CN110141664B - 一种治疗急性髓系白血病的药物组合物 - Google Patents
一种治疗急性髓系白血病的药物组合物 Download PDFInfo
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
- A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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- A—HUMAN NECESSITIES
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- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
Abstract
本发明涉及一种治疗白血病的药物组合物,该药物组合物中活性成分为高三尖杉酯碱和Wee1激酶抑制剂,其中高三尖杉酯碱和Wee1激酶抑制剂的重量比为1:10‑10:1。本发明的药物组合物对于治疗白血病,特别是对于慢性髓系白血病或急性髓系白血病的疗效显著。本发明为开发治疗白血病的联合给药方案提供了一种全新的思路。
Description
技术领域
本发明涉及药物领域,具体涉及一种治疗白血病的药物组合物。
背景技术
白血病是一种始源于骨髓的癌症,是指大量未成熟的血细胞前体细胞不受控制的无限增殖累积并浸润其他组织和器官,同时抑制正常血细胞的生成。白血病患者在初期的症状因不明显而易被忽视,常见症状包括乏力、贫血、心悸、气短以及肝、脾、***肿大和骨骼疼痛等。同时白血病患者通常会出现造血功能紊乱引起的并发症,包括:出血、发烧、难治性感染、极高的白细胞数、呼吸困难、神志不清或器官功能衰竭等症状。白血病的确切病因目前不是很清楚,可能的诱因包括病毒因素、化学因素、放射因素以及遗传因素等,如吸烟、电离辐射、某些化学试剂(如苯)和唐氏综合症等,有家族白血病史的也属高危人群。
白血病根据病程发展的快慢分为急性白血病和慢性白血病。急性白血病的特征是未成熟的血细胞数量迅速增加,由于如此多的异常细胞堆积于骨髓,阻止骨髓制造正常的血细胞。伴随着疾病的快速发展,恶性细胞不断积累再蔓延到血液并逐渐浸润其他的组织和器官,因此,急性白血病必须尽快得到治疗。慢性白血病的特征是有着相对成熟但依然异常的白细胞过度积累,通常发展几个月或者几年导致异常白细胞生成率高于正常白细胞,因此异常细胞积累越来越多。白血病根据发病细胞的来源则可分为淋巴系白血病和髓系白血病。总的来说,结合病情急缓和来源的细胞类型,白血病可分为四个类型:急性淋巴系白血病(ALL)、急性髓系白血病(AML)、慢性淋巴系白血病(CLL)和慢性髓系白血病(CML)。
急性髓系白血病(AML)是一种异质性造血组织恶性增殖性疾病,是成人血液恶性肿瘤中的最常见类型,且近年来随着大气污染等原因,AML的发病有逐年增高的趋势。随着现代血液学基础和临床的不断发展,对于AML的诊断、分型、分级在不断完善,在AML的诊断和预后分层方面也更精确和细致,依据预后分层选择的治疗策略更个体化,但在其治疗领域仍未有新的突破。
近30年来,以阿糖胞苷和蒽环类化疗药为基础的AML诱导方案仍占主导地位,而化疗的完全缓解率(CR)仅维持在50~70%,5年生存率也仅在20-30%左右。尽管一部分患者能从日益成熟的造血干细胞移植技术中获益,但移植供者来源有限、移植相关毒性和并发症、移植后排异及复发等客观因素限制了移植技术在AML患者的广泛应用,难治和复发AML仍是困扰无数血液工作者的难题。因此,国内外的研究机构一直在坚持不懈的探索研究AML的最佳治疗策略。
近年来在AML特殊类型—急性早幼粒细胞白血病(APL)中靶向药物(全反式维甲酸(ATRA)和\或亚砷酸)的应用使其从死亡率最高的AML转变为临床大部分治愈的AML(90%以上的CR率和85%的长期无病生存);同样在慢性粒细胞白血病中针对BCR-ABL融合基因的靶向药物络氨酸激酶抑制剂一、二代应用于临床并取得了很好地疗效;从而使针对基因的靶向药物成为研究的热点,但在除APL外的其他类型AML中尚未发现具有此特点的融合基因,且其机制往往涉及多种核型或基因异常,使针对AML基因靶向药物的研发非常困难。
与此同时,国内外的研究机构在不断研究AML新的药物作用靶点,鉴于表观遗传学变化在AML发病的重要性和机制的日益清晰,针对表观遗传标志的小分子化合物也显现出有效的抗AML活性,如DNA甲基转移酶抑制剂、组蛋白低乙酰化抑制剂等的合成并进行临床I或II期实验,取得了一定的研究成果,表明其具有极大的应用前景,因此针对表观遗传标志的治疗靶点是近年来研究的焦点之一。
高三尖杉酯碱(HHT)是从中国植物中提取出来的抗肿瘤药物。高三尖杉酯碱存在于三尖杉属Cephalotaxus植物中,1963年由Paudler等首次从日本粗榧C.drupaceasieb.etc Zucc和三尖杉C.fortunei Hook.f.中分离出粗榧碱(Cephaloyaxine)。1969年,Powell等从柱冠粗榧中首次分离出高三尖杉酯碱,确定其结构为(2R)-2-羟基-2-(4-羟基-4-甲基戊基)丁二酸(甲基),并发现其对小鼠淋巴白血病P388有明显的活性。
高三尖杉酯碱在甲醇、乙醇或三氯甲烷中易溶,水或***中微溶,推测其口服吸收较差,提示在制药的过程中应采取修饰主药、加入增溶剂等辅料或制成混悬液等手段对改善HHT的口服吸收问题。
高三尖杉酯碱在国内应用于AML的治疗已有30多年的历史。高三尖杉酯碱在治疗AML中主要采用联合用药的方式,以HA(HHT、阿糖胞苷)方案、HAA(HHT、阿糖胞苷和阿克拉霉素)方案和HAD(HHT、阿糖胞苷和柔红霉素)方案为主。另外,还有一些独具特色的联合用药方法,例如,HIA(去甲氧柔红霉素+HHT+阿糖胞苷)方案可降低心血管毒性,提高治疗耐受性;HIA联合地西他滨治疗复发难治性AML;HAAG(HHT+阿柔比星+阿糖胞苷+粒细胞集落刺激因子)+地西他滨(DAC)用于进展期急性髓系白血病;HAAG联合中药治疗,可以减轻老年患者化疗不良反应,降低患者痛苦程度;HHT联合伊布替尼联合对FLT3-ITD突变型急性髓系白血病有显著疗效。
最近浙江大学血液研究所***内其他研究及临床机构应用以HHT为基础联合阿糖胞苷和/或蒽环类抗肿瘤药的诱导方案对AML的治疗取得了很好的疗效,同时因其更经济毒副反应更低而具有极大的应用前景。
高三尖杉酯碱抗AML的作用机制研究表明,HHT可以改变端粒酶的活性、下调MCL-1及survivin、抑制PI3K/AKT信号及JAK2-STAT5通路的磷酸化,有研究在对HHT作用AMLHL-60细胞株后基因表达分析表明,HHT也可以显著下调c-myc基因。
Wee1激酶是丝氨酸/苏氨酸蛋白激酶家族的重要成员之一,在整个细胞周期中起到多种重要作用,如确保DNA复制精准性和染色质完整性,阻滞DNA复制起始和G2期向M期转换等。共济失调毛细血管扩张突变基因ATM和ATM与Rad3相关蛋白ATR是DNA损伤应答的核心应答激酶。Wee1激酶在上述DNA损伤应答通路中起到了关键作用。DNA损伤被识别后,被磷酸化激活的Wee1激酶将cdc2上的Thr15磷酸化,从而抑制cdc2活性,使细胞周期停顿,暂不进入有丝***,以便完成DNA修复。
在细胞周期进程中,p53蛋白通过ATM-Chk2-p53途径在G1/S期和G2/M期对DNA损伤进行检查,监控基因组的完整性。当细胞发生损伤时,p53将会激活p2基因表达,p21蛋白会与相应的CDK-cyclins复合体作用,引起各个检查点的阻滞,修复受损细胞。如果p53基因发生突变或缺失,就不能控制细胞的增殖,导致细胞癌变。研究表明超过50%的肿瘤都存在p53基因缺失或突变,造成细胞周期G1/S检查点的缺陷,使得肿瘤细胞DNA的复制及损伤修复过程更依赖于G2/M检查点。作为G2/M检查点的关键激酶,Wee1激酶在肿瘤细胞DNA损伤应答过程中显得尤为重要,这使得Wee1激酶在许多肿瘤中呈高表达状态。抑制Wee1激酶的活性后,cdc2不发生磷酸化抑制,DNA损伤未经及时修复便进入M期,造成基因组不稳定性和染色体缺失,引发有丝***灾难,导致肿瘤细胞凋亡。另一方面,正常细胞的p53基因功能正常,能够在G1/S和G2/M期检查点分别对DNA损伤进行检查,当正常细胞的Wee1激酶的活性被抑制时,其功能上的缺失可以通过p53依赖的DNA损伤修复机制来补偿,使正常细胞得以存活。因此,理论上抑制Wee1激酶活性能够选择性地杀死p53基因缺陷肿瘤细胞,而不影响正常细胞,是一种理想的肿瘤治疗途径。
铂类、喜树碱类和核苷类似物等传统的化疗药物作用于DNA合成过程,造成DNA的合成损伤,放射治疗同样能够造成肿瘤细胞DNA的直接损伤。由于Wee1激酶是DNA损伤应答通路中的关键激酶,抑制其活性在理论上能够增强传统化疗药物的抗肿瘤作用和放射治疗效果。此外,PARP抑制剂同样是作用于DNA损伤修复过程,与Wee1激酶抑制剂联用有可能会增强肿瘤治疗效果。另一方面,其他作用于非DNA靶点的抗肿瘤药物(如紫杉醇和单抗类抗肿瘤药物)与Wee1激酶抑制剂的联也已经有相关临床研究在进行。
目前将高三尖杉酯碱与Wee1激酶抑制剂联用治疗白血病的文献未见报道。
发明内容
本发明旨在解决前述技术问题,提供一种新型治疗白血病的药物组合物,为临床上开发治疗白血病的联合给药方案提供了一种全新的思路。
本发明的上述目的是通过如下的技术手段来实现的。
本发明提供一种治疗白血病的药物组合物,该药物组合物中活性成分为高三尖杉酯碱和Wee1激酶抑制剂。
优选的,所述Wee1激酶抑制剂选自下述化合物:
(a)2-甲基-1-(6-(2-羟基丙-2-基)吡啶-2-基)-6-(4-(4-甲基哌嗪-1-基)苯基氨基)-1H-吡唑并[3,4-d]嘧啶-3(2H)-酮;
(b)2-乙基-1-(6-(2-羟基丙-2-基)吡啶-2-基)-6-(4-(4-甲基哌嗪-1-基)苯基氨基)-1H-吡唑并[3,4-d]嘧啶-3(2H)-酮;
(c)2-丙基-1-(6-(2-羟基丙-2-基)吡啶-2-基)-6-(4-(4-甲基哌嗪-1-基)苯基氨基)-1H-吡唑并[3,4-d]嘧啶-3(2H)-酮;
(d)2-烯丙基-1-(6-(2-羟基丙-2-基)吡啶-2-基)-6-(4-(4-甲基哌嗪-1-基)苯基氨基)-1H-吡唑并[3,4-d]嘧啶-3(2H)-酮;
(e)2-环丙基-1-(6-(2-羟基丙-2-基)吡啶-2-基)-6-(4-(4-甲基哌嗪-1-基)苯基氨基)-1H-吡唑并[3,4-d]嘧啶-3(2H)-酮;
(f)2-丁基-1-(6-(2-羟基丙-2-基)吡啶-2-基)-6-(4-(4-甲基哌嗪-1-基)苯基氨基)-1H-吡唑并[3,4-d]嘧啶-3(2H)-酮;
(g)2-环丁基-1-(6-(2-羟基丙-2-基)吡啶-2-基)-6-(4-(4-甲基哌嗪-1-基)苯基氨基)-1H-吡唑并[3,4-d]嘧啶-3(2H)-酮。
优选的,上述药物组合物中高三尖杉酯碱和Wee1激酶抑制剂的重量比为1:10-10:1。
更优选的,上述药物组合物中高三尖杉酯碱和Wee1激酶抑制剂的重量比为1:5-5:1。
进一步优选的,上述药物组合物中高三尖杉酯碱和Wee1激酶抑制剂的重量比为4:1或3:1。
最优选的,上述药物组合物中高三尖杉酯碱和Wee1激酶抑制剂(a)2-甲基-1-(6-(2-羟基丙-2-基)吡啶-2-基)-6-(4-(4-甲基哌嗪-1-基)苯基氨基)-1H-吡唑并[3,4-d]嘧啶-3(2H)-酮的重量比为4:1。
最优选的,上述药物组合物中高三尖杉酯碱和Wee1激酶抑制剂(d)2-烯丙基-1-(6-(2-羟基丙-2-基)吡啶-2-基)-6-(4-(4-甲基哌嗪-1-基)苯基氨基)-1H-吡唑并[3,4-d]嘧啶-3(2H)-酮的重量比为3:1。
优选的,上述药物组合物进一步包括药学上可接受的辅料。
优选的,上述药物组合物为固体制剂。
更优选的,上述固体制剂为片剂、胶囊剂或冻干制剂。
本发明还提供上述药物组合物在制备治疗白血病的药物中的应用。
优选的,所述白血病为慢性髓系白血病或急性髓系白血病。
本发明还提供上述药物组合物在制备抑制K562细胞增殖的药物中的应用。
本发明还提供上述药物组合物在制备抑制HL-60细胞增殖的药物中的应用。
本发明产生的有益效果:
发明人在研究中发现,高三尖杉酯碱和Wee1激酶抑制剂的联用对于治疗白血病具有显著的效果。更令人意外的是,两种活性成分在适当重量范围内配比,对于治疗白血病产生了难以预期的优异效果。
具体实施方式
下面结合实施例对本发明作更进一步的说明,但本发明的实施方式不限于此。下述实施例中所使用的实验方法如无特殊说明,均为常规方法。
实施例1
称取高三尖杉酯碱1.6g、2-甲基-1-(6-(2-羟基丙-2-基)吡啶-2-基)-6-(4-(4-甲基哌嗪-1-基)苯基氨基)-1H-吡唑并[3,4-d]嘧啶-3(2H)-酮0.4g、酒石酸1g分别溶于适量热注射用水中,再将酒石酸溶液缓缓加入高三尖杉酯碱和2-甲基-1-(6-(2-羟基丙-2-基)吡啶-2-基)-6-(4-(4-甲基哌嗪-1-基)苯基氨基)-1H-吡唑并[3,4-d]嘧啶-3(2H)-酮的混合溶液中,不断搅拌,使活性成分全部溶解,然后加入乳糖10g、甘露醇15g,搅拌溶解,用4%NaOH调pH至4,补加注射用水至1000ml,无菌过滤,滤液按1ml/支分装于经过灭菌的管制西林瓶中,置冻干机中冷冻干燥24h,压盖已经灭菌的丁基胶塞,轧铝盖,检查,包装即得。
实施例2
称取高三尖杉酯碱1g、2-甲基-1-(6-(2-羟基丙-2-基)吡啶-2-基)-6-(4-(4-甲基哌嗪-1-基)苯基氨基)-1H-吡唑并[3,4-d]嘧啶-3(2H)-酮1g、酒石酸1g分别溶于适量热注射用水中,再将酒石酸溶液缓缓加入高三尖杉酯碱和2-甲基-1-(6-(2-羟基丙-2-基)吡啶-2-基)-6-(4-(4-甲基哌嗪-1-基)苯基氨基)-1H-吡唑并[3,4-d]嘧啶-3(2H)-酮的混合溶液中,不断搅拌,使活性成分全部溶解,然后加入乳糖10g、甘露醇15g,搅拌溶解,用4%NaOH调pH至4,补加注射用水至1000ml,无菌过滤,滤液按1ml/支分装于经过灭菌的管制西林瓶中,置冻干机中冷冻干燥24h,压盖已经灭菌的丁基胶塞,轧铝盖,检查,包装即得。
实施例3
称取高三尖杉酯碱1.8g、2-甲基-1-(6-(2-羟基丙-2-基)吡啶-2-基)-6-(4-(4-甲基哌嗪-1-基)苯基氨基)-1H-吡唑并[3,4-d]嘧啶-3(2H)-酮0.2g、酒石酸1g分别溶于适量热注射用水中,再将酒石酸溶液缓缓加入高三尖杉酯碱和2-甲基-1-(6-(2-羟基丙-2-基)吡啶-2-基)-6-(4-(4-甲基哌嗪-1-基)苯基氨基)-1H-吡唑并[3,4-d]嘧啶-3(2H)-酮的混合溶液中,不断搅拌,使活性成分全部溶解,然后加入乳糖10g、甘露醇15g,搅拌溶解,用4%NaOH调pH至4,补加注射用水至1000ml,无菌过滤,滤液按1ml/支分装于经过灭菌的管制西林瓶中,置冻干机中冷冻干燥24h,压盖已经灭菌的丁基胶塞,轧铝盖,检查,包装即得。
实施例4
称取高三尖杉酯碱1.5g、2-烯丙基-1-(6-(2-羟基丙-2-基)吡啶-2-基)-6-(4-(4-甲基哌嗪-1-基)苯基氨基)-1H-吡唑并[3,4-d]嘧啶-3(2H)-酮0.5g、酒石酸1g分别溶于适量热注射用水中,再将酒石酸溶液缓缓加入高三尖杉酯碱和2-烯丙基-1-(6-(2-羟基丙-2-基)吡啶-2-基)-6-(4-(4-甲基哌嗪-1-基)苯基氨基)-1H-吡唑并[3,4-d]嘧啶-3(2H)-酮的混合溶液中,不断搅拌,使活性成分全部溶解,然后加入乳糖10g、甘露醇15g,搅拌溶解,用4%NaOH调pH至4,补加注射用水至1000ml,无菌过滤,滤液按1ml/支分装于经过灭菌的管制西林瓶中,置冻干机中冷冻干燥24h,压盖已经灭菌的丁基胶塞,轧铝盖,检查,包装即得。
实施例5
称取高三尖杉酯碱1g、2-烯丙基-1-(6-(2-羟基丙-2-基)吡啶-2-基)-6-(4-(4-甲基哌嗪-1-基)苯基氨基)-1H-吡唑并[3,4-d]嘧啶-3(2H)-酮1g、酒石酸1g分别溶于适量热注射用水中,再将酒石酸溶液缓缓加入高三尖杉酯碱和2-烯丙基-1-(6-(2-羟基丙-2-基)吡啶-2-基)-6-(4-(4-甲基哌嗪-1-基)苯基氨基)-1H-吡唑并[3,4-d]嘧啶-3(2H)-酮的混合溶液中,不断搅拌,使活性成分全部溶解,然后加入乳糖10g、甘露醇15g,搅拌溶解,用4%NaOH调pH至4,补加注射用水至1000ml,无菌过滤,滤液按1ml/支分装于经过灭菌的管制西林瓶中,置冻干机中冷冻干燥24h,压盖已经灭菌的丁基胶塞,轧铝盖,检查,包装即得。
实施例6
称取高三尖杉酯碱1.8g、2-烯丙基-1-(6-(2-羟基丙-2-基)吡啶-2-基)-6-(4-(4-甲基哌嗪-1-基)苯基氨基)-1H-吡唑并[3,4-d]嘧啶-3(2H)-酮0.2g、酒石酸1g分别溶于适量热注射用水中,再将酒石酸溶液缓缓加入高三尖杉酯碱和2-烯丙基-1-(6-(2-羟基丙-2-基)吡啶-2-基)-6-(4-(4-甲基哌嗪-1-基)苯基氨基)-1H-吡唑并[3,4-d]嘧啶-3(2H)-酮的混合溶液中,不断搅拌,使活性成分全部溶解,然后加入乳糖10g、甘露醇15g,搅拌溶解,用4%NaOH调pH至4,补加注射用水至1000ml,无菌过滤,滤液按1ml/支分装于经过灭菌的管制西林瓶中,置冻干机中冷冻干燥24h,压盖已经灭菌的丁基胶塞,轧铝盖,检查,包装即得。
试验例1:本发明药物组合物对K562细胞增殖的抑制作用
1、试验方法
(1)细胞培养及试验分组
K562细胞常规培养于含10%灭活胎牛血清的RPMI 1640培养基中,在37℃、含5%CO2、饱和湿度的培养箱中培养。每两日换液传代,取对数生长期细胞用于后续实验。试验时各试验组加入药物浓度分别为:高三尖杉酯碱组和Wee1激酶抑制剂a组(即Wee1激酶抑制剂(a),2-甲基-1-(6-(2-羟基丙-2-基)吡啶-2-基)-6-(4-(4-甲基哌嗪-1-基)苯基氨基)-1H-吡唑并[3,4-d]嘧啶-3(2H)-酮)的药物浓度设定均为2μmol/L,联合组1为1.6μmol/L高三尖杉酯碱+0.4μmol/L Wee1激酶抑制剂a(即高三尖杉酯碱与Wee1激酶抑制剂a的浓度比为4:1),联合组2为1.8μmol/L高三尖杉酯碱+0.2μmol/L Wee1激酶抑制剂a(即高三尖杉酯碱与Wee1激酶抑制剂a的浓度比为9:1),联合组3为1μmol/L高三尖杉酯碱+1μmol/L Wee1激酶抑制剂a(即高三尖杉酯碱与Wee1激酶抑制剂a的浓度比为1:1),观察各试验组培养24h和48h后细胞生长状况。
(2)细胞增殖活力检测
取各实验组细胞,调整细胞数为5×105/ml,接种于96孔板中,100微升/孔,每组6个复孔,37℃、5%CO2条件下培养过夜,后每孔加入10μl CCK-8溶液,继续于培养箱内孵育2h,用酶标仪测量各孔在波长450nm处的吸光度值(A值)。实验重复3次,细胞增殖抑制率(%)=(1-实验组平均A值/对照组平均A值)×100%。
2、试验结果
各试验组抑制K562细胞增殖的试验结果见表1。
表1本发明药物组合物对抑制K562细胞增殖的影响
表1试验结果显示,高三尖杉酯碱和Wee1激酶抑制剂a均可对K562细胞的增殖产生抑制作用,且随着时间的延长而越来越明显。值得注意的是,当高三尖杉酯碱和Wee1激酶抑制剂a联用时,其对K562细胞的增殖抑制作用显著增强,其中联合组1的抑制效果最佳。
试验例2:本发明药物组合物对HL-60细胞凋亡的诱导作用
1、试验方法
(1)细胞培养及试验分组
细胞培养液为含10%小牛血清的RPMI-1640所培养的HL-60细胞台盼蓝染色后计数,拒染活细胞≥98%以上者适用于实验。在24孔细胞培养板中每孔接种1×106/mL的HL-60细胞,37℃、5%CO2条件下预培养24h。试验时各试验组加入药物浓度分别为:高三尖杉酯碱组和Wee1激酶抑制剂d组(即Wee1激酶抑制剂(d),2-烯丙基-1-(6-(2-羟基丙-2-基)吡啶-2-基)-6-(4-(4-甲基哌嗪-1-基)苯基氨基)-1H-吡唑并[3,4-d]嘧啶-3(2H)-酮)的药物浓度设定均为2μmol/L,联合组1为1.5μmol/L高三尖杉酯碱+0.5μmol/L Wee1激酶抑制剂d(即高三尖杉酯碱与Wee1激酶抑制剂d的浓度比为3:1),联合组2为1.8μmol/L高三尖杉酯碱+0.2μmol/L Wee1激酶抑制剂d(即高三尖杉酯碱与Wee1激酶抑制剂d的浓度比为9:1),联合组3为1μmol/L高三尖杉酯碱+1μmol/L Wee1激酶抑制剂d(即高三尖杉酯碱与Wee1激酶抑制剂d的浓度比为1:1)。上述各试验组在37℃、5%CO2条件下分别培养24h和48h后收集细胞,用PBS洗涤2次后重悬,调整细胞浓度为1×106/mL,上述实验均重复3次。
(2)细胞凋亡检测
采用FIT C-annexin V/PI法,取上述各试验组作用不同时间的细胞悬液100μL,加入10μL FIT C-annexin V,37℃孵育10min,PBS洗涤后重悬细胞,加入PI终止液50μL,用流式细胞仪检测。计算各试验组作用24h和48h的HL-60细胞凋亡率。
2、试验结果
各试验组诱导HL-60细胞凋亡的试验结果见表2。
表2本发明药物组合物诱导HL-60细胞凋亡的影响
表2试验结果显示,高三尖杉酯碱和Wee1激酶抑制剂d均可对诱导HL-60细胞发生凋亡作用,且随着时间的延长而越来越明显。值得注意的是,当高三尖杉酯碱和Wee1激酶抑制剂d联用时,其对HL-60细胞凋亡的诱导作用显著增强,其中联合组1的抑制效果最佳。
Claims (6)
1.一种治疗白血病的药物组合物,其特征在于,所述药物组合物中活性成分为高三尖杉酯碱和Wee1激酶抑制剂,其中高三尖杉酯碱和Wee1激酶抑制剂的重量比为4:1或3:1,所述Wee1激酶抑制剂选自下述化合物:
(a)2-甲基-1-(6-(2-羟基丙-2-基)吡啶-2-基)-6-(4-(4-甲基哌嗪-1-基)苯基氨基)-1H-吡唑并[3,4-d]嘧啶-3(2H)-酮;或
(d)2-烯丙基-1-(6-(2-羟基丙-2-基)吡啶-2-基)-6-(4-(4-甲基哌嗪-1-基)苯基氨基)-1H-吡唑并[3,4-d]嘧啶-3(2H)-酮。
2.根据权利要求1所述的药物组合物,其特征在于,所述药物组合物进一步包括药学上可接受的辅料。
3.根据权利要求1或2所述的药物组合物,其特征在于,所述药物组合物为固体制剂。
4.根据权利要求3所述的药物组合物,其特征在于,所述固体制剂为片剂、胶囊剂或冻干制剂。
5.权利要求1-4任一项所述的药物组合物在制备治疗白血病的药物中的应用。
6.根据权利要求5所述的应用,其特征在于,所述白血病为慢性髓系白血病或急性髓系白血病。
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