Natl Acad Sci USA,84:3004-3008,1987。
非专利文献3:Tada Y等人,Int J Cancer,98:630-635,2002。
非专利文献4:Guidelines for the treatment of hematopoietic tumorsedited by the Japanese Society of Hematology
非专利文献5:Casas A等人,Curr Med Chem.18(16):2486-515,2011。
非专利文献6:Luksiene Z等人,Medicina(Kaunas).2003;39(7):677-82。
发明内容
本发明解决的技术问题
本发明的目的是提供一种用于治疗或预防耐药癌症的药物组合物。
技术方案
本发明人已深入研究以解决上述问题。因此,他们发现使用5-ALA的PDT可以有效治疗或预防耐药癌症。本发明基于这些发现而完成。
即,本发明涉及:
(1)一种用于使用光动力疗法PDT治疗或预防耐药癌症的药物组合物,包括下式(1)所示的5-氨基乙酰丙酸(5-ALA)、或其衍生物或其盐:
(化学式1)
其中,每个R1和R2相同或不同地为氢原子、烷基基团、酰基基团、烷氧基羰基基团、芳基基团或芳烷基基团,R3为羟基基团、烷氧基基团、酰氧基基团、烷氧基羰基氧基基团、芳氧基基团、芳烷基氧基基团或氨基基团),其中,该药物是减少干扰素调节因子表达的免疫调节剂,或是靶向CD分子、cereblon、mTOR蛋白、PML-RARα、BCR-Abl酪氨酸激酶或KIT酪氨酸激酶的分子靶向治疗剂;
(2)一种用于使用光动力疗法PDT治疗或预防耐药白血病的药物组合物,包括下式(1)所示的5-氨基乙酰丙酸(5-ALA)、或其衍生物或其盐:
(化学式2)
其中,每个R1和R2相同或不同地为氢原子、烷基基团、酰基基团、烷氧基羰基基团、芳基基团或芳烷基基团,R3为羟基基团、烷氧基基团、酰氧基基团、烷氧基羰基氧基基团、芳氧基基团、芳烷基氧基基团或氨基;
(3)如(2)的药物组合物,其中白血病为成人T细胞白血病;
(4)如(1)至(3)中的任一项所述的药物组合物,其中所述药物为来那度胺或莫利珠单抗;
(5)如(1)至(3)中的任一项所述的药物组合物,其中所述药物为维甲酸;
(6)如(1)至(3)中的任一项所述的药物组合物,其中药物为伊马替尼;
(7)一种用于使用光动力疗法PDT治疗或预防癌症的药物组合物,包括以下式(1)所示的5-氨基乙酰丙酸(5-ALA)、或其衍生物或其盐:
(化学式3)
其中,每个R1和R2相同或不同地为氢原子、烷基基团、酰基基团、烷氧基羰基基团、芳基基团或芳烷基基团,R3为羟基基团、烷氧基基团、酰氧基基团、烷氧基羰基氧基基团、芳氧基基团、芳烷基氧基基团或氨基基团,其中,所述药物组合物与来那度胺、莫利珠单抗、维甲酸和伊马替尼中的至少一种组合使用;
(8)如(1)至(7)中的任一项所述的药物组合物,其中所述癌症为血液学癌症;
(9)如(1)至(8)中的任一项所述的药物组合物,其中在体外进行PDT光辐照。
发明效果
通过使用本发明的组合物,可治疗或预防耐药癌症。
附图说明
图1显示了来那度胺耐药细胞系和莫利珠单抗-和维甲酸-耐药细胞系的细胞活力图。
图2显示了伊马替尼耐药细胞系和阿霉素耐药细胞系的细胞活力图。
发明详述
下面将详细描述本发明。一方面,本发明提供一种用于通过光动力疗法(PDT)治疗或预防耐药癌症的药物组合物,包括5-氨基乙酰丙酸(5-ALA)或其衍生物或其盐(在本文中也称为“5-ALA”)。
如本文所用,5-ALA或其衍生物是具有以下式(1)的化合物:
(化学式4)
式中,每个R1和R2相同或不同地为氢原子、烷基基团、酰基基团、烷氧基羰基基团、芳基基团或芳烷基基团,R3为羟基基团、烷氧基基团、酰氧基基团、烷氧基羰基氧基基团、芳氧基基团、芳烷基氧基基团或氨基基团。
在式(1)中,由R1和R2表示的烷基的实例包括以下:具有1至24个碳的直链或支链烷基基团,更具体地说,具有1至18个碳的烷基基团和具有1至6个碳的烷基基团。烷基基团的更具体实例包括甲基、乙基、正丙基、异丙基、正丁基和仲丁基。酰基基团的实例包括直链或支链烷酰基或烯基羰基基团,以及具有1至12个碳的芳酰基基团,更具体地,具有1至6个碳的烷酰基基团。酰基基团的更具体实例包括甲酰基、乙酰基、丙酰基和丁酰基。烷氧基羰基基团的实例包括总碳数为2至13的烷氧基羰基基团,更具体地说,烷氧基羰基基团的总碳数为2至7。烷氧基羰基基团的更具体实例包括甲氧基羰基、乙氧基羰基、正丙氧基羰基和异丙氧基羰基。芳基基团的实例包括具有6至16个碳的芳基基团,例如苯基和萘基。芳烷基的实例包括其中具有6至16个碳的芳基基团与具有1至6个碳的烷基基团结合的基团,例如苯基-C1-6烷基和萘基-C1-6烷基。
在一个实施方式中,式(1)中的R1和R2为氢原子。在另一个实施方式中,R3是羟基基团、烷氧基基团或芳烷基氧基基团,更具体地说是羟基基团或C1-12烷氧基基团。
5-ALA或其衍生物的盐不受特别限制,只要该盐在药学上是可接受的。具体实例包括有机或无机酸的酸加成盐,更具体地说,包括盐酸盐、氢溴酸盐、硫酸盐、磷酸盐、醋酸盐、乳酸盐、柠檬酸盐、酒石酸盐、琥珀酸盐、马来酸盐、富马酸盐和抗坏血酸盐。
5-ALA或其衍生物或其盐可通过例如JPH04-9360 A和JPH11-501914A中所述的方法制备。
该方面的药物组合物用于治疗或预防耐药癌症。如本文所用,耐药性是指未获得或难以获得药物的治疗或预防效果。耐药细胞可包括获得性耐药细胞和先天性耐药细胞。在一些实施方式中,药物是免疫调节剂、分子靶向治疗剂或抗癌抗生素。免疫调节剂的实例包括降低干扰素调节因子(更具体地,干扰素调节因子4)的表达的试剂。分子靶向治疗剂的实例包括CD分子,例如CD20、CD22、CD33、CD52和CD194(CCR4)、cereblon、mTOR蛋白、PML-RARα、BCR-Abl酪氨酸激酶和KIT酪氨酸激酶。更具体的实例包括来那度胺、莫利珠单抗、利妥昔单抗、奥法图单抗、阿勒姆珠单抗、吉妥珠单抗、本妥昔单抗、替伊莫单抗、维甲酸、达沙替尼、博舒替尼、尼罗替尼和伊马替尼。抗癌抗生素的实例包括蒽环类抗生素,更具体地说,阿霉素。该药物更具体的实例包括来那度胺、莫利珠单抗、维甲酸和伊马替尼。进一步的具体实例包括来那度胺、莫利珠单抗和维甲酸。
耐药癌症的类型不受特别限制,其实例包括包含或不包含人类的哺乳动物的或人类的癌症、肉瘤、腺癌、淋巴瘤、白血病、实体癌和淋巴瘤,或人类。更具体的癌症实例包括肺癌,如非小细胞肺癌和NSCLC、卵巢癌、前列腺癌、结直肠癌、肝癌、肾癌、膀胱癌、乳腺癌、甲状腺癌、胸膜癌、胰腺癌、子宫癌、宫颈癌、睾丸癌、肛门癌、胰腺癌、胆管癌、胃肠道类癌、食管癌、胆囊癌、阑尾癌、小肠癌、胃癌、中枢神经系统癌、皮肤癌、绒毛膜癌、头颈癌、血液学癌症、骨肉瘤、纤维肉瘤、神经母细胞瘤、胶质瘤、黑色素瘤、B细胞淋巴瘤、非霍奇金淋巴瘤、伯基特淋巴瘤、小细胞淋巴瘤、大细胞淋巴瘤、单核细胞白血病、髓系白血病、急性淋巴细胞白血病、急性髓系白血病和多发性骨髓瘤。更具体的癌症包括血液学癌症,如白血病、淋巴瘤、多发性骨髓瘤、蕈样肉芽肿和塞扎里综合征。优选的实例包括慢性髓系白血病和成人T细胞白血病,尤其是成人T细胞白血病。
该方面的药物组合物的给药方式不受特别限制,并且包括例如口服给药、静脉给药、肌肉内给药、对受影响区域的局部给药、经皮给药和经直肠给药。
本方面的药物组合物的剂型不受特别限制,例如包括口服剂型,如颗粒剂、细颗粒剂和片剂;可注射剂型,如液体和时溶性粉末;经皮剂型,如软膏、液体、乳膏和凝胶;还有栓剂。
除5-ALA或其衍生物或其盐外,该方面的药物组合物可包含另一医药上可接受的原料,例如医药上可接受的载体、赋形剂、稀释剂、等渗剂、添加剂、崩解剂、粘合剂、稳定剂、包衣剂、分散剂、增量剂、pH缓冲剂,润滑剂、调味剂、甜味剂、增溶剂、溶剂、凝胶剂和营养剂。其它原料可能会影响这方面药物成分的吸收和血药浓度,导致药代动力学的变化。其它原料的具体实例包括水、盐水、动物脂肪、植物脂肪、乳糖、淀粉、明胶、结晶纤维素、树胶、滑石粉、硬脂酸镁、羟丙基纤维素、聚亚烷基二醇、聚乙烯醇和甘油。
该方面的药物组合物的剂量可由本领域技术人员确定,只要在靶向耐药癌细胞中累积的PpIX量为PDT中的有效量即可。本领域技术人员可根据受试者的年龄、体重、症状和状况,以及待预防或治疗的受试者中的细胞、组织或器官的状况和给药难易程度,确定给受试者的剂量、时间、频率和给药持续时间。更具体剂量的示例包括每千克体重约1mg至约1000mg、约5mg至约100mg、约10mg至约30mg、约15mg至约25mg(以ALA计)。
该方面的药物组合物的给药频率不受特别限制,并且示例包括每天一次或多次,例如每天两次、三次、四次或五次,以及通过静脉输注连续给药。本领域技术人员可基于多种临床参数(例如受试者的症状或状况)来确定该方面的药物组合物的给药周期。
该方面的药物组合物用于光动力疗法(PDT)。PDT是一种治疗方法,所述治疗方法通过给药一种光反应性化合物并用光线辐照它来治疗靶区。一个典型的例子是使用5-ALA类的PDT。
在施用该方面的药物组合物后,通过辐照特定波长的光来进行PDT。所使用的波长可由本领域技术人员确定。所用波长的实例包括约350nm至约700nm、约400nm至约640nm、约480nm至约640nm、505nm±10nm、540nm±10nm、580nm±10nm和630nm±10nm。
从施用该方面的药物组合物到开始辐照的时间不受特别限制,并且可由本领域技术人员根据癌症类型、施用手段等设定。例如,光辐照可在给药后约15分钟至约48小时,以及在给药后约1小时至约24小时开始。
PDT中的辐照次数和每次辐照的辐照时间不受特别限制,可由本领域技术人员确定。例如,可以进行一个或多个辐照,例如,2、3、4或5到大约100次辐照。光可以用相同的波长或不同的波长辐照。当多次施用该方面的药物组合物时,可在每次施用之间通过一次或多次辐照来进行PDT。
本领域技术人员可根据癌症类型、给药方式、光源等设置PDT中待辐照光的光强度。光强度的示例包括约0.01J/cm2至约200J/cm2、约5J/cm2至约150J/cm2、约10J/cm2至约100J/cm2,约30J/cm2至约100J/cm2、约10J/cm2至约30J/cm2、10J/cm2±10J/cm2、30J/cm2±10J/cm2和100J/cm2±10J/cm2。
当靶癌为血液学癌症时,PDT中的光辐照可在体外进行。例如,在施用该方面的药物组合物之后,血液可通过血液灌注装置在体外循环,并且灌注装置中的血液可被光辐照。
在一些实施方式中,该方面的药物组合物可与另一药物(例如抗癌药物)组合使用。其它药物可包括在该方面的药物组合物中,或作为该方面的药物组合物与药物的组合。可在施用药物后施用该方面的药物组合物并进行PDT,或可在施用药物组合物并进行PDT后施用药物。该药物也可在施用该方面的药物组合物与PDT之间施用,或在施用该方面的药物组合物之后在多个PDT之间施用。其它药物的实例包括抗癌剂,例如酪氨酸激酶抑制剂、免疫调节剂和分子靶向治疗剂。此外,使用该方面的药物组合物的PDT可与来那度胺、莫利珠单抗、维甲酸、伊马替尼或阿霉素联合进行,例如,在将要、曾经或继续使用来那度胺、莫利珠单抗、维甲酸、伊马替尼或阿霉素治疗的受试者中。在更具体的实施方式中,组合使用的药物为来那度胺、莫利珠单抗、维甲酸或伊马替尼。在进一步的具体实施方式中,组合使用的药物为来那度胺、莫利珠单抗或维甲酸。在一些实施方式中,其它药物不包括酪氨酸激酶抑制剂。在其它实施方式中,其它药物不包括ABCG2抑制剂。
在另一方面,本发明涉及一种使用含有5-ALA的PDT用于治疗或预防耐药癌症的试剂盒。在另一方面中,本发明涉及一种使用5-ALA的PDT治疗或预防耐药癌症的方法。在另一方面中,本发明涉及用于使用PDT治疗或预防耐药癌症的5-ALA。在另一个方面中,本发明涉及5-ALA用于制备药物组合物的用途,所述药物组合物用于使用PDT治疗或预防耐药癌症。这些方面的更具体实施方式如药物组合物方面中所述。
如本文所使用的,数字范围的描述,例如“1次到5次”被理解为表示该范围内的任何数字,例如1、2、3、4和5。如本文所用,术语“大约”指±10%的范围,优选±5%。作为范围边界的值被认为在本文中描述。
将通过示例详细描述本发明。然而,本发明不必受到示例的限制。
具体实施方式
实施例1:确认成人T细胞白血病(ATL)细胞系中的细胞杀伤作用
ATN-1、C8166、TL-Om1、Hut102和MT-1用作ATL细胞系。其中来那度胺敏感细胞系为Hut102,来那度胺耐药细胞系为C8166。ATN-1、TL-Om1和MT-1对来那度胺的敏感性未知。同时,维甲酸敏感细胞系为C8166,维甲酸耐药细胞系为Hut102。ATN-1、TL-Om1和MT-1对维甲酸的敏感性未知。此外,莫利珠单抗敏感细胞系为ATN-1、TL-Om1和MT-1,莫利珠单抗耐药细胞系为Hut102。C8166对莫利珠单抗的敏感性未知。这些细胞传代培养。对于实验,在实验开始时将细胞制备成1×106细胞/ml的密度。
向细胞悬浮液中添加浓度为0、0.0625mM、0.125mM、0.25mM和0.5mM的5-ALA,并负载4小时。将5-ALA负载后的细胞洗涤并用中心波长630nm的光(0、10J/cm2、30J/cm2和100J/cm2)辐照,并通过细胞计数试剂盒8计算细胞存活率(%)。
结果如图1所示。如图1所示,使用5-ALA的PDT杀死了C8166细胞系,该细胞系为来那度胺耐药细胞系,以及HuT102细胞系,该细胞系为莫利珠单抗耐药细胞系和维甲酸耐药细胞系。因此,结果表明使用5-ALA的PDT对这些耐药癌细胞有效。
关于对来那度胺的耐药性,在C8166(耐药细胞系)和Hut102(来那度胺敏感细胞系)中,在每个辐照能量密度下5-ALA对细胞存活率(%)的每个EC50值及其95%置信区间如表1所示。
表1
每个EC50值的结果表明,在来那度胺耐药细胞系C8166中使用5-ALA的PDT的细胞杀伤作用与来那度胺敏感细胞系Hut102相当。由此表明,使用5-ALA的PDT即使在来那度胺非敏感患者细胞中也具有极好的细胞毒性作用,同时,来那度胺和使用5-ALA的PDT联合使用也可有效。
关于对维甲酸的耐药性,在Hut102(耐药细胞系)和C8166(维甲酸敏感细胞系)中,对于每个辐照能量密度的细胞存活率(%),5-ALA的每个EC50值及其95%置信区间如表2所示。
表2
每个EC50值的结果表明,使用5-ALA的PDT在维甲酸耐药细胞系C8166中的细胞杀伤作用与维甲酸敏感细胞系Hut102相当。由此表明,使用5-ALA的PDT即使在维甲酸非敏感患者细胞中也具有极好的细胞毒性作用,同时,维甲酸和使用5-ALA的PDT联合使用也可有效。
关于莫利珠单抗的耐药性,在耐药细胞系Hut102和莫利珠单抗敏感细胞系ATN-1、TL-Om1和MT-1中,对于每个辐照能量密度的细胞存活率(%),5-ALA的每个EC 50值及其95%置信区间如表3所示。
表3
每个EC50值的结果表明,在莫利珠单抗耐药细胞系Hut102中使用5-ALA的PDT的细胞杀伤作用至少与其它敏感细胞系相当。由此表明,使用5-ALA的PDT即使在莫利珠单抗非敏感患者细胞中也具有极好的细胞毒性作用,同时,联合使用莫利珠单抗和使用5-ALA的PDT也可有效。
实施例2:确认慢性粒细胞白血病(CML)细胞系中的细胞杀伤作用
LAMA84-r用作伊马替尼耐药CML细胞系,原始细胞系LAMA84-s(伊马替尼敏感)用作对照。此外,K562/ADR被用作阿霉素耐药CML细胞系,原始细胞系K562(阿霉素敏感)被用作对照。将这些细胞传代培养。对于实验,在实验开始时将细胞制备成1×106个细胞/ml的密度。
向细胞悬浮液中添加浓度为0mM、0.0625mM、0.125mM、0.25mM和0.5mM的5-ALA,并负载4小时。将5-ALA负载后的细胞洗涤并用中心波长630nm的光(0、10J/cm2、30J/cm2和100J/cm2)辐照,并通过细胞计数试剂盒8计算细胞存活率(%)。
结果如图2所示。如图2所示,使用5-ALA的PDT杀死了LAMA84-r细胞系(伊马替尼耐药细胞系)和K562/ADR细胞系(阿霉素耐药细胞系)。这些细胞杀伤作用与相应的敏感细胞系相当。由此表明,使用5-ALA的PDT对伊马替尼-和阿霉素-非敏感患者细胞有效。
工业适用性
本发明能够通过使用5-ALA的PDT预防或治疗耐药癌症。本发明可用于医学领域和其它领域。
Claims (9)
3.根据权利要求2所述的药物组合物,其中所述白血病为成人T细胞白血病。
4.根据权利要求1至3中任一项所述的药物组合物,其中所述药物为来那度胺或莫利珠单抗。
5.根据权利要求1至3中任一项所述的药物组合物,其中所述药物为维甲酸。
6.根据权利要求1至3中任一项所述的药物组合物,其中所述药物为伊马替尼。
8.根据权利要求1至7中任一项所述的药物组合物,其中所述癌症为血液学癌症。
9.根据权利要求1至8中任一项所述的药物组合物,其中所述PDT光辐照在体外进行。
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PCT/JP2020/017805 WO2020218562A1 (ja) | 2019-04-26 | 2020-04-24 | 治療抵抗性がんの予防又は治療用の医薬組成物 |
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US20140010761A1 (en) * | 2012-06-28 | 2014-01-09 | Photocure Asa | Form of hexyl-5-aminolevulinate hydrochloride and methods of using the same |
CN106232115A (zh) * | 2014-02-21 | 2016-12-14 | Sbi制药株式会社 | 用于治疗抗性的癌症的预防或治疗性组合物 |
CN113453750A (zh) * | 2019-02-19 | 2021-09-28 | 大塚电子株式会社 | 光动力疗法条件参数的确定方法和光动力疗法装置 |
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JP2005132766A (ja) | 2003-10-30 | 2005-05-26 | Cosmo Oil Co Ltd | 光動力学的癌治療薬 |
GB2525432A (en) | 2014-04-24 | 2015-10-28 | Univ Oslo Hf | Modification of extracorporeal photopheresis technology with porphyrin precursors |
WO2017201528A1 (en) * | 2016-05-20 | 2017-11-23 | The University Of Chicago | Nanoparticles for chemotherapy, targeted therapy, photodynamic therapy, immunotherapy, and any combination thereof |
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2019
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US20140010761A1 (en) * | 2012-06-28 | 2014-01-09 | Photocure Asa | Form of hexyl-5-aminolevulinate hydrochloride and methods of using the same |
CN106232115A (zh) * | 2014-02-21 | 2016-12-14 | Sbi制药株式会社 | 用于治疗抗性的癌症的预防或治疗性组合物 |
CN113453750A (zh) * | 2019-02-19 | 2021-09-28 | 大塚电子株式会社 | 光动力疗法条件参数的确定方法和光动力疗法装置 |
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WO2020218562A1 (ja) | 2020-10-29 |
WO2020217472A1 (ja) | 2020-10-29 |
EP3960243A4 (en) | 2023-01-18 |
US20220175925A1 (en) | 2022-06-09 |
TWI834868B (zh) | 2024-03-11 |
TW202106292A (zh) | 2021-02-16 |
JPWO2020218562A1 (zh) | 2020-10-29 |
EP3960243A1 (en) | 2022-03-02 |
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