CN103230394B - ***性疾病的化合物及其用途 - Google Patents
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- CN103230394B CN103230394B CN201310024563.XA CN201310024563A CN103230394B CN 103230394 B CN103230394 B CN 103230394B CN 201310024563 A CN201310024563 A CN 201310024563A CN 103230394 B CN103230394 B CN 103230394B
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Abstract
本文公开了***性疾病的化合物和用途。包括有效对抗对常规治疗和硼替佐米治疗产生耐药性的多发性骨髓瘤细胞的化合物和用途。此外,显示使用两种不同蛋白酶体抑制剂的组合治疗对治疗多发性骨髓瘤具有协同作用。
Description
发明背景
发明领域
本发明涉及化学和医药领域。更具体地,本发明涉及诸如癌症等肿瘤性疾病的治疗。
相关技术的描述
在美国,癌症是死亡的主要原因。尽管人们为寻找治疗癌症的新方法付出了显著的努力,但是主要的治疗选择仍然是单独或联合使用的外科手术、化学治疗以及放射治疗。然而,外科手术和放射治疗通常仅对相当局限的癌症有用,对于患有播散性疾病的患者作用有限。化学治疗是一般用于治疗患有转移癌或诸如白血病等弥散性癌症的患者的方法。虽然化学治疗能够提供治疗益处,但是由于患者的癌细胞对化学治疗剂产生耐药性,致使它通常不能治愈所述疾病。
因此,存在对治疗癌症的另外化学疗法的需求。个体研究人员、学术界以及公司对于鉴定新的、潜在有用的化学治疗剂和抗微生物治疗剂做出了持续不断的努力。
用于治疗复发性/难治性多发性骨髓瘤(MM)的硼替佐米(Bortezomib)/PS-341的成功开发确立了蛋白酶体抑制剂作为有效治疗方案。所述二肽硼酸类似物硼替佐米是有效的、高选择性的、以及可逆的蛋白酶体抑制剂,其以26S蛋白酶体复合体为靶并且抑制其功能。所述26S蛋白酶体是介导细胞内蛋白降解的三磷酸腺苷(ATP)依赖的多催化蛋白酶。通过识别被26S蛋白酶体的19S调节亚基多遍在蛋白化的蛋白质,以及随后水解为较小的多肽进行错误折叠或损伤蛋白的蛋白酶体降解。硼替佐米主要抑制糜蛋白酶的蛋白酶体活性,而不改变胰蛋白酶的或半胱天冬酶(caspase)样的蛋白酶体活性。除了抑制NF-kB外,硼替佐米还通过靶向下列对MM生物学具有多效作用:1)细胞周期调节蛋白;2)通过调节浆细胞分化因子X盒结合蛋白-1(XPB-1)的转录活性的UPR途径;3)p-53介导的细胞凋亡/MDM2;4)DNA修复机理;5)经由内在(半胱天冬酶9介导的)和外在(半胱天冬酶8介导的)细胞死亡级联的标准应激反应途径。具体地,硼替佐米对JNK的活化引发线粒体细胞凋亡信号:细胞色素C(cyto-c)和第二个线粒体来源的半胱天冬酶活化剂(Smac)从线粒体到胞浆的释放,然后半胱天冬酶9和半胱天冬酶3活化。然而,已经观察到内在抗性和获得性抗性,并且目前尚没有克服硼替佐米抗性的疗法。
发明概述
本发明的一方面是***性疾病的方法,包括对患有肿瘤性疾病的患者给予式(I)化合物或其药物可接受盐或前药:
其中X选自氟、氯、溴或碘,并且其中所述肿瘤性疾病容易对至少一种其它化学治疗剂产生抗性。
本发明的另一方面是***性疾病的方法,包括对患有肿瘤性疾病的患者联合给予式(I)化合物或其药物可接受盐或前药与至少一种其它的化学治疗剂,其中X选自氟、氯、溴或碘。
本发明的另一方面是药物组合物,其包括式(I)化合物或其药物可接受盐或前药以及至少一种其它的化学治疗剂,其中X选自氟、氯、溴或碘。
本发明的另一方面是***性疾病的方法,包括对患有肿瘤性疾病的患者给予协同组合的至少两种蛋白酶体抑制剂。
附图简述
图1显示NPI-0052对人红细胞来源的20S蛋白酶体中的糜蛋白酶样、半胱天冬酶样和胰蛋白酶样蛋白酶体活性的抑制作用。
图2显示小鼠中NPI-0052的体内糜蛋白酶样活性。
图3描述用NPI-0052(7nM)处理MM.1S多发性骨髓瘤(MM)细胞并且在37°C下用AdaY(125I)Ahx3L3VS孵育蛋白质提取物后得到的放射自显影照片。
图4描述用NPI-0052处理MM.1S细胞,随后用丹酰基-Ahx3L3VS孵育后得到的免疫印迹。
图5A显示经过指示剂量的NPI-0052处理24h的不同多发性骨髓瘤细胞系的细胞存活率。
图5B显示用NPI-0052处理从患者处获得的MM细胞后,细胞凋亡的DNA断裂分析。
图6显示用NPI-0052处理从患者处获得的骨髓基质细胞后,细胞凋亡的DNA断裂分析。
图7显示存在或缺乏IL-6或IGF-I的条件下,用NPI-0052或Dex处理后,MM.1S细胞存活率的MTT测定。
图8显示NPI-0052对VEGF诱导的MM.1S细胞迁移的影响。
图9显示NPI-0052对Bcl-2过量表达的MM.1S细胞存活率的影响。
图10A和10B描述当对小鼠口服给药时,NPI-0052对肿瘤生长的影响。
图10C显示当对小鼠口服给药时,NPI-0052对存活的影响。
图10D显示当对小鼠口服给药时,NPI-0052对体重的影响。
图10E显示来自NPI-0052处理的以及对照处理的小鼠的接种位点的组织切片。
图10F比较当对小鼠静脉给药时,NPI-0052和硼替佐米对肿瘤生长的影响。
图10G比较当对小鼠静脉给药时,NPI-0052和硼替佐米对存活的影响。
图11A显示NPI-0052对用CMXRos孵育的MM.1S细胞中的线粒体膜电位的影响。
图11B显示NPI-0052对用膜可渗透染料二氢乙锭(dihydroethidium)(HE)染色的MM.1S细胞中的超氧化物产生的影响。
图11C描述从用NPI-0052处理的MM.1S细胞得到的线粒体和胞浆蛋白碎片的免疫印迹。
图11D描述从用NPI-0052处理的MM.1S细胞得到的胞浆蛋白的免疫印迹,该免疫印迹使用抗半胱天冬酶9Abs分析。
图11E描述从用NPI-0052处理的MM.1S细胞得到的胞浆蛋白的免疫印迹,该免疫印迹使用抗半胱天冬酶8Abs分析。
图11F描述MM.1S或MM.1R细胞的免疫印迹,其中用NPI-0052对所述细胞进行处理并通过PARP和半胱天冬酶3切割分析对其细胞凋亡进行评估。
图12A显示在存在或缺乏半胱天冬酶3、半胱天冬酶8、或半胱天冬酶9抑制剂的条件下,NPI-0052或硼替佐米处理后的MM.1S细胞存活率。
图12B显示对于用单独载体、DN-半胱天冬酶8、以及DN-半胱天冬酶9转染的细胞,用NPI-0052或硼替佐米处理后的MM.1S细胞存活率。
图12C描述胞浆提取物的免疫印迹,该胞浆提取物来自用***或抗FasMoAb处理的DN-半胱天冬酶8和DN-半胱天冬酶9转染的MM.1S细胞。
图12D显示对于载体或DN-FADD转染的细胞,用NPI-0052或硼替佐米处理后的MM.1S细胞存活率。
图12E描述线粒体蛋白提取物的免疫印迹,该线粒体蛋白提取物来自用指示浓度的NPI-0052或硼替佐米处理的MM.1SMM细胞,该免疫印迹使用抗Bax或抗Hsp60Abs分析。
图12F显示用指示浓度的NPI-0052或硼替佐米处理的野生型或删除了Bax(敲除)的小鼠胚胎成纤维细胞(MEFs)的细胞存活率。
图13显示来自用指示浓度的NPI-0052或硼替佐米处理的五名健康供者的正常淋巴细胞的存活率。
图14A显示对于用单独载体或Bcl-2转染的细胞,用NPI-0052或硼替佐米处理后的MM.1S细胞存活率。
图14B描述胞浆提取物的免疫印迹,该胞浆提取物来自用NPI-0052或硼替佐米处理的载体-或Bcl-2转染的MM.1S细胞。
图15显示用指示浓度的NPI-0052、硼替佐米、或NPI-0052+硼替佐米处理的MM.1S和MM.1RMM细胞的细胞存活率。
优选实施方案的详细描述
在一实施方案中,提供了用于本文所述用途的式(I)化合物:
其中X可以为氟、氯、溴或碘。在一实施方案中,X为氯。在一实施方案中,式(I)化合物具有式(II)的立体化学结构:
X=Cl时的式(II)化合物在本文中也被称为NPI-0052。式(I)化合物或式(II)化合物可以来源于海洋革兰氏阳性放线菌Salinospora的发酵。
在某些实施方案中,提供用于本文所述用途的、本文公开化合物的前药、代谢产物、立体异构体、以及药物可接受盐。
“前药”指在体内转变为母药的试剂。前药经常是有用的,这是因为在某些情况下,它们比起母体药物更易于给药。例如,通过口服给药,前药是生物可利用的,而母体药物则不然。在药物组合物中,前药还可以具有改善的、优于母体药物的溶解性。前药的非限制性例子是以酯的形式(“前药”)进行给药的化合物以辅助跨细胞膜传送,这时水溶性不利于迁移,然而随后一旦进入细胞内该化合物被代谢水解为作为活性实体的羧酸,此时水溶性是有利的。前药的另一例子可以是与酸基团结合的短肽(多氨基酸),其中该肽被代谢以显露活性部分。在例如DesignofProgrugs(前药的设计),(ed.H.Bundgaard,Elsevier,1985)中描述了用于合适前药衍生物的选择和制备的常规方法,此处通过参考的方式并入其全部内容。
术语“酯类前药”指本文公开化合物的衍生物,该衍生物是通过若干个在生理条件下可水解的成酯基团中的任何一个的加成而形成的。前药中的酯基团的例子包括pivoyloxymethyl、乙酸基甲基、2-苯并[c]呋喃酮亚基、2,3-二氢化茚基和甲氧基甲基,以及其它本领域已知的这类基团,包括(5-R-2-氧-1,3-二氧杂环戊烯-4-基)甲基基团。前药中的酯基团的其它例子可以在例如下列文献中找到:T.Higuchi和V.Stella,“Pro-drugasNovelDeliverySystems”(“作为新颖的递药***的前药”),第14卷,A.C.S.SymposiumSeries,AmericanChemistrySociety(1975);和“BioreversibleCarriersinDrugDesign:TheoryandApplication”(“药物设计中生物可逆性载体:原理和应用”),E.B.Roche编辑,PergamonPress:NewYork,14-21(1987)(为包含羧基基团的化合物提供了用作前药的酯类的例子)。此处通过参考的方式并入上述每一参考资料的全部内容。
本文公开化合物的代谢产物包括将所述化合物引入生物环境时产生的活性种类。
当本文公开的化合物具有至少一个手性中心时,它们可以以外消旋化合物或对映体的方式存在。应当指出,所有这些异构体及其混合物都被包括在本发明的范围中。此外,本文公开化合物的一些晶形可以以多晶形物的方式存在。这些多晶形物被包括在本发明的一个实施方案中。此外,本发明的一些化合物可以与水形成溶剂合物(即水合物)或与常见的有机溶剂形成溶剂合物。这些溶剂合物被包括在本发明的一个实施方案中。
术语“药物可接受盐”指不会对被给药生物体产生显著刺激且不会消除化合物的生物活性和特性的该化合物的盐。在一些实施方案中,所述盐为化合物的酸加成盐。可以通过化合物与诸如氢卤酸(例如,盐酸或氢溴酸)、硫酸、硝酸、磷酸等无机酸反应得到药物可接受盐。还可以通过化合物与诸如脂肪族或芳香族的羧酸或磺酸等有机酸反应得到药物可接受盐,例如醋酸、琥珀酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、烟酸、甲磺酸、乙磺酸、对苯磺酸、水杨酸或萘磺酸。还可以通过化合物与碱反应形成盐以得到药物可接受盐,例如铵盐、诸如钠盐或钾盐等碱金属盐、诸如钙盐或镁盐等碱土金属盐、诸如二环己基胺、N-甲基-D-葡糖胺、三羟甲基氨基甲烷、C1-C7烷基胺、环己胺、三乙醇胺、乙二胺等有机碱盐、以及与诸如精氨酸、赖氨酸等氨基酸形成的盐。
如果药物制剂的生产涉及将药物赋形剂和盐形式的活性成分均质混合时,那么使用非碱性的药物赋形剂,即酸性或中性的赋形剂可能是理想的。
在不同的实施方案中,本文公开的化合物可以被单独使用、与本文公开的其它化合物联合使用、或与一种或多种在本文所述的治疗领域中具有活性的其它药物联合使用。
本文所使用的术语“卤素原子”是指任意一个元素周期表第7栏的非放射性原子,即氟、氯、溴或碘,氟和氯是优选的。
术语“酯”指具有式-(R)n-COOR’的化学部分,其中R和R’独立地选自烷基、环烷基、芳基、杂芳基(通过环碳键合的)以及杂脂环(通过环碳键合的),并且其中n为0或1。
“酰胺”是具有式-(R)n-C(O)NHR’或-(R)n-NHC(O)R’的化学部分,其中R和R’独立地选自烷基、环烷基、芳基、杂芳基(通过环碳键合的)以及杂脂环(通过环碳键合的),并且其中n为0或1。酰胺可以是连接在本发明的分子上的氨基酸或肽分子,从而形成前药。
本发明化合物上的任何胺、羟基、或羧基侧链均可以被酯化或酰胺化。达到此目标所使用的方法和具体基团为本领域技术人员已知,并且可以容易地在参考资料中找到,例如Greene和Wuts,ProtectiveGroupsinOrganicSynthesis(有机合成中的保护基),3rdEd.,JohnWiley&Sons,NewYork,NY,1999,在此通过参考的方式并入其全部内容。
本文所使用的术语“纯化的、”“基本上纯化的、”以及“分离的”指本文公开的化合物不含其它的、不同的化合物,本发明化合物在其自然状态下与所述其它的、不同的化合物相伴随,使得本发明化合物包含至少0.5%、1%、5%、10%或20%重量比的给定样品,且最优选地包含至少50%或75%重量比的给定样品。
使用方法
如本文介绍的实例所证明,式(I)化合物抑制糜蛋白酶样、胰蛋白酶样、以及半胱天冬酶样蛋白酶体活性。相反,已经显示硼替佐米仅仅抑制糜蛋白酶样蛋白酶体活性。参见Goldberg,A.L.&Rock,K.(2002)NatMed8,338-40以及Adams,J.(2004)NatRevCancer4,349-60;在此通过参考的方式并入其全部内容。另外还证明了式(I)化合物具有与硼替佐米不同的作用机理。此外,式(I)化合物在不同的多发性骨髓瘤细胞系中诱导细胞凋亡,该细胞系包括但不限于***敏感MM.1S、抗***MM.1R、RPMI-8226、OPM2、U266、以及抗阿霉素Dox-40。式I化合物还在取自复发的人类多发性骨髓瘤患者的细胞系中诱导细胞凋亡,所述患者在复发前曾使用***、硼替佐米、以及沙利度胺进行多次治疗。因此,式(I)化合物对于对包括***、阿霉素、硼替佐米/PS-341、以及沙利度胺的其它化学治疗剂具有耐药性的MM细胞是有效的。
因此,在一实施方案中,提供了治疗容易对至少一种化学治疗剂产生耐药性的肿瘤性疾病的方法,该方法包括给予诸如人的患者式(I)化合物或其药物可接受盐或酯类前药。“对至少一种化学治疗剂产生耐药性”指对患者给予该化学治疗剂无法显著改善肿瘤性疾病的症状。在一些特征为肿瘤的肿瘤性疾病的实施方案中,“对至少一种化学治疗剂产生耐药性”指化学治疗剂的给药无法产生可察觉到的对肿瘤生长的抑制或肿瘤尺寸的减小。“对至少一种化学治疗剂产生耐药性”还可以指,当使该试剂暴露于抗性肿瘤细胞时,没有可察觉到的细胞凋亡被诱导。“容易”对至少一种化学治疗剂抗性,其表示目前肿瘤性疾病对至少一种化学治疗剂具有耐药性或由于化学治疗剂的重复给药将会产生耐药性。
本文的实例还证明,当式(I)化合物与硼替佐米联合时,在MM细胞中引发协同细胞凋亡。因此,可以将式(I)化合物与硼替佐米/PS-341联合给药以实现细胞凋亡,其中使用的每一种试剂的剂量比单独给予该试剂时少,因此降低了试剂的毒性。意想不到的是,这些结果证明通过给予两种不同的蛋白酶体抑制剂可以获得协同效果。“协同的”指两种或多种试剂的联合产生的联合指数(CI)<1.0。还证明,式(I)化合物与非蛋白酶体抑制剂的联合提供加合效果。“加合的”指两种或多种药物的联合产生的CI约等于1。例如,可以根据以下等式通过Chou-Talalay方法确定CI:“CI=(D)1/(Dx)1+(D)2/(Dx)2+(D)1(D)2/(Dx)1(Dx)2”,其中(D1)和(D)2是联合使用时具有x效果的药物1和药物2的剂量;并且(Dx)1和(Dx)2是单独使用时具有相同x效果的药物1和药物2的剂量。
因此,在一实施方案中,提供了***性疾病的方法,该方法包括将两种或多种蛋白酶体抑制剂协同联合给药。可以联合的蛋白酶体抑制剂类型的非限制性例子包括肽硼酸盐蛋白酶体抑制剂、肽醛蛋白酶体抑制剂、以及非肽蛋白酶体抑制剂。肽硼酸盐蛋白酶体抑制剂的非限制性例子是硼替佐米。肽醛蛋白酶体抑制剂的非限制性例子是MG-132。非肽蛋白酶体抑制剂的非限制性例子包括omuralide和式(I)化合物。在一实施方案中,至少一种蛋白酶体抑制剂是式(I)化合物或硼替佐米。“联合”给药指,不管实际上在何时或如何对患者给药,可以在他们的血流中同时发现两种或多种试剂。在一实施方案中,同时给予所述试剂。在一个这样的实施方案中,通过在单次剂型中组合所述试剂完成联合给药。在另一实施方案中,顺序给予所述试剂。在一实施方案中,通过相同的途径,例如口服,给予所述试剂。在另一实施方案中,通过不同的途径给予所述试剂,例如一种口服给药而另一种静脉注射给药(i.v.)。在一个有利的实施方案中,所述两种或多种试剂的药代动力学基本上相同。
在一实施方案中,提供了***性疾病的方法,该方法包括将式(I)化合物和另一种化学治疗剂联合给药。在一实施方案中,另一种化学治疗剂是***、多柔比星或沙利度胺。在一实施方案中,另一种化学治疗剂是诸如硼替佐米的另一种蛋白酶体抑制剂。在一实施方案中,提供组合了式(I)化合物与另外的化学治疗剂的药物组合物。
在一些实施方案中,通过上述任何方法治疗的肿瘤性疾病可能是选自乳腺癌、肉瘤、白血病、卵巢癌、输尿管癌、膀胱癌、***癌、结肠癌、直肠癌、胃癌、肺癌、淋巴瘤、多发性骨髓瘤、胰腺癌、肝癌、肾癌、内分泌癌、皮肤癌、黑素瘤、血管瘤、以及脑或中枢神经***(CNS)癌的癌症。在一实施方案中,所述肿瘤性疾病是多发性骨髓瘤。
药物组合物
另一方面,本公开涉及药物组合物,其包括生理可接受的表面活性剂、载体、稀释剂、赋形剂、光滑剂、混悬剂、成膜物质、以及包衣辅助剂或其联合;以及本文公开的化合物或组合。用于治疗用途的可接受载体或稀释剂在制药领域中是公知的,并且在例如Remington'sPharmaceuticalSciences(雷明顿制药学),18thEd.,MackPublishingCo.,Easton,PA(1990))中有描述,在此通过参考的方式并入其全部内容。在药物组合物中可以提供防腐剂、稳定剂、染料、甜味剂、芳香剂、香料等等。例如,可加入作为防腐剂的苯甲酸钠、抗坏血酸以及对羟基苯甲酸的酯。此外,可以使用抗氧化剂和混悬剂。在不同的实施方案中,醇、酯、硫酸化脂族醇等等可用作表面活性剂;蔗糖、葡萄糖、乳糖、淀粉、结晶纤维素、甘露醇、轻质无水硅酸盐、铝酸镁、铝酸甲基硅酸镁、合成硅酸铝、碳酸钙、碳酸氢钙、磷酸氢钙、羟甲基纤维素钙等等可用作赋形剂;硬脂酸镁、滑石、氢化油等等可用作光滑剂;椰子油、橄榄油、芝麻油、花生油、大豆油可用作混悬剂或润滑剂;作为诸如纤维素或糖等碳水化合物的衍生物的醋酸邻苯二甲酸纤维素、或作为聚乙烯的衍生物的乙酸甲酯-异丁烯酸共聚物可用作混悬剂;且诸如邻苯二甲酸酯等等的增塑剂可用作混悬剂。
术语“药物组合物”指本文公开的化合物或化合物的组合物与其它诸如稀释剂或载体等化学组分的混合物。药物组合物辅助对生物体给予所述化合物。在本领域中存在多种给予化合物的技术,其包括但不限于口服给药、注射给药、气雾剂给药、肠胃外给药和局部给药。通过化合物与诸如盐酸、氢溴酸、硫酸、硝酸、磷酸、甲磺酸、乙磺酸、对甲苯磺酸、水杨酸等等无机酸或有机酸反应也可以得到药物组合物。
术语“载体”定义为辅助将化合物引入细胞或组织的化合物。例如二甲亚砜(DMSO)是普遍使用的载体,这是因为它辅助许多有机化合物向生物体的细胞或组织中的吸收。
术语“稀释剂”定义为稀释在水中的化合物,它溶解目的化合物并且稳定该化合物的生物活性形式。在本领域中,溶解在缓冲溶液中的盐被用作稀释剂。一种常用的缓冲溶液是磷酸盐缓冲盐水,因为它模拟了人血的盐状态。由于缓冲盐在低浓度时可以控制溶液的pH值,所以缓冲的稀释剂很少改变化合物的生物活性。
术语“生理可接受的”定义为不消除化合物的生物活性和特性的载体或稀释剂。
可以对人类患者给予本文所描述的药物组合物本身,或者给予药物组合物,其中所述药物组合物与合适的载体或赋形剂混合。在“Remington'sPharmaceuticalSciences”(雷明顿制药学),MackPublishingCo.Easton,PA,18thedition,1990中可找到本申请化合物的制剂和给药技术。
合适的给药途径可以例如包括口服、直肠、透膜、局部或肠内给药;肠胃外输送包括肌内、皮下、静脉、髓内注射,以及鞘内、直接心室内、腹膜内、鼻内或眼内注射。还可以以缓释或控释剂型给予所述化合物,包括储库型注射(depotinjections)、渗透泵、丸剂、透皮(包括电迁移)贴片等等,用于以预先确定的速率进行延长和/或定时、脉冲给药。
本发明的药物组合物可按已知的方式制造,例如,通过常规的混合、溶解、粒化、糖锭剂制造、研磨、乳化、包囊、包封(entrapping)或压片过程。
因此,用于本发明用途的药物组合物可以使用一种或多种生理可接受的载体以常规方式进行组方,所述载体包含辅助将活性化合物加工到药物可接受制剂中的赋形剂和辅助剂。合适的制剂取决于所选的给药途径。可以如本领域中适合并理解的那样使用任何公知的技术、载体和赋形剂;例如,在《雷明顿制药学》中,同上。
可将注射剂制备成下列常规形式:作为溶液或混悬液,在注射前适合制成溶液或混悬液的固体剂型,或作为乳剂。合适的赋形剂是,例如水、盐水、葡萄糖、甘露醇、乳糖、卵磷脂、白蛋白、谷氨酸钠、盐酸半胱氨酸等等。另外,如果需要,注射剂药物组合物可以含有少量无毒性辅助物,例如湿润剂、pH缓冲剂等等。生理相容的缓冲剂包括但不限于Hank溶液、Ringer溶液或生理盐水缓冲液。如果需要,可使用吸收增强制剂(例如脂质体)。
对于透膜给药,在所述制剂中可使用适于通透屏障的渗透剂。
肠胃外给药的药物制剂,例如,通过推注或连续输注,包括水可溶形式的所述活性化合物的水溶液。此外,可以将所述活性化合物的混悬液制备为合适的油状注射悬剂。适合的亲脂溶剂或载体包括诸如芝麻油等脂肪油、或诸如豆油、葡萄柚油或杏仁油等其它有机油、或诸如油酸乙酯或甘油三酯等合成脂肪酸酯、或脂质体。水性注射悬液可包含增加该悬液粘度的物质,例如羟甲基纤维素钠、山梨糖醇或葡聚糖。任选地,所述混悬液还可以包含合适的稳定剂或增加所述化合物溶解性以制备高浓度制剂的试剂。注射制剂可以以单位剂型存在,例如在安瓿或多次剂量容器中,并加入有防腐剂。所述组合物可以采用油性或水性载体中的混悬剂、溶液或乳剂这样的形式,并且可以包含诸如助悬剂、稳定剂和/或分散剂等组方试剂。或者,所述活性组分可以是粉末形式,用于在使用前与诸如灭菌无热原水等合适的载体复溶。
对于口服给药,通过组合所述活性化合物与本领域公知的药物可接受载体可以容易地组方所述化合物。这样的载体能够使本发明的化合物被组方为片剂、丸剂、糖锭剂、胶囊、液体、凝胶、糖浆、膏剂(slurry)、混悬液等等,用于接受治疗的患者口服摄取。可通过下述方法获得用于口服的药物制剂:混合活性化合物和固体赋形剂,任选地研磨所得混合物,以及加工该颗粒混合物,如果需要,在加入合适的辅助剂后进行所述加工,以得到片剂或糖锭剂核。合适的赋形剂特别是诸如糖的填充剂,包括乳糖、蔗糖、甘露醇或山梨糖醇;纤维素制剂,例如玉米淀粉、小麦淀粉、大米淀粉、马铃薯淀粉、明胶、西黄蓍胶、甲基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠、和/或聚乙烯吡咯烷酮(PVP)。如果需要可加入崩解剂,例如交联的聚乙烯吡咯烷酮、琼脂或藻酸或诸如藻酸钠的藻酸盐。对糖锭剂核进行合适的包被。为了这个目的,可使用浓缩的糖溶液,该糖溶液可任选地包含***胶、滑石、聚乙烯吡咯烷酮、卡波普凝胶(carbopolgel)、聚乙二醇和/或二氧化钛、紫胶漆溶液、以及合适的有机溶剂或溶剂混合物。为了识别或表征活性化合物剂量的不同组合,可向片剂或糖锭剂包衣中加入染料或色素。为了这个目的,可使用浓缩的糖溶液,该糖溶液可任选地包含***胶、滑石、聚乙烯吡咯烷酮、卡波普凝胶、聚乙二醇和/或二氧化钛、紫胶漆溶液、以及合适的有机溶剂或溶剂混合物。为了识别或表征活性化合物剂量的不同组合,可向片剂或糖锭剂包衣中加入染料或色素。
可用于口服的药物制剂包括明胶制成的推入配合(push-fit)胶囊,以及诸如甘油或山梨糖醇的明胶和增塑剂制成的软的、密封的胶囊。推入配合胶囊可包含与诸如乳糖的填充剂、诸如淀粉的粘合剂、和/或诸如滑石或硬脂酸镁的润滑剂,以及任选的稳定剂混合的活性成分。在软胶囊中,活性成分可溶解或悬浮在合适的液体中,例如脂肪油、液态石蜡、或液态聚乙二醇。另外,可加入稳定剂。所有口服给药的制剂的剂量均应适合这种给药。
对于口腔给药,所述组合物可以是按常规方法组方的片剂或锭剂的形式。
对于吸入给药,使用合适的推进剂,将用于本发明用途的化合物从增压包或喷雾器中以喷雾形式方便地输送,所述合适的推进剂例如二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷、二氧化碳或其它合适气体。在加压气溶胶的情况下,可通过提供阀以输送计量的量来确定剂量单位。在吸入器或吹入器中使用的诸如明胶的胶囊和药筒可被组方成包含化合物和诸如乳糖或淀粉等合适粉末基质的粉末混合物。
本文还公开了在制药领域中公知的用于包括眼内、鼻内以及耳内输送的多种药物组合物。用于这些用途的适合的渗透剂是本领域公知的。用于眼内输送的药物组合物包括水可溶形式的所述活性化合物的水性眼用溶液,例如滴眼剂,或以结冷胶(gellangum)形式(shedden等人,Clin,Ther.,23(3):440-50(2001))或水凝胶形式(Mayer等人,Ophthalmologica,210(2):101-3(1996));眼用软膏;眼用混悬液,例如微粒、悬浮在液体载体介质中的包含药物的小聚合颗粒(Joshi,A.,J.Ocul.Pharmacol.,10(1):29-45(1994)),脂溶性制剂(Alm等人,Prog.Clin.Biol.Res.,312:447-58(1989)),以及微球(Mordenti,Toxicol.Sci.,52(1):101-6(1999));以及眼用嵌入剂。在此通过参考的方式并入所有上述文献的全部内容。为了稳定性和舒适性,这些合适的药物制剂最经常且优选地组方成无菌的、等渗的、和缓冲的。用于鼻内输送的药物组合物还可包括滴剂和喷雾剂,通常将其制备成在许多方面模拟鼻分泌物以确保维持正常纤毛作用。如在Remington’sPharmaceuticalSciences(雷明顿制药学),18thEd.,MackPublishingCo.,Easton,PA(1990)中所公开的,在此通过参考的方式并入其全部内容,以及本领域技术人员所公知的,适合的制剂最经常且优选为等渗的,轻度缓冲以维持pH5.5至6.5,并且最经常且优选地包括抗菌性防腐剂和适当的药物稳定剂。用于耳内输送的药物制剂包括在耳内局部应用的混悬剂和软膏。用于这类耳用制剂的常用溶剂包括甘油和水。
化合物也可以被组方成诸如栓剂或保留灌肠剂的直肠组合物,例如含有诸如可可脂或其它甘油脂的常规栓剂基质。
除了前述的制剂,化合物还可以被组方成为储库型制剂。可以通过植入(例如皮下或肌内)或通过肌内注射给予这种长效制剂。因此,举例来说,所述化合物可以与合适的聚合物或疏水材料(例如可接受油中的乳剂)或离子交换树脂组方,或作为微溶衍生物,例如微溶盐。
对于疏水化合物,合适的药物载体可以为包含苯甲醇、非极性表面活性剂、可与水混溶的有机聚合物、以及水相的共溶剂***。常用的共溶剂***为VPD共溶剂***,其为3%w/v的苯甲醇、8%w/v的非极性表面活性剂聚山梨醇酯80TM、以及65%w/v的聚乙二醇300且由无水乙醇补足体积的溶液。自然地,共溶剂***的比例可以有相当大的改变而不破坏其溶解度和毒性特征。此外,共溶剂组分可以改变:例如可以使用其它低毒性的非极性表面活性剂代替POLYSORBATE80TM;可以改变聚乙二醇的片断大小;诸如聚乙烯吡咯烷酮等其它生物相容性聚合物可以代替聚乙二醇;以及其它糖或多糖可代替葡萄糖。
或者,可采用用于疏水性药物化合物的其它输送***。脂质体和乳剂是疏水药物的输送媒介物或载体的公知实例。还可以使用诸如二甲亚砜等某些有机溶剂,尽管通常要以较高的毒性为代价。另外,可以使用缓释***输送化合物,例如含有治疗剂的固体疏水性聚合物的半透性基质。已经确定了多种缓释材料且它们为本领域技术人员所公知。根据其化学性质,缓释胶囊可以释放化合物数周至超过100天。根据治疗剂的化学性质和生物稳定性,可采用使蛋白质稳定的其它方案。
可以使用本领域普通技术人员公知的技术给予用于细胞内给药的试剂。例如,这类试剂可以被包囊进脂质体。在脂质体形成时,在水溶液中存在的所有分子都被包括到水性内部。所述脂质体的内含物不仅受到保护不受外部微环境的影响,而且因为脂质体与细胞膜相融合,所以该内含物被有效输送至细胞的细胞质。可以使用组织特异性抗体包被脂质体。该脂质体将会被靶向至期望的器官并被选择性吸收。或者,可以直接细胞内给予小的疏水性有机分子。
可将另外的治疗或诊断试剂并入药物组合物。或者或此外,药物组合物可与包含其它治疗或诊断试剂的其它组合物组合。
给药方法
可以使用任何合适的方法对患者给予所述化合物或药物组合物。给药方法的非限制性例子包括,在其它方法中,(a)通过口服途径给药,该给药包括以胶囊、片剂、颗粒剂、喷雾剂、糖浆剂或其它这类形式进行给药;(b)通过非口服途径给药,例如直肠、***、尿道内、眼内、鼻内或耳内,该给药包括作为水性混悬液、油性制剂等等或作为滴剂、喷雾剂、栓剂、药膏、软膏剂等等;(c)通过皮下、腹膜内、静脉内、肌内、皮内、眶内、囊内、脊柱内、胸骨内等等注射给药,包括输液泵输送;(d)局部(locally)给药,例如直接在肾脏区域或心脏区域中进行注射,例如通过储库型植入;以及(e)局部(topically)给药;当本领域技术人员认为使本发明的化合物与活组织接触是适当的时。
适合给药的药物组合物包括含有活性成分的组合物,其中所述活性成分的含量有效达到其预期效果。剂量中要求的本文公开药物组合物的治疗有效量将取决于给药途径、包括人在内的接受治疗的动物的类型、以及考虑中的特定动物的身体特征。可以调整剂量以达到期望的效果,但是这将取决于下列因素:体重、饮食、同时的药物治疗以及医学领域的技术人员认识到的其它因素。更具体地,治疗有效量指有效防止、减轻或改善疾病症状,或延长接受治疗个体的存活的化合物量。本领域技术人员有能力确定治疗有效量,特别是按照本文提供的详细公开。
正如本领域技术人员所显而易见的,用于体内给药的剂量和具体的给药方式将根据年龄、体重和接受治疗的哺乳动物种类、所使用的具体化合物、以及使用这些化合物的具体用途而变化。本领域技术人员使用常规的药理学方法可以完成有效剂量水平,即实现预期效果所必需的剂量水平的确定。通常,产物的人体临床应用从较低剂量水平开始,随着剂量水平的增加直至达到期望的效果。或者,采用已确定的药理学方法,能够使用可接受的体外研究来建立本方法鉴别的组合物的有用剂量和给药途径。
在非人类动物研究中,潜在产物的应用以较高剂量水平开始,随着剂量的减少直至不再实现期望的效果或不良副作用消失。根据预期效果和治疗指征,剂量范围可较宽泛。通常,剂量可为约10微克/公斤至100毫克/公斤体重,优选为约100微克/公斤至10毫克/公斤体重。或者,正如本领域技术人员所理解的,剂量可基于患者的表面积并按照其计算。
各医师可根据患者的状况选择本发明药物组合物的确切制剂、给药途径和剂量。(参见例如,Fingl等人,1975,“ThePharmacologicalBasisofTherapetutics”(治疗学的药理学基础),在此通过参考的方式并入其全部内容,特别参考第1章、第1页)。通常,对患者给药的组合物的剂量范围可以为约0.5至1000mg/kg患者体重。根据患者需要,所述剂量可以是单次的或者在一天或更多天期间两次或更多次给予。在对于至少一些条件已确立了化合物的人用剂量的情况下,本发明将使用那些相同的剂量,或剂量范围为约0.1%至500%的确定的人用剂量,更优选的剂量范围为25%至250%的确定的人用剂量。如果没有确定的人用剂量,如新发现的药物化合物的情况,可以从ED50或ID50值,或来自体外或体内研究的其它适当的值推断合适的人用剂量,如动物中的毒性研究和效能研究所定性的。
应当指出,根据毒性或器官功能障碍,主治医师将知道如何且何时终止、中断或调整给药。相反,如果临床反应不充分(排除毒性),则主治医生也将知道将治疗调整至更高水平。在所关注病症的治疗中给药剂量的大小将随着待治疗的疾病状态的严重程度和给药途径而变化。例如通过标准的预后评价方法可以部分评价所述疾病状态的严重程度。此外,所述剂量或可能的剂量频率也将根据个体患者的年龄、体重以及反应而变化。与上述讨论方案相当的方案可用于兽医学中。
虽然通过逐一的药物分析可以决定确切的剂量,但是在大多数情况下,关于剂量可以进行一些概括。成人患者的日给药方案,例如口服剂量范围为0.1mg至2000mg的各活性成分,优选为1mg至500mg,例如5至200mg。在其它实施方案中,使用的静脉内、皮下或肌内剂量为各活性成分0.01mg至100mg,优选为0.1mg至60mg,例如1至40mg。在给予药物可接受盐的情况下,剂量可按照游离碱计算。在一些实施方案中,每日给予所述组合物1至4次。或者,可通过连续的静脉输注给予本发明的组合物,各活性成分的剂量优选为高至每日1000mg。正如本领域技术人员所理解的,在某些情况中,为了有效且迅速地治疗特别迅速发展的疾病或传染,以超过、或远远超过上述优选的剂量范围的量给予本发明所述化合物是必要的。在一些实施方案中,在连续治疗期间给予所述化合物,例如一周或数周、或数月或数年。
可以个别地调整剂量和用药间隔以提供足以维持调整效果或最低有效浓度(MEC)的活性部分的血浆水平。每种化合物的MEC不同,但是可以从体外数据估算。达到MEC所需要的剂量将取决于个体特征和给药途径。然而,可以使用HPLC测定或生物测定来确定血浆浓度。
还可以使用MEC值确定用药间隔。应使用在10-90%的时间内、优选在30-90%的时间内、以及更优选在50-90%的时间内将血浆水平维持在MEC以上的给药方案给予组合物。
在局部给药或选择性吸收的情况下,药物的有效局部浓度可以与血浆浓度无关。
当然,给予的组合物的量取决于被治疗的个体,根据所述个体的体重、痛苦的严重性、给药方式以及开处方医师的判断。
可以使用已知的方法对本文公开的化合物的效能和毒性进行评估。例如,通过在体外测定对细胞系的毒性可以建立具体化合物或共享某些化学部分的该化合物子集的毒理学,所述细胞系例如哺乳动物细胞系,且优选人的细胞系。这类研究的结果经常可预测动物体内,如哺乳动物或更具体地人体内的毒性。或者,使用已知的方法可以测定具体化合物在诸如小鼠、大鼠、家兔或猴的动物模型中的毒性。可以使用几种公认的方法确立具体化合物的效能,例如体外方法、动物模型或人体临床试验。几乎对每一类疾病状态都存在着公认的体外模型,该疾病状态包括但不限于癌症、心血管疾病、以及多种免疫功能障碍。类似地,可以使用可接受的动物模型建立治疗这些疾病状态的化学物质的效能。当选择模型确定效能时,本领域所属技术人员可在本领域现状指导下选择适当的模型、剂量、给药途径以及方案。当然,人体临床试验也可以用于确定化合物在人体内的效能。
如果需要,可将所述组合物置于包装或分配装置中,该包装或分配装置可以包含一个或多个含有活性成分的单位剂型。所述包装例如可以包含金属或塑料箔,例如泡罩包装。所述包装或分配装置可带有给药说明书。所述包装或分配装置还可以带有与所述容器相关的注意事项,该注意事项是由管理药物生产、使用或销售的政府机构规定的,该注意事项反映了所述药物形式已经由该机构批准用于人类或兽类给药。这样的注意事项,例如,可以是由美国食品和药物管理局批准的用于处方药的标签,或者是批准的产品说明书。还可以在合适的容器中制备、放置包含组方在相容药物载体中的本发明化合物的组合物,并标记其用于指定的疾病状态的治疗。
实施例
实施例1—一般程序
细胞培养和试剂.从Dr.StevenRosen(NorthwesternUniversity,Chicago,IL)处得到Dex敏感性MM.1S和Dex抗性MM.1R人MM细胞系。参见Moalli,P.A.,Pillay,S.,Weiner,D.,Leikin,R.&Rosen,S.T.(1992)Blood79,213-22和Chauhan,D.,Catley,L.,Hideshima,T.,Li,G.,Leblanc,R.,Gupta,D.,Sattler,M.,Richardson,P.,Schlossman,R.L.,Podar,K.,Weller,E.,Munshi,N.&Anderson,K.C.(2002)Blood100,2187-94;在此通过参考的方式并入其全部内容。从Dr.WilliamDalton(MoffitCancerCenter,Tampa,FL)处得到RPMI-8226和多柔比星(Dox)抗性(Dox-40)细胞。从美国典型培养物保藏中心(Rockville,MD)得到U266和OPM2MM细胞系。从ATCC(Manassas,VA)购得人肿瘤细胞系DU145、HT-29、Jurkat、LoVo、MDA-MB-231、MIAPaCa-2、NCI-H292、OVCAR-3、PANC-1和PC-3。将MM细胞系培养在补充有10%热灭活胎牛血清(FBS)、100单位/毫升青霉素、100μg/m链霉素和2mML-谷氨酰胺的RPMI-1640培养基中。从复发的患者新鲜分离出MM细胞,所述患者在接受包括***(Dex)、美法仑、沙利度胺或硼替佐米的多次在先治疗后复发。通过使用CD138(粘结蛋白聚糖-1)微磁珠和自动MACS磁性细胞分选仪(MiltenyiBiotecInc.,Auburn,CA)的CD138正向选择法从患者骨髓样本中纯化MM细胞。参见Chauhan,D.,Catley,L.,Hideshima,T.,Li,G.,Leblanc,R.,Gupta,D.,Sattler,M.,Richardson,P.,Schlossman,R.L.,Podar,K.,Weller,E.,Munshi,N.&Anderson,K.C.(2002)Blood100,2187-94;在此通过参考的方式并入其全部内容。从ATCC得到的正常的人皮肤成纤维细胞CCD-27sk被培养在补充有10%热灭活FBS、100单位/毫升青霉素、100μg/m链霉素、4mML-谷氨酰胺以及1mM丙酮酸钠的DMEM中。使用不同浓度的式II化合物(X=Cl)(NereusPharmaceuticals,Inc,SanDiego,CA)、硼替佐米或Dex(SigmaChemicalCo,St.Louis,MO)处理细胞。
细胞存活率和凋亡测定.通过溴化3-(4,5-二甲基噻唑)-2-基)-2,5-二苯基四唑(MTT;ChemiconInternationalInc.,Temecula,CA)测定评估细胞存活率,根据生产商的说明书(RocheMolecularBiochemicals,Indianapolis,IN)以及如Chauhan,D.,Catley,L.,Hideshima,T.,Li,G.,Leblanc,R.,Gupta,D.,Sattler,M.,Richardson,P.,Schlossman,R.L.,Podar,K.,Weller,E.,Munshi,N.&Anderson,K.C.(2002)Blood100,2187-94中所述,在此通过参考的方式并入其全部内容。根据生产商说明书(RocheAppliedSciences,Indianapolis,IN)所述,使用CellDeathDetectionELISAplus定量细胞死亡。
实施例2—体外20S蛋白酶体活性测定
如Stein,R.L.,Melandri,F.&Dick,L.(1996)Biochemistry35,3899-908和Lightcap,E.S.,McCormack,T.A.,Pien,C.S.,Chau,V.,Adams,J.&Elliott,P.J.(2000)ClinChem46,673-83中所述,测量20S蛋白酶体活性的糜蛋白酶样活性,在此通过参考的方式包括其全部内容。从Biomol,PlymouthMeeting,PA获得纯化的人红细胞来源的20S蛋白酶体。分别使用Suc-LLVY-AMC,Z-LLE-AMC(BostonBiochem,Cambridge,MA)和Boc-LRR-AMC(BachemBioscience,KingofPrussia,PA)作为肽底物测定20S蛋白酶体的糜蛋白酶样、半胱天冬酶样以及胰蛋白酶样活性。使用FluoroskanAscent96孔自动酶标仪(ThermoElectron,Waltham,MA)测量切割肽底物的荧光。通过使用sigmoidal剂量响应、变斜率模型(slopemodel)的Prism(GraphPadSoftware)计算EC50值。EC50值被定义为在最大相对荧光的50%被抑制时的药物浓度。图1绘出的结果表明,虽然在不同的浓度下,但是式(II)化合物(X=Cl)抑制所有三种蛋白酶体活性。
实施例3—小鼠全血细胞中离体20S蛋白酶体活性的分析(单次静脉给
药或口服给药)
为了直接测定式(II)化合物(X=Cl)是否抑制体内蛋白酶体活性,将式(II)化合物(X=Cl)溶解在100%DMSO中并用5%聚乙二醇硬脂酸酯(HS15;聚乙二醇66012-羟基硬脂酸酯,BASF,Shreveport,LA)连续稀释,得到终浓度为2%DMSO。载体对照由2%DMSO和98%(5%HS15)组成。在BolderBioPATH,Inc.(Boulder,CO),用不同浓度的化合物以10mL/kg的体积、静脉或口服给药方式处理雄性Swiss-Webster小鼠(每组5只,体重20-25克)。一组动物未被处理以建立蛋白酶体活性的基线。在给予该化合物90分钟后,所述动物被麻醉,并通过心脏穿刺抽血。通过离心收集聚集的全血细胞,用PBS洗涤,并且在干冰上冷冻,用于确定离体蛋白酶体活性。使用肽底物suc-LLVY-AMC测定白细胞(WBC)溶胞产物中20S蛋白酶体的糜蛋白酶样活性。使用细胞溶胞产物的蛋白浓度标准化相对荧光单位(RFU)。图2显示了单个小鼠的20S蛋白酶体活性,横线表示平均活性。基线表示在从未处理小鼠制备的WBC溶胞产物中观察到的20S蛋白酶体活性。图2中描述的结果表明,式(II)化合物(X=Cl)以剂量依赖方式抑制白细胞中20S蛋白酶体的糜蛋白酶样活性。重要的是,这些结果证实该化合物口服有效且抑制体内蛋白酶体活性。
实施例4—MM细胞中被引发的蛋白酶体活性变化的测定(体外)
通过使用AdaY125Iahx3L3VS的竞争试验确定式(II)化合物(X=Cl)是否影响体外多发性骨髓瘤细胞中的蛋白酶体活性。在本测定中,AdaY(125I)Ahx3L3VS标记式(II)的化合物(X=Cl)未靶向的位点并通过放射自显影法可视化,而在放射自显影照片上无法看见式(II)的化合物(X=Cl)靶向的位点。将MM.1SMM细胞与式(II)化合物(X=Cl)(7nM)一起孵育30mins、1h、3h、或6h,用玻璃珠进行细胞溶解。在37°C下,将60μg蛋白质提取物与碘化蛋白酶体抑制剂AdaY125Iahx3L3VS一起孵育2h。然后通过在还原性样品缓冲液中煮沸使蛋白质变性、并在12.5%SDS-PAGE凝胶上分离、然后进行放射自显影。如图3中所见,与对照细胞相比,处理细胞中被AdaY(125I)Ahx3L3VS标记的蛋白酶体beta-5(β-5)亚基显著减少。鉴于β-5亚基介导糜蛋白酶样活性,这些结果表明式(II)化合物(X=Cl)与β-5亚基结合,从而抑制MM.1S细胞中的糜蛋白酶样活性。此外,用所述化合物(7nM)处理MM.1S细胞6h还降低β-2亚基(胰蛋白酶活性)和β-1亚基(半胱天冬酶样活性)的标记(数据未显示)。
实施例5—MM细胞中被引发的蛋白酶体活性变化的测定(体内)
通过使用丹酰基-Ahx3L3VS的竞争试验进行蛋白酶体活性的体内测定,丹酰基-Ahx3L3VS共价修饰所有的活性蛋白酶体亚基。该抑制剂包含丹酰基氨磺酰己酰基半抗原,其可以通过使用抗丹酰基部分的抗体的免疫印迹被可视化。用式(II)化合物(X=Cl)(7nM)处理MM.1S细胞30分钟、1h或3h,然后在37°C下,与5μM丹酰基-AhX3L3VS一起孵育1h。通过将细胞在NP-40溶解缓冲液(50mMTris-HClpH8.0,150mMNaCl,1%NP-40)中孵育30分钟使其溶解,然后离心5分钟以除去膜碎片、细胞核和细胞碎片。用12.5%SDS-PAGE凝胶分离60μg蛋白质提取物,然后使用多克隆抗单酰基多克隆Ab(1:7500,兔,MolecularProbes)和与辣根过氧化物酶偶联羊抗兔二级抗体(SouthernBiotech)进行免疫印迹分析。通过增强的化学发光产生印迹(WesternLightning,Perkin-Elmer)。如图4中所见,用式(II)的化合物(X=Cl)处理MM.1S细胞减少了丹酰基Ahx3L3VS对β-5亚基的标记。此外,该化合物还减少了丹酰基Ahx3L3VS对β-1和β-2亚基的标记,虽然是在较高的浓度下,分别为1nM和20nM。相反,即使用更高剂量的硼替佐米对MM.1S细胞进行处理,却不抑制β-2亚基(数据未显示)。综上所述,这些研究结果证明了式(II)化合物(X=Cl)抑制MM细胞中所有三种蛋白酶体活性的能力。
实施例6—对MM细胞存活率的影响
根据生产商的说明书(RocheMolecularBiochemicals,Indianapolis,IN)以及如Chauhan,D.,Catley,L.,Hideshima,T.,Li,G.,Leblanc,R.,Gupta,D.,Sattler,M.,Richardson,P.,Schlossman,R.L.,Podar,K.,Weller,E.,Munshi,N.&Anderson,K.C.(2002)Blood100,2187-94中所述,通过溴化3-(4,5-二甲基噻唑)-2-基)-2,5-二苯基四唑(MTT;ChemiconInternationalInc.,Temecula,CA)测定评估细胞存活率,在此通过参考的方式并入上述文献的全部内容。图5A显示用式(II)化合物(X=Cl)处理MM.1S(-■-)、Dex-抗性MM.1R(-□-)、RPMI-8226(-●-)、多柔比星抗性Dox-40(-◆-)、OPM2(-O-)和U266(-◇-)细胞24h后的细胞存活率。结果为来自三个独立实验的平均值±S.D(对于所有细胞系,P<0.005;n=3)。观察到在所有细胞系中细胞存活率的剂量依赖性显著降低(IC50范围7-24nM)。
还评估了纯化的患者MM细胞的细胞存活率。用式(II)化合物(X=Cl)(10nM)处理从9名MM复发患者新鲜分离的肿瘤细胞24h并分析其细胞凋亡,这些患者在接受包括Dex、硼替佐米和沙利度胺的多次在先治疗后复发。如图5B中所见,如通过DNA断裂分析所测量的,在这些细胞中观察到显著的细胞凋亡(P<0.005;n=2)。标示值为来自三份重复样品的平均值±标准差。重要的是,所检查的9名患者中的4名对硼替佐米治疗产生耐药性,而5名患者对沙利度胺和Dex治疗产生耐药性。这些数据表明1)式(II)化合物(X=Cl)在对常规治疗和硼替佐米治疗敏感和产生抗药性的MM细胞中诱导细胞凋亡;以及2)对于MM细胞,该化合物的IC50在纳摩尔浓度范围内。
实施例7—对骨髓基质细胞(BMSCs)存活率的影响
MM细胞主要位于骨髓微环境中且它们与BMSCs的相互作用诱导细胞因子的产生,该细胞因子介导MM细胞的生长以及对抗药物诱导的细胞凋亡。参见Anderson,K.C.(2003)Cancer97,793-801;在此通过参考的方式并入其全部内容。因此,测定式(II)化合物(X=Cl)对来自5名患者MM的BMSCs的影响。如图6中所见,正如由DNA断裂分析所证明的,在这些细胞中,用式(II)化合物(X=Cl)(20nM)处理BMSCs(患者#1-5)24h不诱导细胞凋亡。所示的阳性对照是该测定的内部对照。在相同的实验中还检查了来自5名MM患者中的2名患者的纯化MM细胞(CD138+)。结果为来自三份重复样品的平均值±标准差。所述化合物诱导纯化的患者MM细胞(CD138阳性)的细胞凋亡显著增加(10-12倍)。这些结果表明式(II)化合物(X=Cl)直接作用于MM细胞,而非BMSCs。
实施例8—重组人白介素6(rhIL-6)和重组人***-I
(rhIGF-I)抗细胞凋亡的效果
MM细胞与BMSCs的粘附诱导来自BMSCs的IL-6和IGF-I分泌,这不仅调节MM细胞的生长,还保护其免受化学治疗的伤害。参见Hardin,J.,MacLeod,S.,Grigorieva,I.,Chang,R.,Barlogie,B.,Xiao,H.&Epstein,J.(1994)Blood84,3063-70和Chauhan,D.,Kharbanda,S.,Ogata,A.,Urashima,M.,Teoh,G.,Robertson,M.,Kufe,D.W.&Anderson,K.C.(1997)Blood89,227-234;在此通过参考的方式并入其全部内容。因此,评价rhIL-6或rhIGF-I是否抑制由式(II)化合物(X=Cl)诱导的MM细胞的细胞凋亡。在存在或缺乏rhIL-6(10ng/ml)或rhIGF(50ng/ml)的条件下,用式(II)化合物(X=Cl)(7nM)或Dex(0.5μM)处理MM.1S细胞24h。在第24h采集细胞并通过MTT测定分析细胞存活率。如图7中所见,在用所述化合物单独处理后,细胞存活率的中值为47±2.3%;用所述化合物+rhIL-6处理后,其中值为51.2±3.2%(P=0.26,Wilcoxon检验)、以及用所述化合物+rhIGF-I处理后,其中值为50.3%±2.0%(P=0.28)。在用Dex处理后,存活率的中值为51±2.1%,以及对于Dex+rhIL-6,则其中值为92±5.5%(P=0.05,通过单侧Wilcoxon秩和检验确定)。结果为三次独立实验的平均值±标准差。这些研究结果表明无论IL-6或IGF-I均不阻滞式(II)化合物(X=Cl)的抗MM活性。相反并如其它研究所示,IL-6和IGF-I均阻滞Dex诱导的MM.1S细胞存活率的下降。参见Chauhan,D.,Hideshima,T.&Anderson,K.C.(2003)IntJHematol78,114-20和Mitsiades,C.S.,Mitsiades,N.,Poulaki,V.,Schlossman,R.,Akiyama,M.,Chauhan,D.,Hideshima,T.,Treon,S.P.,Munshi,N.C.,Richardson,P.G.&Anderson,K.C.(2002)Oncogene21,5673-83;在此通过参考的方式并入其全部内容。因此,数据表明式(II)化合物(X=Cl)克服IL-6和IGF-I对MM细胞的生长和保护效应,并且表明所述化合物和Dex对抗MM细胞的不同作用机理。IL-6的高血清水平促成临床化疗抗性和治疗失败,以及在存在IL-6或IGF-I的条件下,式(II)化合物(X=Cl)依然诱导MM细胞凋亡能力的报告表明,所述化合物可以克服晚期MM患者的抗药性。参见Kyrstsonis,M.C.,Dedoussis,G.,Baxevanis,C.,Stamatelou,M.&Maniatis,A.(1996)BrJHaematol92,420-422;在此通过参考的方式并入其全部内容。
实施例9-对细胞血管内皮生长因子(VEGF)诱导的MM迁移的影响
VEGF在骨髓微环境中升高并引发MM细胞的迁移、生长和血管生成。参见Podar,K.,Tai,Y.T.,Lin,B.K.,Narsimhan,R.P.,Sattler,M.,Kijima,T.,Salgia,R.,Gupta,D.,Chauhan,D.&Anderson,K.C.(2002)JBiolChem277,7875-81;在此通过参考的方式并入其全部内容。因此,评估式(II)化合物(X=Cl)是否改变VEGF诱导的MM细胞迁移。在存在或缺乏所述化合物(7nM或10nM)的条件下,研究VEGF诱导的迁移。如先前在Podar,K.,Tai,Y.T.,Davies,F.E.,Lentzsch,S.,Sattler,M.,Hideshima,T.,Lin,B.K.,Gupta,D.,Shima,Y.,Chauhan,D.,Mitsiades,C.,Raje,N.,Richardson,P.&Anderson,K.C.(2001)Blood98,428-35中所述地分析细胞迁移,在此通过参考的方式并入其全部内容。如图8中所示,式(II)化合物(X=Cl)显著(P<0.05)降低VEGF诱导的MM.1SMM细胞的迁移。这些研究结果表明所述化合物可以逆向调节MM细胞向骨髓的归巢以及它们向外周血的流出。
实施例10—对Bcl2介导的保护效应的影响
Bcl2使包括MM等癌细胞对常规治疗产生抗性。参见Cory,S.&Adams,J.M.(2002)NatRevCancer2,647-56和Gazitt,Y.,Fey,V.,Thomas,C.&Alvarez,R.(1998)IntJOncol13,397-405;在此通过参考的方式并入其全部内容。Bcl2能够适度地减轻硼替佐米诱导的细胞凋亡。因此,评估Bcl2在MM.1S细胞中的异位表达是否影响对式(II)化合物(X=Cl)的反应性。用Bcl2构建体稳定转染MM.1S细胞,并使用MTT测定分析其细胞存活率的变化。如图9所示,式(II)化合物(X=Cl)以剂量依赖方式显著降低了Bcl2转染的MM.1S细胞(P<0.005)的细胞存活率。虽然如此,与空载体转染的MM.1S细胞相比,在Bcl2转染的细胞中所述化合物诱导的细胞死亡减少了15±1.1%。结果为三次独立实验的平均值±标准差。这些研究结果表明所述化合物能够克服Bcl2介导的保护作用。
实施例11—在鼠科动物肿瘤模型中的体内评估
从Frederick肿瘤研究和发展中心(Frederick,MD)得到六周大的、三重免疫缺陷的beige-nude-xid(BNX)小鼠。所有的动物研究均根据Dana-Farber癌症研究所的动物伦理委员会批准的实验方案进行。每日观察小鼠的毒性症状。在使用异氟烷吸入剂的麻醉状态下完成最终取血,并通过CO2窒息将动物处死。为了测定式(II)化合物(X=Cl)的体内抗MM活性,用100μlRPMI-1640培养基中的3×107RPMI8226MM细胞对21只BNX小鼠的平坦部位进行皮下接种。当肿瘤变得可测量时,将小鼠分配到接受0.25mg/kg(n=7)、0.5mg/kg(n=7)的式(II)化合物(X=Cl)的实验组,或仅接受载体的对照组(n=7)。在发展出可测量的肿瘤后开始药物治疗。一周两次口服给予所述药物(0.25mg/kg或0.5mg/kg)。每隔一天用测径器进行垂直直径的系列测量以计算肿瘤体积,使用以下公式:4/24×(最短直径)2×(最长直径)。如果所述肿瘤≥2cm或坏死,则将动物处死。对于肿瘤生长研究,每组中使用7只小鼠。
如图10A-C中所见,用式(II)化合物(X=Cl),而不只用载体对带有肿瘤的小鼠的治疗显著抑制了MM肿瘤生长并延长了这些小鼠的存活。对照组的所有小鼠均发展出进行性肿瘤,而在70%的接受治疗的小鼠中,观察到肿瘤完全消退。图10B上图的小鼠接受口服剂量的单独载体,而下图的小鼠接受式(II)化合物(X=Cl)(0.25mg/kg)。图10B中的左图是生长在小鼠右侧腹的皮下浆细胞瘤的放大。评估从治疗的第一天直至死亡的存活;当小鼠的肿瘤直径到达2cm或变为濒死状态时,将小鼠处死(图10C)。此外,甚至在治疗12周后,也没有观察到神经学的行为变化。小鼠很好地耐受了给予化合物的浓度,没有明显的体重减轻。每周对未治疗组和治疗组的小鼠进行称重。图10D显示小鼠体重的平均变化。
第300天的分析显示在57%的式(II)化合物(X=Cl)治疗的小鼠中无肿瘤复发(图10C)。此外,在接种位点进行的组织学分析证实了与接受载体治疗的小鼠相比,接受式(II)化合物(X=Cl)治疗的小鼠中浆细胞消失(图10E,分别为右图和左图)。这些数据显示该化合物是口服有效的、抑制MM肿瘤体内生长并且延长存活。
实施例12—体内抗肿瘤活性的比较分析
为了比较式(II)化合物(X=Cl)和硼替佐米的体内活性,每周两次用式(II)化合物(X=Cl)(0.15mg/kg静脉注射)或硼替佐米(1.0mg/k静脉注射)对如上所述的小鼠模型进行治疗。两种试剂都显著减轻了肿瘤进展(p<0.01)并延长了存活(p=0.0137)(图10F和10G)。
实施例13—介导抗MM活性的机理
线粒体在逆境中的细胞凋亡诱导中具有关键作用。参见Bossy-Wetzel,E.&Green,D.R.(1999)MutatRes434,243-51和Chauhan,D.&Anderson,K.C.(2003)Apoptosis8,337-43;在此通过参考的方式并入其全部内容。用式(II)化合物(X=Cl)(7nM)处理未用血清培养的MM.1S细胞12h并与CMXRos一起孵育20分钟;在37°C下,用在磷酸盐缓冲盐水(PBS)中的亲脂阳离子染料CMXRos(MitotrackerRed)(MolecularProbes,Eugene,OR)染色20分钟;并且通过流式细胞术测定分析Δψm(线粒体膜电位)的变化。通过用膜可渗透染料二氢乙锭(HE)对细胞染色15分钟测量超氧化物(O2 -)的产生。超氧阴离子氧化HE得到荧光的乙锭,使得能够通过流式细胞术进行分析。
如图11A和11B中所见,由CMXRos阴性细胞(P<0.005,n=2)的数目增加所证明,式(II)化合物(X=Cl)降低Δψm,并引发MM.1S细胞中的O2 -产生。结果为两次独立实验的平均值±标准差。Δψm的改变与线粒体蛋白cyto-c和Smac向胞浆中的释放相关,由此引发半胱天冬酶9和半胱天冬酶3。参见Du,C.,Fang,M.,Li,Y.,Li,L.&Wang,X.(2000)Cell102,33-42和Liu,X.,NaekyungKim,C.,Yang,J.,Jemmerson,R.&Wang,X.(1996)Cell86,147-157;在此通过参考的方式并入其全部内容。
如图11C中所示,式(II)化合物(X=Cl)对MM.1S细胞的处理引发了线粒体cyto-c(左上图)和smac(右上图)的减少,以及这些蛋白在胞浆部分中的同时增加(分别位于中左图和中右图)。用抗Hsp60(左下图)和抗微管蛋白(右下图)Abs再次探针检测(reprobe)免疫印迹证实了线粒体提取物的纯度和等量的蛋白加样。线粒体凋亡蛋白cyto-c和Smac/DIABLO的释放诱导半胱天冬酶9和半胱天冬酶3的活化。用式(II)化合物(X=Cl)(7nM)处理MM.1S细胞24h并收集;通过12.5%SDS-PAGE分离线粒体和胞浆的蛋白部分,并且通过使用抗cyto-c(上图)或抗Smac(中图)Abs的免疫印迹进行分析。作为等量蛋白加样和线粒体部分纯度的对照,还分别用抗微管蛋白(右下图)和抗Hsp60Abs(左下图)再次探针检测过滤器。印迹是三个独立实验的代表。
用式(II)化合物(X=Cl)(7nM)处理MM.1S细胞24h并收集;通过12.5%SDS-PAGE分离胞浆蛋白,并且通过使用抗半胱天冬酶8Abs和抗半胱天冬酶9Abs的免疫印迹进行分析。如图11D中所见,用式(II)化合物(X=Cl)处理MM.1S细胞诱导半胱天冬酶9的蛋白水解切割。此外,所述化合物还活化半胱天冬酶8(图11E)。已知半胱天冬酶9(线粒体依赖的)和半胱天冬酶8(非线粒体依赖的)都被蛋白水解切割并活化共同的下游效应子半胱天冬酶3,导致PARP切割。参见Miller,L.K.(1999)TrendsCellBiol9,323-8;在此通过参考的方式并入其全部内容。因此,用式(II)化合物(X=Cl)(7nM)处理MM.1S或MM.1RMM细胞24h并通过PARP和半胱天冬酶3切割分析评估其细胞凋亡。总蛋白溶胞产物经过SDS-PAGE分析。用抗PARP(上图)或抗半胱天冬酶3(下图)Abs进行所述溶胞产物的免疫印迹分析。“FL”表示“全长”并且“CF”表示切割片断。该数据进一步显示式(II)化合物(X=Cl)引发半胱天冬酶3和PARP切割(图11F)。
使用细胞色素C,Smac,半胱天冬酶8、半胱天冬酶9或半胱天冬酶3的抗体(CellSignaling,Beverly,MA),微管蛋白的抗体(Sigma,St.Louis,MO),PARP、Hsp60或Bax的抗体(BDBiosciencePharmingen,SanDiego,CA)进行免疫印迹分析。通过增强的化学发光显影印迹(ECL;Amersham,ArlingtonHeights,IL)。
实施例14—与硼替佐米相比MM细胞凋亡的机理不同
在存在或缺乏半胱天冬酶9抑制剂(LEHD-FMK)、半胱天冬酶8抑制剂(IETD-fmk)或半胱天冬酶3抑制剂(Z-Val-Ala-Asp-氟甲基酮,z-VAD-fmk)的条件下,用式(II)化合物(X=Cl)或硼替佐米处理MM.1S细胞。如图12A所示,半胱天冬酶3的抑制明显消除了式(II)化合物(X=Cl)和硼替佐米诱导的细胞凋亡。结果为四次独立实验的平均值±标准差(P<0.004)。半胱天冬酶8的阻滞导致由式(II)化合物(X=Cl)(P<0.005,n=4)引发的细胞死亡显著减少,而半胱天冬酶9的抑制仅中度地阻滞了由所述化合物引发的MM.1S细胞存活率的降低。相反,在存在半胱天冬酶8或半胱天冬酶9抑制剂(P<0.005)的条件下,硼替佐米诱导的MM.1S细胞存活率的减少被同等地阻滞。综上,这些数据表明在硼替佐米引发细胞死亡期间,半胱天冬酶8和半胱天冬酶9的活化同等地起作用,而由式(II)化合物(X=Cl)引发的细胞凋亡主要通过半胱天冬酶8的信号传导途径进行。
通过使用显性负调节(DN)方案的遗传研究证实了这些生物化学数据。还根据生产商的说明书(AmaxaBiosystems,Germany),使用CelllineNucleofectokitV瞬时转染了MM.1S细胞,转染中使用单独载体、DN-半胱天冬酶8、DN-半胱天冬酶9、或DN-FADD以及与仅含有绿色荧光蛋白(GFP)的载体共转染。转染后,通过流式细胞术选择GFP阳性细胞,用式(II)化合物(X=Cl)或硼替佐米处理,并且分析其存活率。与用DN-半胱天冬酶9转染的细胞相比,用式(II)化合物(X=Cl)(IC50,7nM)处理DN-半胱天冬酶8转染的MM细胞明显提高了这些细胞的存活率(图12B)。相反,用硼替佐米(IC50,5nM)处理DN-半胱天冬酶8或DN-半胱天冬酶9转染的MM.1S细胞将存活率提高到了相似的程度。在这些细胞中(抗FasMoAb),通过用已知的半胱天冬酶9诱导物(Dex)和半胱天冬酶8诱导物处理MM.1S细胞证实了DN半胱天冬酶8和DN-半胱天冬酶9的功能特异性(Chauhanetal.,1997)(图12C)。这些数据表明(1)式(II)化合物(X=Cl)诱导的MM细胞凋亡主要由半胱天冬酶8介导;以及(2)硼替佐米诱导的细胞凋亡需要半胱天冬酶8和半胱天冬酶9的活化。
接下来测定导致半胱天冬酶8活化的上游信号传导途径的抑制是否影响对式(II)化合物(X=Cl)或硼替佐米的反应。Fas相关死亡结构域(FADD)蛋白是死亡诱导信号复合体(DISCs)的重要部分,一旦诸如Fas等TNF受体家族成员衔接(engagement),该复合体就组装,导致半胱天冬酶8前体的蛋白水解加工和自体活化。由于式(II)化合物(X=Cl)和硼替佐米都引发半胱天冬酶8的活化,所以使用DN-FADD评估在该过程中FADD在MM细胞中的作用。与空载体转染的MM.1S细胞相比,用DN-FADD阻滞FADD显著降低了式(II)化合物(X=Cl)诱导的细胞毒性(与在载体转染的细胞中42%±2.0%的存活细胞相比,在DN-FADD转染的细胞中具有76%±5.1%的存活细胞;p<0.05)(图12D)。DN-FADD减少了式(II)化合物(X=Cl)诱导的半胱天冬酶8的活化;然而,仍发现最小限度的半胱天冬酶8的活化(数据未显示),这可能是由FADD之外的半胱天冬酶8的上游活化物造成的。重要的是,与载体转染的细胞相比,用硼替佐米处理DN-FADD转染的MM.1S细胞导致存活率仅增长了16%(与在载体转染的细胞中39%±2.4%的存活细胞相比,在DN-FADD转染的细胞中具有55%±4.1%的存活细胞;p<0.05)(图12D)。结合半胱天冬酶8和半胱天冬酶9抑制的研究,这些数据表明式(II)化合物(X=Cl)比硼替佐米更依赖FADD-半胱天冬酶8信号传导轴,进一步证实式(II)化合物(X=Cl)与硼替佐米在MM细胞中不同的作用机理。
之前的研究已确立Bax诱导线粒体细胞凋亡的途径。参见Wei,M.C.,Zong,W.X.,Cheng,E.H.,Lindsten,T.,Panoutsakopoulou,V.,Ross,A.J.,Roth,K.A.,MacGregor,G.R.,Thompson,C.B.&Korsmeyer,S.J.(2001)Science292,727-30和Lei,K.,Nimnual,A.,Zong,W.X.,Kennedy,N.J.,Flavell,R.A.,Thompson,C.B.,Bar-Sagi,D.&Davis,R.J.(2002)MolCellBiol22,4929-42;在此通过参考的方式并入其全部内容。因此,评估由式(II)化合物(X=Cl)诱导的MM细胞凋亡是否与Bax的变化相关。用式(II)化合物(X=Cl)或硼替佐米处理MM.1SMM细胞,并且对线粒体蛋白提取物进行使用抗Bax或抗Hsp60Abs的免疫印迹分析。如图12E中所见,如果式(II)化合物(X=Cl)诱导线粒体中Bax水平的任何增加,其增加量也很少。印迹是三个独立的实验的代表。重要的是,硼替佐米引发Bax在线粒体中的显著聚积。
用式(II)化合物(X=Cl)或硼替佐米处理带有野生型Bax或Bax敲除的小鼠胚胎成纤维细胞(MEFs)48h,并通过MTT测定分析其细胞存活率。如图12F中所见,式(II)化合物(X=Cl)在Bax(WT)和Bax(敲除)中均减少了存活率,而Bax的缺失导致对硼替佐米的显著抗性。结果为三次独立实验的平均值±标准差(P<0.05)。这些数据显示在由式(II)化合物(X=Cl)和硼替佐米诱导的细胞凋亡期间对Bax的不同需要并且表明这些试剂的不同作用机理。
实施例15—与硼替佐米相比,对正常淋巴细胞的不同影响
在患者中,硼替佐米治疗伴随着毒性。因此,比较式(II)化合物(X=Cl)和硼替佐米对正常细胞的影响。用不同浓度的式(II)化合物(X=Cl)(0-20nM)和硼替佐米(0-20nM)处理来自五名健康供者的淋巴细胞72h,并且通过MTT测定分析细胞毒性。如图13中所见,即使在较高的剂量(20nM)时,式(II)化合物(X=Cl)也不显著降低正常淋巴细胞的存活率(P=0.27,来自J-T趋势检验)。结果为三次独立实验的平均值±标准差。相反,即使在6-10nM的较低浓度下,硼替佐米也显著降低淋巴细胞的存活率。显而易见,患者MM细胞达到IC50时的式(II)化合物(X=Cl)的浓度对正常淋巴细胞没有影响,而硼替佐米对MM细胞的IC50引发正常淋巴细胞的存活率降低50%。综上,这些数据表明式(II)化合物(X=Cl)具有选择性抗MM活性;并且特别地,与硼替佐米相比,它对正常细胞的毒性较小。
还研究式(II)化合物(X=Cl)或硼替佐米是否改变正常淋巴细胞和皮肤成纤维细胞中的蛋白酶体活性。在这些细胞中,式(II)化合物(X=Cl)和硼替佐米都显著抑制蛋白酶体活性:20nM的式(II)化合物(X=Cl)或硼替佐米分别引发对糜蛋白酶样蛋白酶体活性的99%或59±11%的抑制(数据未显示)。因此,虽然20nM的式(II)化合物(X=Cl)不在正常淋巴细胞中引发显著的细胞毒性,然而它降低了这些细胞中的糜蛋白酶样蛋白酶体活性。类似地,使用IC50的式(II)化合物(X=Cl)(317nM)或硼替佐米(15nM)处理正常CCD-27sk成纤维细胞也抑制了蛋白酶体活性(数据未显示)。
实施例16-与硼替佐米相比,对过量表达Bcl-2的MM细胞的不同影
响
在细胞凋亡期间,Bax中和Bcl-2的抗细胞凋亡功能,由此辅助cyto-c的释放和半胱天冬酶9的活化。Bcl-2还使包括MM等癌细胞产生耐药性,并提供部分保护对抗硼替佐米诱导的杀伤。因此,评估Bcl-2在MM.1S细胞中的异位表达是否影响式(II化合物(X=Cl)或硼替佐米在MM细胞中引发细胞毒性和线粒体后细胞凋亡信号传导的能力。Bcl-2的过量表达促使用两种试剂处理的细胞的存活率轻度提高:对于式(II)化合物(X=Cl),在Bcl-2转染的细胞中,存活率为50%±2.6%,而在载体转染的细胞中,存活率为39%±1.5%(p<0.05);对于于硼替佐米,在Bcl-2转染的细胞中,存活率为61%±2.9%,而在载体转染的细胞中,存活率为40%±2.1%(p<0.05)(图14A)。Bcl-2转染子响应硼替佐米的提高的存活率(21%)比Bcl-2转染子响应式(II)化合物(X=Cl)的提高的存活率(11%)高(p<0.04;n=3)(图14A)。此外,硼替佐米在对照载体转染的细胞中引发显著的半胱天冬酶9切割,该切割在Bcl-2转染的细胞中明显减弱(由光密度法测定,减少到原来的1/3);相反,Bcl-2的过量表达最小程度地影响式(II)化合物(X=Cl)诱导的半胱天冬酶9切割(图14B)。结合存活率的结果,这些研究结果表明与式(II)化合物(X=Cl)相比,Bcl-2提供了对抗硼替佐米的更多保护。
实施例17—联合治疗
如图15中所见,用式(II)化合物(X=Cl)和硼替佐米联合处理MM.1S或MM.1RMM细胞24h诱导了协同的生长抑制。结果为三次独立实验的平均值±标准差(P<0.005)。通过使用“CalcuSyn”软件程序(Biosoft,Ferguson,MOandCambridge,UK)的等效应图分析抗MM试剂式(II)化合物(X=Cl)和硼替佐米间的相互作用。从细胞存活率测定(MTT)中得到的数据被表示为经药物处理的细胞中生长受影响的细胞对未经处理的细胞中生长受影响的细胞的分数(FA)。CalcuSyn程序基于根据如下等式的Chou-Talalay方法:“CI=(D)1/(Dx)1+(D)2/(Dx)2+(D)1(D)2/(Dx)1(Dx)2”,其中(D)1和(D)2为当联合使用时具有x效果的药物1和药物2的剂量;且(Dx)1和(Dx)2为当单独使用时具有相同的x效果的药物1和药物2的剂量。当CI=1时,该等式代表守恒等效应图并表明加合效应。CI值<1.0表明协同作用。得到硼替佐米+NPI-0052的联合指数(CI)<1.0,表明协同作用。此外,最大的抗MM活性是在同时给予时观察到的,而不是其它治疗方案。低剂量的联合的式(II)化合物(X=Cl)和硼替佐米不显著影响正常PBMNCs的存活率(数据未显示)。因此使用硼替佐米和式(II)化合物(X=Cl)的联合治疗可以:1)使得能够使用每种试剂的亚毒性浓度;2)延迟或防止耐药性的产生;以及3)允许逐步升高这些试剂的协同剂量以提高细胞凋亡的阀值。
Claims (8)
1.式(I)化合物或其药物可接受盐在制备***性疾病的药物中的用途:
其中X选自氟、氯、溴或碘,以及
其中所述肿瘤性疾病对硼替佐米有耐药性。
2.根据权利要求1所述的用途,其中X是氯。
3.根据权利要求1所述的用途,其中所述式(I)化合物具有式(II)的结构:
4.根据权利要求1所述的用途,其中所述肿瘤性疾病是癌症。
5.根据权利要求4所述的用途,其中所述癌症选自乳腺癌、肉瘤、白血病、卵巢癌、输尿管癌、膀胱癌、***癌、结肠癌、直肠癌、胃癌、肺癌、淋巴瘤、多发性骨髓瘤、胰腺癌、肝癌、肾癌、内分泌癌、皮肤癌、黑素瘤、血管瘤以及脑或中枢神经***癌症。
6.根据权利要求4所述的用途,其中所述癌症选自多发性骨髓瘤、结肠直肠癌、***癌、乳腺癌、非小细胞肺癌以及卵巢癌或黑素瘤。
7.根据权利要求6所述的用途,其中所述癌症是多发性骨髓瘤。
8.根据权利要求1所述的用途,其中所述药物是对人给药的。
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