CN101222938A - 组蛋白脱乙酰酶抑制剂与nsaid组合用于治疗癌症和/或炎性疾病的用途 - Google Patents
组蛋白脱乙酰酶抑制剂与nsaid组合用于治疗癌症和/或炎性疾病的用途 Download PDFInfo
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Abstract
本发明涉及化合物作为具有组蛋白脱乙酰酶活性抑制剂的的医学用途,其在与已知为NSAID(非甾体抗炎药物)的化合物组合时在下述症状中导致增强的有益疗效。这些症状包括癌症、癌症诱病症状、炎性和代谢性疾病。而且,本发明包括生产用于治疗本文所提及的疾病的临床使用药物,以两种独立药物的形式分别施用该化合物或者以单一应用单元中含有两种药物的施用方式施用该化合物。
Description
技术领域
本发明涉及作为具有组蛋白脱乙酰酶活性的酶的抑制剂的化合物的医学用途,其在与已知为NSAID(非甾体抗炎药物)的化合物组合时在下述症状中导致增强的有益疗效。这些症状包括癌症、癌症诱因病症、炎性和代谢性疾病。而且,本发明包括生产用于治疗本文所提及的疾病的临床使用药物,以两种独立药物的形式分别施用该化合物或者以单一应用单元中含有两种药物的施用方式施用该化合物。
背景技术
染色质调控和疾病
染色质的局部重建是基因转录活化中的关键步骤。DNA的核小体包装必须发生动力学改变从而使转录蛋白质与DNA模板相接触。影响染色质重建和基因转录的最重要的机制之一是组蛋白和其它细胞蛋白质通过乙酰化以及随后的染色质结构改变而进行的翻译后修饰(Davie,1998,CurrOpin Genet Dev 8,173-8;Kouzarides,1999,Curr Opin Genet Dev 9,40-8;Strahl and Allis,2000,Nature 403,41-4)。在组蛋白高度乙酰化的情形中,对DNA的静电引力以及疏水乙酰基引起的空间位阻的变化使得组蛋白与DNA的相互作用不稳定。结果,组蛋白的乙酰化破坏了核小体并使得DNA接近转录机器。除去该乙酰基使得组蛋白与DNA和邻近的核小体结合更加紧密,并因此维持了转录抑制的染色质结构。乙酰化是通过一系列具有组蛋白乙酰转移酶(HAT)活性的酶介导的。相反,乙酰基通过特定的组蛋白脱乙酰酶(HDAC)而除去。这些机制的破坏导致转录失调并且可以导致多种人类疾病,包括自身免疫病、炎性疾病或者过度增生性疾病(包括致瘤性转化和肿瘤进展)。
另外,其它分子如转录因子依赖其乙酰化状态改变它们的活性和稳定性。例如PML-RAR(与急性早幼粒细胞白血病(APL)相关的融合蛋白质)通过介导p53的脱乙酰化和降解来抑制p53,因此使得APL母细胞避开了p53依赖的癌症监视途径。造血前体细胞中PML-RAR的表达导致p53介导的转录活化的抑制,并且保护免受基因毒性应激(X-射线,氧化应激)诱导的p53依赖性凋亡。然而,p53的功能在HDAC抑制剂存在时得以重建,暗示HDAC通过PML-RAR主动地募集p53是抑制p53的机制(Insinga et al.,February 2004,EMBO Journal,1-11)。因此,除了组蛋白以外的蛋白质的乙酰化如p53的乙酰化在HDAC抑制剂的抗肿瘤活性中扮演了关键的角色。
细胞核受体和组蛋白脱乙酰酶
细胞核激素受体是配体依赖的转录因子,其通过对基因表达的正调控和负调控从而控制发育和内环境稳定。这些调控过程中的缺陷成为许多疾病的原因并且在癌症的发展中发挥重要作用。许多细胞核受体,包括T3R、RAR和PPAR,可以与协阻抑物如N-CoR和SMRT在配体不存在时相互作用,并因此抑制转录。并且,还已报导N-CoR与拮抗物占据的孕酮和雌激素受体相互作用。最有意义的是,已显示N-CoR和SMRT以大的蛋白质复合体存在,其还包含mSin3蛋白和组蛋白脱乙酰酶(Pazin and Kadonaga,1997;Cell 89,325-8)。因此,配体诱导的从抑制向活化的细胞核受体开启反映出具有拮抗的酶活性的协阻抑物和辅激活物复合体的交换。
通过细胞核受体调控基因
包含HDAC活性的这些协阻抑物复合体不但通过细胞核受体介导抑制作用,还与另外的转录因子包括Mad-1、BCL-6和ETO相互作用。许多这样的蛋白质在细胞增殖和分化的病症中起到关键的作用(Pazin andKadonaga,1997,Cell 89,325-8;Huynh and Bardwell,1998,Oncogene 17,2473-84;Wang,J.et al.,1998,Proc Natl Acad Sci U S A 95,10860-5)。例如,T3R最初基于其与病毒癌基因v-erbA的同源性而鉴定出来,与野生型受体相反的是,其不与配体结合并作为转录的组成性阻抑物。而且,RAR中的突变与许多人类癌症有关,尤其是急性早幼粒细胞白血病(APL)和肝细胞癌。在APL患者中,染色体易位形成的RAR融合蛋白包括早幼粒细胞性白血病蛋白(PML)或早幼粒细胞锌指蛋白(PLZF)。尽管两种融合蛋白质均可与协阻抑物复合体的组分相互作用,但加入视黄酸使该协阻抑物复合体从PML-RAR解离下来,而PLZF-RAR则组成性地相互作用。这些发现解释了为什么PML-RAR APL患者在视黄酸治疗后得到完全好转,而PLZF-RAR APL患者的应答则很弱(Grignani et al.,1998,Nature391,815-8;Guidez et al.,1998,Blood 91,2634-42;He et al.,1998,NatGenet 18,126-35;Lin et al.,1998,Nature 391,811-4)。
最近,用HDAC抑制剂丁酸苯酯治疗曾用视黄酸治疗后多次复发的PML-RAR患者,结果其白血病得到完全好转(Warrell et al.,1998,J.Natl.Cancer Inst.90,1621-1625)。
组蛋白脱乙酰酶的蛋白家族
募集组蛋白乙酰转移酶(HAT)和组蛋白脱乙酰酶(HDAC)被视为动态调节许多在细胞增殖和分化中起重要作用的基因的关键要素。组蛋白H3和H4的N端尾部的高度乙酰化与基因活化有关,而脱乙酰化可介导转录抑制。因此,许多疾病与影响转录因子的突变引起的基因表达变化有关。在这方面,由白血病融合蛋白质如PML-RAR、PLZF-RAR、AML-ETO和Stat5-RAR引起的异常抑制作为原型的实例。在所有这些情形中,染色体易位将转录激活剂转换为阻抑物,所述阻抑物通过募集HDAC组成性地抑制对造血分化具有重要性的靶基因。可能类似的事件还可以引起许多其它类型癌症的发病。越来越多的证据表明,自身免疫病、炎性疾病或者过度增生性病症也是如此。
哺乳动物组蛋白脱乙酰酶可分为三个亚类(Gray and Ekstrm,2001)。HDAC 1、2、3和8组成第I类,其与酵母RPD3蛋白同源。HDAC 4、5、6、7、9和10与酵母Hda 1蛋白有关并形成第II类。最近,已鉴定出几个酵母Sir2蛋白的哺乳动物同源物,其形成脱乙酰酶的第三类,并其且是NAD依赖性的。另外,HDAC11已归类为具有第II类HDAC的结构特征的第I类组蛋白脱乙酰酶。所有这些HDAC似乎作为多血质的多蛋白复合体的亚单位存在于细胞中。特别地,第I类和第II类HDAC已显示出与转录协阻抑物mSin3、N-CoR和SMRT的相互作用,其作为将HDAC募集至转录因子所需的桥连因子。
使用HDAC抑制剂的治疗
最近已开始用HDAC抑制原理对癌症患者的全身性临床治疗进行另外的临床研究。迄今,已完成了用密切相关的丁酸衍生物Pivanex(TitanPharmaceuticals)作为单药治疗的II期临床试验,表明其在III/IV期非小细胞肺癌中的活性(Keer et al.,2002,ASCO,Abstract No.1253)。已鉴定出更多的HDAC抑制剂,其中NVP-LAQ824(Novartis)和SAHA(AtonPharma Inc.)是在II期临床试验中检测的异羟肟酸结构类别的成员(Markset al.,2001,Nature Reviews Cancer 1,194-202)。另一类包括环状四肽,如酯肽(FR901228-Fujisawa),其成功地用于治疗T细胞淋巴瘤的II期试验中(Piekarz et al.,2001,Blood 98,2865-8)。另外,MS-27-275(MitsuiPharmaceuticals)(与苯甲酰胺类相关的化合物)正在治疗患有恶性血液病患者的I期试验中进行试验。
HDAC抑制剂丙戊酸
丙戊酸(VPA;2-丙基-戊酸)依赖不同的分子作用机制具有多种生物活性:
-VPA是抗癫痫药物。
-VPA是致畸的。在怀孕期间用作抗癫痫药物时,VPA能诱导小部分新生儿的出生缺陷(神经管闭合缺陷及其它畸形)。在小鼠中,VPA在适当给药的大多数小鼠胚胎中是致畸的。
-VPA活化细胞核激素受体(PPARδ)。几种另外的转录因子也被去阻遏,而一些因子未被显著地去阻遏(糖皮质激素受体,PPARα)。
-VPA有时导致肝脏毒性,这可能取决于与辅酶A形成的不充分代谢的酯。
-VPA是HDAC抑制剂。
-VPA诱导HDAC-2的蛋白酶体降解。
使用VPA衍生物能够确定不同的活性是通过不同的分子作用机制介导的。致畸性和抗癫痫活性遵循不同的作用模式,这是因为可以分离或优选致畸或优选抗癫痫的化合物(Nau et al.,1991,Pharmacol.Toxicol.69,310-321)。发现PPARδ的活化确实与致畸性有关(Lampen et al.,1999,Toxicol.Appl.Pharmacol.160,238-249),表明PPARδ活化和致畸性都需要相同的VPA分子活性。同样,如Lampen等,1999所提出的,F9细胞的分化密切地与PPARδ活化和致畸性有关,并且通过分析分化标记进行了证明(Werling et al.,2001,Mol.Pharmacol.59,1269-1276)。表明,PPARδ活化由VPA及其衍生物的HDAC抑制活性所导致(WO 02/07722A2;WO03/024442A2)。另外,表明已建立的HDAC抑制剂TSA活化PPARδ并且诱导与VPA相同类型的F9细胞分化。从这些结果可以推论,不仅PPARδ的活化由HDAC抑制导致,而且F9细胞分化的诱导、以及VPA或VPA衍生物的致畸性也由HDAC抑制导致。
VPA促进HDAC-2的选择性蛋白酶体降解的活性与其作为HDAC的酶活性抑制剂的活性是不同的,这是因为充分表征的HDAC抑制剂Trichostatin A和MS-27-275均不影响HDAC-2的降解(Krmer et al,2003,22(13),3411-3420)。
抗癫痫和镇静活性遵循不同的结构活性关系并因此明显依赖VPA非HDAC抑制的主要活性。对肝脏毒性的机制了解较少,并且它是否与VPA-CoA酯的形成有关是未知的。然而,HDAC抑制似乎不需要CoA酯的形成。
丙戊酸作为组蛋白脱乙酰酶的抑制剂
已开发VPA作为用于治疗癫痫的药物。因此,为了实现其抗癫痫的作用,以全身、口服或静脉内的方式使用VPA从而使该药物穿过血脑屏障到达脑组织中的癫痫靶区域。而且,当用于治疗许多不同类型人类癌症时,VPA作为单一药剂或者与全部的多种其它抗肿瘤治疗组合已显示出具有有益的效果,其它抗肿瘤治疗组合通过抑制具有HDAC活性的特定组的酶并因此诱导分化和/或凋亡而分别基于显著不同的作用方式(WO 02/07722 A2,EP 1170008;WO 03/024442 A2,EP 1293205 A1)。为了治疗或预防恶性疾病、自身免疫病或者其它炎性或过度增生性疾病,还可以全身、口服或静脉内的方式施用VPA。另外,表明,VPA有效地透过人皮肤,因此当用于局部治疗或预防自身免疫病、炎性或者过度增生性人类皮肤疾病(例如银屑病和人类皮肤癌)时可以在皮肤上局部施用并表现有益的效果(EP申请No.03014278.0)。
非甾体抗炎药物(NSAID)及其用途
非甾体抗炎药物(NSAID)是环加氧酶的抑制剂,环加氧酶是花生四烯酸代谢为前列腺素和血栓烷的关键酶。最近发现环加氧酶包含两个亚型:COX-1和COX-2。COX-1组成性地表达于引起生理功能的大多数组织中。其通过NSAID的抑制与这些药剂的常见毒性(包括胃溃疡和出血)有关。COX-2是诱导酶,也就是说在炎症位点处以及某些肿瘤中对细胞因子和生长因子产生应答而诱导,所述肿瘤包括而不限于结肠腺瘤、结肠和结肠直肠癌、乳腺肿瘤、肺肿瘤和前列腺肿瘤。
COX抑制剂正用于治疗多种疾病和症状,包括疼痛、炎性病症如类风湿性关节炎,而且用于抑制肠息肉生长,例如在患有家族性腺瘤性息肉病(FAP)的患者中。流行病学的研究已显示,已长期使用NSAID的人与预期相比具有较低的患结肠直肠腺瘤和癌的比率。
广泛使用的NSAID种类有阿司匹林、水杨酸甲酯、双氯酚酸钠[Voltaren,Nu-Diclo,Cataflam]、甲氯灭酸钠[Meclomen]、甲芬那酸[Ponstel]、美洛昔康[Mobic]、萘丁美酮[Relafen]、萘普生[Aleve,Anaprox,Naprosyn,Naprelan,Naxen,NoVo-Naprox,Synflex]、奥沙普嗪[Daypro]、保泰松[Cotylbutazone,Alka Butazolidine]、吡罗昔康[Feldene,Nu-Pirox]、舒林酸[Clinoril,Novo-Sundac]、替诺昔康[Mobiflex]、二氟尼柳[Dolobid]、噻洛芬酸[Albert Tiafen,Surgam]、托美汀[Tolectin]、依托度酸[Lodine]、苯氧苯丙酸钙[Nalfon]、弗洛非宁[Idarac]、氟比洛芬[Ansaid,Froben]、布洛芬[Advil,Dolgesic,Excedrin,Genpril,Haltran,Ibifon,Ibren,Ibu,Ibuprin,Ibuprohm,Medipren,Midol,Motrin,Nuprin,Pamprin,Q-Profen,Rufen,Trendar]、吲哚美辛[Indocin,Indocid]、酮基布洛芬[Orudis,Oruvail,Actron,Rhodis]、尼美舒利[Aulin]。许多NSAID(名为coxib类)选择性地抑制Cox-2酶活性:该亚类包括塞来昔布[Celebrex,Celebra,Onsenal]、洛芬昔布[Vioxx,Vioxx Dolor,Ceoxx]、伐地昔布[Bextra,Valdyn]、帕瑞昔布[Dynastat,Rayzon]、罗美昔布[Prexige]、依托考昔[Arcoxia]、德拉昔布、替马考昔、罗贝考昔、非罗考昔和西米考昔。
然而,安全委员会对用于类风湿性关节炎和骨关节炎疼痛的最常见处方药物Celebrex(塞来昔布;Pfizer Inc.)的两个五年药物试验之一进行监视,在2004年12月,其从初步数据发现服用高剂量该药物的患者具有心脏问题或中风的风险稍有增加。这些发现导致研究的终止。
先前,Merck&Co.也在临床试验获得类似副作用之后停止出售其COX-2抑制剂药物Vioxx。
如上所述,COX酶调控前列腺素的水平,前列腺素调节机体中多种重要功能。例如,一种类型的前列腺素有助于将称为胃黏膜的保护性流体表覆于胃内。当这种保护性流体的产生减少时,一些人有发生胃溃疡的风险。
在体内COX-2将花生四烯酸转化为前列腺素。在癌细胞中,COX-2的水平也上升并引起前列腺素的产生。前列腺素与肿瘤细胞结合并帮助开启参与新血管生成的基因,并因而支持该细胞的快速生长。
同样,研究了NSAID、前列腺素(PG)、增殖和凋亡之间的关系,例如,在表达COX并合成PG的结肠腺癌细胞中。例如,产生前列腺素的HT-29结肠癌细胞的生长被COX抑制剂舒林酸和吡罗昔康抑制。结肠直肠癌在西方国家是第二频发的癌症,当发生侵入和/或转移时其常常是致命的。除了肝细胞生长因子(HGF)以外,现在认为结肠癌侵入也由前列腺素驱动,前列腺素通过环加氧酶-2(Cox-2)酶产生。
因此,对于许多细胞来说,已在前列腺素合成和细胞生长调控之间建立了联系,如同样在Balb/c 3T3细胞中表现的,其中表皮生长因子依赖性增殖被COX抑制剂吲哚美辛抑制。
同样,阿司匹林用于控制疼痛和炎症已逾百年,通过流行病学研究已将其在二十世纪八十年代初期的长期使用与结肠直肠癌发生的减少联系起来。几乎同时,第一次报道了应答NSAID舒林酸的结肠直肠腺瘤有所消退。在随后的几年中,使用抑制环加氧酶(COX)的另一些NSAID与包括乳腺、前列腺和肺的多种组织中的癌症风险减少有关。
现今,已在多种癌症和某些肿瘤前损伤中证明了COX-2以及所述前列腺素合成途径的上游和下游的酶的过量表达。前列腺素与其受体通过自分泌或旁分泌途径直接相互作用,以提高细胞存活或刺激血管生成,已提议作为环加氧酶的前致癌功能的分子机制(有关综述参见:Cancer Lett.2004Nov 8;215(1):1-20.Cyclooxygenases in cancer:progress and perspective.Zha S,Yegnasubramanian V,Nelson WG,Isaacs WB,De Marzo AM.)。
在这方面,最近的临床前研究还表明环加氧酶COX-2可以参与某些类型肺癌的分子发病机理。大多数已有研究表明,它参与非小细胞肺癌。患有表达高水平COX-2的非小细胞肺癌的患者存活力显著降低。在患有非小细胞肺癌的患者中,用所述选择性COX-2抑制剂塞来昔布治疗人类增强了化疗的抗癌效果。COX-2已显示出调节肿瘤相关的血管生成的某些方面(Clin Cancer Res.2004 Jun 15;10(12 Pt 2):4266s-4269s.Cyclooxygenaseas a target in lung cancer.Brown JR,DuBois RN.)。
另外,一些研究已表明环加氧酶-2(COX-2)的表达与侵袭性乳癌的参数有关,包括大肿瘤的尺寸、阳性的腋淋巴结转移以及HER2阳性的肿瘤状态。对小鼠和大鼠中的乳腺肿瘤的研究已表明,COX-2的适度表达至高表达与乳腺肿瘤的发生有关,所述乳腺肿瘤对于用非特异性和特异性COX-2抑制剂治疗是敏感的(Semin Oncol.2004 Apr;31(2 Suppl 7):22-9.The role of COX-2 inhibition in breast cancer treatment and prevention.Arun B,Goss P.)。
COX-2还在前列腺癌中高表达,特别是在高等级前列腺上皮内瘤变和癌症的上皮细胞中高表达。据证实,用选择性COX-2抑制剂治疗人类前列腺癌细胞系在体外和体内均诱导凋亡。体内结果还表明,该COX-2抑制剂降低了肿瘤微血管的密度和血管发生。COX-2抑制剂可防止有效血管生成因子、血管内皮生成因子的缺氧上调。因此,这些结果表明COX-2抑制剂可作为前列腺癌中有效的化学预防和治疗剂(Urology.2001Aug;58(2Suppl 1):127-31.The role of cyclooxygenase-2 in prostate cancer.Kirschenbaum A,Liu X,Yao S,Levine AC)。
HDAC抑制剂和NSAID的组合
WO 03/039599 A1一般性地公开了环加氧酶-2抑制剂与组蛋白脱乙酰酶抑制剂的组合,以及它们在治疗恶化前结肠损伤或结肠癌或其它恶性肿瘤中的用途。
发明内容
本申请的发明人意外地发现,HDAC抑制剂与COX酶抑制剂组合对于治疗以组蛋白脱乙酰酶HDAC-2上调为特征的疾病特别有用。还发现这样的组合导致下游生物学事件的非预期的协同抑制,所述生物学事件也通过COX酶进行调节,如前列腺素的分泌。
因此,本发明涉及组蛋白脱乙酰酶抑制剂与NSAID组合用于制造治疗或预防疾病的药物的用途,其中通过组蛋白脱乙酰酶HDAC-2在受该疾病影响的组织中的上调限定所述疾病。
本发明还涉及用于治疗或预防以HDAC-2上调为特征的疾病的方法,包括对有此需要的个体施用有效量的组蛋白脱乙酰酶抑制剂和有效量的NSAID。
本发明的另一个方面是组蛋白脱乙酰酶抑制剂与NSAID组合用于制造治疗或预防疾病的药物的用途,在所述疾病中诱导组蛋白发生高度乙酰化具有有益的效果,其特征在于待治疗个体的至少一种组织表现出组蛋白脱乙酰酶HDAC-2的上调。当所述疾病为肿瘤时,所述组织通常是肿瘤组织。
受所述疾病影响的组织中HDAC-2的上调可能是各种突变的结果或与其相关。导致APC功能缺失的APC突变或者导致获得β-联蛋白功能的β-联蛋白突变可以造成HDAC-2水平的提高。类似地,c-myc功能的上调或提高可以导致HDAC-2的上调。通常,Wnt途径的突变和改变可以导致HDAC-2的上调。因此,受所述疾病影响的组织可能具有在APC基因中的至少一种突变。或者,受所述疾病影响的组织可能具有在β-联蛋白基因中的至少一种突变,所述突变导致获得β-联蛋白的功能或者稳定或提高β-联蛋白的半衰期。在另一个实施方案中,受所述疾病影响的组织表现出c-myc功能的上调或提高。在又另一个实施方案中,受所述疾病影响的组织表现出Wnt途径的突变和/或改变,其导致HDAC-2的上调。
在优选的实施方案中,受所述疾病影响的组织具有APC基因中的至少一种突变以及β-联蛋白基因中的至少一种突变。在另一个实施方案中,受所述疾病影响的组织具有APC基因中的至少一种突变和β-联蛋白基因中的至少一种突变以及c-myc功能的上调或提高。
本文使用的术语″组织″表示来自个体机体的生物材料。该术语″组织″包括从所述个体机体获得的细胞。短语″受所述疾病影响″指细胞或组织不同于健康个体的相应细胞或组织的情形。例如,该细胞或组织可以表现为不受控制的细胞分裂,或者具有在健康个体的相应细胞中不存在的基因突变,或者表现出炎症的迹象。在任选的第一步骤中,所述组织材料可以通过获得来自个体机体的活组织检查来提供。
在受所述待治疗疾病影响的组织中,与健康个体相应组织的HDAC-2(蛋白质或mRNA)水平相比,HDAC-2的上调为至少10%,更优选至少25%,最优选至少50%。术语″上调″涉及HDAC-2蛋白和/或HDAC-2mRNA的数量。优选地,蛋白质和mRNA均上调。
可以通过测量HDAC-2的量和/或表达来确定受疾病影响的组织是否表现出组蛋白脱乙酰酶HDAC-2的上调或者上调的程度。例如,可以通过使用针对HDAC-2的抗体的免疫测定来确定HDAC-2蛋白的量。这样的免疫测定对于本领域技术人员是已知的。针对HDAC-2的抗体公开于Krmer et al.(2003)EMBO J.22,3411-3420中,并且可从各种来源如Santa Cruz Biotechnology,Inc.、Zymed、SigmaAldrich及其它公司获得。
可以使用Western印迹法,这在本领域通常是已知的。可以将细胞材料或组织进行匀浆以及用变性剂和/或还原剂进行处理从而获得所述样品。可以将该样品加样于聚丙烯酰胺凝胶上以分离所述蛋白质,然后转移至膜或者直接点样到固相上。然后使抗体与所述样品接触。在一次或多次洗涤步骤后,使用本领域已知的技术检测结合的抗体。蛋白质凝胶电泳以及Western印迹法描述于Golemis,“Protein-Protein Interactions:ALaboratory Manual”,CSH Press 2002,Cold Spring Harbor N.Y.。
可以在固定和透化组织材料后使用免疫组织化学,所述组织材料例如实体瘤的切片。然后将抗体与该样品进行培养,并在一次或多次洗涤步骤后检测结合的抗体。该技术概括于Harlow and Lane,″Antibodies,ALaboratory Manual″CSH Press 1988,Cold Spring Harbor N.Y.中。
在一个优选的实施方案中,HDAC-2蛋白质的量通过ELISA进行测定。可以设想多种形式的ELISA。在一种形式中,抗体被固定于固相(如微量滴定板)上,之后封闭非特异的结合位点并与所述样品进行孵育。在另一种形式中,所述样品首先与固相接触以固定该样品中包含的HDAC-2蛋白质。在封闭和任选地洗涤之后,抗体与固定的样品接触。ELISA技术描述于Harlow and Lane,″Antibodies,A Laboratory Manual″CSH Press1988,Cold Spring Harbor N.Y.。
或者,可以利用普通技术人员所知的核酸技术测定HDAC-2mRNA或cDNA的量。优选使用杂交技术和/或PCR技术。Northern印迹法可以用于测定所述样品中HDAC-2RNA的量。在优选的实施方案中,使用RT-PCR。本领域的技术人员能够基于HDAC-2的核苷酸序列设计出用于这些方法中的合适的引物和/或探针。用于测定HDAC-2的量和/或表达的核苷酸序列和适当方法描述于WO 2004/027418 A2中。
根据本发明的用途或方法的一个方面,为了测定个体是否患有以HDAC-2上调为特征的疾病,可以进行诊断步骤。该诊断步骤可以包括测定组织样品中HDAC-2核酸或蛋白质的量或表达。如果该组织样品表现出HDAC-2的上调,则可以根据本发明的用途或方法对从中获得该组织的个体进行治疗。
因此,在根据本发明所述的联合治疗之前,可以进行测定组织样品中的HDAC-2核酸(例如mRNA)或者蛋白质的量或表达的步骤。任选地,如果所述样品中的HDAC-2核酸或蛋白质的量或表达明显高于来自健康个体的参考样品的量或表达(至少10、25或50%),则可以选择所述个体。
还可以另外测定APC基因中或β-联蛋白基因中是否存在突变。另外,可以根据本领域已知的方法测定c-myc的上调或功能提高的存在与否。
人类癌症中的某些β-联蛋白突变公开于Polakis(2000)Genes &Development 14:1837-1851的表格1(参见其第1840页)中。这些突变通过引用并入本文中。在本发明的一个实施方案中,待治疗疾病的特征在于在受该疾病影响的组织中具有这些β-联蛋白突变的至少一种。
所述APC基因中的突变已广泛地描述于文献中并常常与胃肠癌症的发展有关,所述胃肠癌症包括胃癌、十二指肠癌、结肠癌和直肠癌,这使得APC基因作为结肠癌症发生的看门基因(Behrens and Lustig,Int.J.Dev.Biol.48:477-487,2004;及其引用文献)。另外,还在多种另外的癌症中发现了APC突变(Beroud and Soussi,Nucleic Acids Res.24(1):121-4,1996),包括胰腺癌(Flanders and Foulkes,Med.Genet.33:889-898,1996)、甲状腺癌(Kurihara et al;Thyroid 14(12):1020-9,2004)、肺癌(Ohgaki et al.;Cancer Lett.207(2):197-203,2004)、肾癌(Pecina-Slaus etal.,Pathology 36(2):145-51,2004)以及黑素瘤(Worm et al.,Oncogene23(30):5215-26,2004;Reifenberger et al.,Int J Cancer 100(5):549-56,2002)。另外,在FAP和特科特(Turcot)综合征患者中的APC突变还与髓母细胞瘤、甲状腺乳头状癌、成肝细胞瘤和硬纤维瘤(Lynch et al.,Dig.Dis.Sci.46(11):2325-32,2001)以及脑肿瘤(Sunahara et al.,Nippon Rinsho58(7):1484-9,2000;Hamilton et al.,N.Engl.J.Med.332(13):839-47,1995)的发展有关。这些文献的公开及其所描述的突变通过引用并入本文中。
优选地,待治疗或预防的疾病为导致癌症的遗传状况。该疾病还可以是癌症或炎性疾病。在一个特别优选的实施方案中,所述导致癌症的遗传状况为家族性腺瘤性息肉病(FAP)。
本发明的一个方面是组蛋白脱乙酰酶抑制剂与NSAID组合用于制造治疗或预防炎性病症的药物的用途。
待治疗或预防的疾病可以是:雌激素受体依赖性乳癌、雌激素受体非依赖性乳癌、激素受体依赖性前列腺癌、激素受体非依赖性前列腺癌、脑癌、肾癌、结肠癌、结肠直肠癌、胰腺癌、膀胱癌、食道癌、胃癌、泌尿生殖器癌、胃肠癌、子宫癌、卵巢癌、星形细胞瘤、神经胶质瘤、皮肤癌、鳞状细胞癌、角化棘皮瘤、鲍恩(Bowen)病、皮肤T细胞淋巴瘤、黑素瘤、基底细胞癌、光化性角化病;ichtiosis;痤疮、寻常痤疮、肉瘤、卡波西(Kaposi’s)肉瘤、骨肉瘤、头颈癌、小细胞肺癌、非小细胞肺癌、白血病、淋巴瘤和/或其它血细胞癌症。
在另一方面,所述疾病为:类风湿性关节炎、甲状腺抵抗综合征、糖尿病、地中海贫血、硬化、原虫感染、类风湿性脊椎炎、所有形式的风湿病、骨关节炎、痛风性关节炎、多发性硬化、胰岛素依赖型糖尿病、非胰岛素依赖型糖尿病、哮喘、鼻炎、葡萄膜炎、红斑狼疮、溃疡性结肠炎、克罗恩病(Morbus Crohn)、炎性肠病、慢性腹泻、银屑病、特应性皮炎、骨病、纤维增生性疾病、动脉粥样硬化、再生障碍性贫血、迪格奥尔格(DiGeorge)综合征、格雷夫斯(Graves)病、癫痫、癫痫持续状态、阿尔茨海默(Alzheimer)病、抑郁症、精神分裂症、分裂情感性障碍、躁狂症、中风、心境不协调精神病症状、双相障碍、情感障碍、脑膜炎、肌营养不良、多发性硬化、躁动、心脏肥大、心力衰竭、再灌注损伤和/或肥胖。
用于所述组合治疗中的NSAID可以是环加氧酶抑制剂,优选其为环加氧酶-2抑制剂。根据本发明优选的NSAID为水杨酸盐/酯、芳基链烷酸、2-芳基丙酸、N-芳基邻氨基苯甲酸、昔康类如美洛昔康和吡罗昔康、昔布类(如塞来昔布、伐地昔布、罗美昔布、依托考昔和洛芬昔布)、磺苯胺、吲哚美辛、舒林酸、阿司匹林、氟比洛芬、布洛芬、萘普生药物及其衍生物。
本文使用的术语″组蛋白脱乙酰酶抑制剂″表示:能够抑制具有组蛋白脱乙酰酶活性之酶的组蛋白脱乙酰酶活性的物质。
如本领域技术人员已知的(WO03/001403),组蛋白脱乙酰酶抑制剂的抑制活性可以在体外试验中测定。可将IC50值用作组蛋白脱乙酰酶抑制剂的抑制活性的度量。低IC50值表明高抑制活性;高IC50值表明低抑制活性。根据本发明使用的组蛋白脱乙酰酶抑制剂,对于至少一种组蛋白脱乙酰酶来说,优选具有小于1mM,更优选小于500μM的IC50值。
根据优选的实施方案,所述组蛋白脱乙酰酶抑制剂能够优先地抑制某亚群的组蛋白脱乙酰酶或所选的脱乙酰酶。本文使用的术语″优选地抑制″指其中第一组组蛋白脱乙酰酶较之第二组组蛋白脱乙酰酶更强烈地被给定的组蛋白脱乙酰酶抑制剂抑制的情形。通常,对于所述第一组的组蛋白脱乙酰酶来说,优先抑制第一组组蛋白脱乙酰酶的组蛋白脱乙酰酶抑制剂具有小于800μM,优选小于500μM的IC50值。对于第二组的组蛋白脱乙酰酶来说,IC50值通常大于800μM,优选大于1mM。
在一个优选的实施方案中,所述组蛋白脱乙酰酶抑制剂能够优先地抑制第I类组蛋白脱乙酰酶。依据该第一实施方案,第I类组蛋白脱乙酰酶较之第II类组蛋白脱乙酰酶被更强烈地抑制。在该第一实施方案中,对于组蛋白脱乙酰酶HDAC 1、2、3和8来说,所述组蛋白脱乙酰酶抑制剂通常具有小于800μM,优选小于500μM的IC50值。另外,对于第II类酶HDAC 4、5、6、7、9和10来说,所述组蛋白脱乙酰酶抑制剂通常具有大于800μM,优选大于1mM的IC50值。在一个特定的实施方案中,较之其它组蛋白脱乙酰酶,待使用的组蛋白脱乙酰酶抑制剂更强烈地抑制HDAC-2。最优选地是,对于HDAC-2来说,根据本发明使用的组蛋白脱乙酰酶具有小于800μM,优选小于500μM的IC50值。
优选地,根据本发明使用的组蛋白脱乙酰酶抑制剂能够在用其处理的细胞中下调HDAC-2蛋白或mRNA的水平。这可以如Krmer et al.(2003)EMBO J.22,3411-3420所述的进行测定,其公开内容通过引入并入本文。所述下调可以为至少10%,或者至少25%,或者至少50%。
用于本发明所述的组合治疗中的组蛋白脱乙酰酶抑制剂可以是通式I的化合物或者其药学上可接受的盐
其中R1和R2独立地为直链的或支链的,饱和的或不饱和的,任选包含一个或几个杂原子并且可被取代的脂族C3-25烃链,R3为羟基、卤素、烷氧基或任选地烷基化的氨基基团。优选地,R1和R2独立地为直链的或支链的C3-25烃链,其任选地包含一个双键或三键。
最优选地,所述组蛋白脱乙酰酶抑制剂为丙戊酸或其药学上可接受的盐。
在本发明的其它方面中,所述组蛋白脱乙酰酶抑制剂可以选自异羟肟酸衍生物、苯甲酰胺、pyroxamides及其衍生物、表现出HDAC抑制活性的微生物代谢物、脂肪酸及其衍生物、环状四肽、肽化合物、HDAC第III类抑制剂以及SIRT抑制剂或其药学上可接受的盐。
所述异羟肟酸衍生物可以是化合物如NVP-LAQ824、LBH-589、MGCD0103、曲古抑菌素A(TSA)、N-辛二酰基苯胺异羟肟酸(suberoylanilide hydroxamic acid)、CBHA、G2M-701、G2M-702、G2M-707、Pyroxamide、Scriptaid、CI-994、CG-1521、Chlamydocin、联芳基异羟肟酸酯/盐、A-161906、双环芳基-N-羟基甲酰胺、PXD-101、磺酰胺异羟肟酸、TPX-HA类似物(CHAP)、Oxamflatin、Trapoxin、Depudecin、Apidicin、苯甲酰胺、MS-27-275、丁酸及其衍生物、Pivanex(丁酸新戊酰氧基甲酯)、trapoxin A、酯肽(FK-228)以及相关的肽化合物、Tacedinaline以及MG2856或其药学上可接受的盐。
本发明的一个优选实施方案是,丙戊酸与塞来昔布(市售的例如Celebrex)(或其它昔布类)组合用于制造预防或治疗本文上述所定义疾病的药物的用途。最优选地,组合使用丙戊酸与用于治疗FAP的塞来昔布。
本发明的另一个优选实施方案是,丙戊酸与舒林酸(或其它芳基链烷酸)组合用于制造预防或治疗本文上述所定义疾病的药物的用途。最优选地,组合使用丙戊酸与用于治疗FAP的舒林酸。
本发明的另一个优选实施方案是,丙戊酸与阿司匹林(或其它水杨酸酯/盐)组合用于制造预防或治疗本文上述所定义疾病的药物的用途。最优选地,组合使用丙戊酸与用于治疗FAP的阿司匹林。
本发明的另一个优选实施方案是,丙戊酸与布洛芬(或其它2-芳基丙酸)组合用于制造预防或治疗本文上述所定义疾病的药物的用途。最优选地,组合使用丙戊酸与用于治疗FAP的布洛芬。
本发明的另一个优选实施方案是,丙戊酸与灭酸(fenamic acid)(或其它N-芳基邻氨基苯甲酸)组合用于制造预防或治疗本文上述所定义疾病的药物的用途。最优选地,组合使用丙戊酸与用于治疗FAP的灭酸。
本发明的另一个优选实施方案是,丙戊酸与吡罗昔康(或其它昔康类)组合用于制造预防或治疗本文上述所定义疾病的药物的用途。最优选地,组合使用丙戊酸与用于治疗FAP的吡罗昔康。
在具体的方面,本发明涉及组合,如组合的制剂或药物组合物,其包含(a)丙戊酸或其药学上可接受的盐,以及(b)塞来昔布。在另一个具体的方面,本发明涉及组合,如组合的制剂或药物组合物,其包含(a)丙戊酸或其药学上可接受的盐,以及(b)舒林酸。在另一个具体的方面,本发明涉及组合,如组合的制剂或药物组合物,其包含(a)丙戊酸或其药学上可接受的盐,以及(b)阿司匹林。在另一个具体的方面,本发明涉及组合,如组合的制剂或药物组合物,其包含(a)丙戊酸或其药学上可接受的盐,以及(b)布洛芬。在另一个具体的方面,本发明涉及组合,如组合的制剂或药物组合物,其包含(a)丙戊酸或其药学上可接受的盐,以及(b)灭酸。在另一个具体的方面,本发明涉及组合,如组合的制剂或药物组合物,其包含(a)丙戊酸或其药学上可接受的盐,以及(b)吡罗昔康。
所述活性成分(a)和(b)可以游离形式或药学上可接受的盐的形式存在,用于同时的、并行的、分开的或者连续的使用。该成套药盒的组分可以同时或按顺序交错施用,也就是说,对于成套药盒的任何组分来说,在相等或不同时间间隔的不同时间点施用。
可以通过基于静脉内、肌肉内、皮下、局部、口服、鼻部、腹膜内或者栓剂给药来应用根据本发明的药物。
不同的药物化合物可以以两种独立药物的形式或者在单一应用单位中包含两种药物的施用方式施用。不同的药物化合物可以同时或按顺序交错地施用,也就是说,对于该组合的任何化合物来说,在相等或不同时间间隔的不同时间点施用。
意外地发现,与使用这些化合物分别进行的单药治疗比较,可显著降低NSAID和组蛋白脱乙酰酶抑制剂的治疗剂量。
因此,当与组蛋白脱乙酰酶抑制剂组合使用时,NSAID的优选剂量可以减少至推荐或批准剂量的30-60%,更优选至60-80%,并且更优选至80-90%。
在一个具体方面,本发明涉及组合,如组合的制剂或者药物组合物,其包含(a)丙戊酸或其药学上可接受的盐,以及(b)塞来昔布,其中用于治疗的塞来昔布的日剂量在100mg到600mg之间,并且丙戊酸或其药学上可接受的盐的日剂量在10mg/kg体重到60mg/kg体重之间。更优选,塞来昔布的日剂量在200mg到500mg之间,并且丙戊酸或药学上可接受的盐的日剂量在20mg/kg体重到45mg/kg体重之间。最优选,这些组合用于治疗FAP。
在另一个具体方面,本发明涉及组合物,如组合的制剂或者药物组合物,其包含(a)PXD101或其药学上可接受的盐,以及(b)塞来昔布,其中用于治疗的塞来昔布的日剂量在100mg到600mg之间,并且PXD101的日剂量在300mg到10g之间。更优选,塞来昔布的日剂量在200mg到500mg之间,并且PXD101的日剂量在500mg到5g之间。最优选,这些组合用于治疗FAP。
在本发明的另一个实施方案中,当与NSAID组合使用时,组蛋白脱乙酰酶抑制剂的优选剂量可以减少至该药物推荐或批准剂量的30-60%,更优选至60-80%,并且更优选至80-90%。
根据先前已知的这些药物的副作用状况(另外根据最近的数据,在该可能的副作用列表中还增加了潜在增长的心脏毒性和中风的风险),可能需要降低这些药物的剂量水平,特别是当需要长期乃至慢性应用时。事实上,这可以通过组合COX抑制剂的使用与另外的治疗方法的新的治疗方法来实现,因此允许COX抑制剂药物的剂量降低,并且维持至少相同的治疗效果以及减少的副作用乃至提高该患者的受益。
在本发明中,我们提供的数据显示,HDAC抑制剂能下调COX-2的表达并因此能够抑制细胞分泌前列腺素。这进而促进这种HDAC抑制剂的抗癌性能。然而并且最重要地,在本发明中我们意外地发现,HDAC抑制剂与COX酶抑制剂的组合导致非预期的对下游生物学事件的协同抑制,所述生物学事件也通过COX酶进行调节,如前列腺素的分泌。这些协同活性可以部分地归因于COX抑制剂引起的酶抑制以及其次COX基因表达的下调。然而,因为二者的机制包括相同的靶结构,所以可以预期该解释不足以解释观察到的协同效应,特别是在动物中最为相关的体内试验系统中所观察到的。因此,一定能推导出:很可能与组蛋白脱乙酰酶的抑制活性有关的另外的意外活性可有助于引起这种有益的协同效应。为了向患有癌症或炎性疾病的患者提供基于使用HDAC抑制剂与COX抑制剂的组合治疗的新的治疗选择,现在可以将这些发现移至人类临床试验。
另外可以预期的是,基于该组合的协同活性,当与HDAC抑制剂组合使用时,可降低NSAID的使用剂量,这会导致与这些NSAID使用相关的副作用的减少。
因此,如在家族性腺瘤性息肉病(FAP)的情形中,预期HDAC抑制剂与NSAID的组合导致肠息肉生长和息肉负担的协同降低。结果,目前对FAP患者的护理标准,即预防性结肠切除术(手术切除肠)可以推迟,可能推迟几年。另外,因为这些患者中的个别息肉最终发展为结肠癌,所以可以抑制和延迟该进展。
另外,本发明涵盖了HDAC抑制剂与COX抑制剂的组合用于治疗全部的多种癌症适应征的用途,所述癌症适应征包括但不限于结肠癌、乳癌、肺癌和前列腺癌。
同样,基于HDAC抑制剂的抗炎活性,可以与抗炎作用的COX抑制剂组合使用,以实现在炎性疾病中组合两种抑制原理以实现增加的乃至协同的治疗效果的新治疗选择。
具体实施方式
实施例1
利用组蛋白脱乙酰酶抑制剂下调COX-2的RNA和蛋白质表达。
HDAC抑制剂下调Cox-2的表达(图1和图2)。这可以针对HDAC抑制化合物丙戊酸(VPA、TSA、G2M-701、G2M-702和G2M-707(对于G2M-701、G2M-702和G2M-707的详述参见WO 2004/009536 A1)在几个系统中在RNA和蛋白质水平展示,所述系统例如为A-549人类肺上皮癌细胞、SK-Mel黑素瘤细胞、HT-29结肠癌细胞、MDA-MB-231乳腺癌细胞、THP-1单核细胞以及原代人类淋巴细胞和巨噬细胞。如图1所示,在相同时间分析的Cox-1的水平未受影响。相反地,COX-2抑制剂塞来昔布(图2)不改变COX-2的表达。
通过向生长培养基添加20ng/ml的TPA 3天以诱导THP-1细胞分化。以5×105个细胞/6孔板之孔的密度接种贴壁细胞,并且用1mM VPA或者10μM G2M-707培养过夜(图1A)。然后通过添加10μg/ml的LPS 6小时以诱导Cox-2表达。根据制造商的说明书,使用来自Qiagen的RNeasy试剂盒制备RNA。使用在20μl体积中的1μg RNA进行逆转录。对于每个PCR反应,使用1μl以及指定基因的特异引物。除了TNF-α、IFN-γ和IL-6的下调,还可以观察到两种HDAC抑制剂对COX-2RNA而非COX-1RNA的下调(图1A)。
还使用自分别用30mg/kg/天(患者1)或120mg/kg/天(患者2)VPA的剂量处理的患者的外周血淋巴细胞分离的RNA进行半定量RT-PCR。图1B清楚地显示出VPA治疗对Cox-2而非对照基因GAPDH的下调。
图2中显示出在多种细胞类型中HDAC抑制剂对COX-2在蛋白水平上的调节。这里,A549细胞和SK-Mel黑素瘤细胞显示出COX-2的组成性表达并且未被进一步诱导。在HT-29结肠癌细胞中,通过用100ng/mlTNF-α处理4小时来诱导Cox-2表达。对于MDA-MB-231乳癌细胞和THP-1单核细胞来说,分别用10μg/ml LPS作为Cox-2表达的诱导物处理16小时或6小时。HDAC抑制剂处理进行72小时(A-549)、48小时(SK-Mel),在诱导前16小时开始(对于THP-1细胞),或者在诱导前30分钟开始(对于HT29和MDA-MB-231细胞)。
以24孔板的每个孔中5×104到1×105个细胞的密度接种细胞。通过除去生长培养基并加入每孔200μl的Laemmli样品缓冲液进行溶胞。将60μl加样至8%丙烯酰胺凝胶上并进行不连续电泳。将蛋白质印迹至PVDF膜上,使用山羊抗Cox-2抗体(St.Cruz,sc1747)或小鼠抗泛肌动蛋白抗体(Ab-5,NeoMarkers)作为探针。在所有系统中,可以观察到HDAC抑制剂对Cox-2蛋白而非对照蛋白质肌动蛋白的下调(图2)。
实施例2
利用组蛋白脱乙酰酶抑制剂及其与COX酶抑制剂(NSAID)的组合抑制前列腺素分泌。
通过HDAC抑制剂对Cox-2蛋白水平的抑制还导致几个系统中前列腺素分泌的下调。如图3所示,前列腺素的这种减少与使用Cox-2抑制剂塞来昔布(Cel)达到相同的水平。
在HT-29结肠癌细胞中,通过用100ng/ml TNF-α处理4小时诱导Cox-2表达,对于MDA-MB-231乳癌细胞来说,使用10μg/ml LPS作为Cox-2表达的诱导物处理16小时。在诱导前30分钟(HT-29,MDA-MB-231)或者溶胞前16小时(A549)进行HDAC抑制剂和Cox抑制剂处理。根据制造商的说明书,使用来自Cayman的前列腺素E2 EIA试剂盒对上清液中的前列腺素水平进行分析。条柱显示两个值的平均数,误差条柱反映两个值的范围(图3)。
如图4所示,HDAC抑制剂甚至可以加强由Cox抑制剂塞来昔布在THP-1单核细胞和MDA-MB-231乳癌细胞中引起的前列腺素分泌的减少。在THP-1单核细胞中,甚至在其已通过塞来昔布被抑制之后,HDAC抑制剂G2M-707和TSA还可以减少前列腺素的水平。这种前列腺素分泌抑制的加强一定被认为是协同的,这是因为,与将各自的抑制活性仅仅相加所揭示的抑制相比较,使用塞来昔布和HDAC抑制剂的组合导致了更加显著的前列腺素分泌的抑制。因此,这些HDAC抑制剂的HDAC抑制功能似乎意外地支持了在下调前列腺素分泌中的COX抑制功能,其通过得到这些协同结果的迄今未发现的机制起作用。同样地,在MDA-MB-231细胞中,HDAC抑制剂VPA可以剂量依赖性地加强塞来昔布对前列腺素分泌的抑制。同时,如前所述Cox-2的蛋白水平降低。
详细地说,在24孔板中以每孔7.5×104个细胞的密度接种细胞。根据制造商的说明书,使用来自Cayman的前列腺素E2 EIA试剂盒对1∶3稀释的上清液一式两份进行分析。条柱显示两个值的平均数。通过完全除去生长培养基并每孔加入200μl的Laemmli样品缓冲液制备细胞提取物。随后,将60μl加样至8%丙烯酰胺凝胶上并进行不连续电泳。将蛋白质印迹至PVDF膜上,使用山羊抗Cox-2抗体(St.Cruz,sc1747)或小鼠抗泛肌动蛋白(为了分析该对照蛋白质的表达)抗体(Ab-5,NeoMarkers)作为探针。
实施例3
通过使用组蛋白脱乙酰酶抑制剂与Cox-2抑制剂的组合协同抑制体内腺瘤的生长。
用VPA处理显著地减少了在APCmin小鼠模型中的腺瘤数目。在该模型中,通过使用Cox-2抑制剂塞来昔布得到了类似的结果。然而,在该模型中同时使用两种药物进行组合治疗时,观察到腺瘤数目的协同减少。这些再次强烈地论证了VPA的双重活性,即其下调Cox-2蛋白水平的能力及其HDAC抑制功能引起与常规的Cox-2抑制剂一起使用时观察到的协同疗效(图5A)。
所示为每组15(对照组)、17(VPA组)、13(塞来昔布组)或5(组合处理组)只动物的具有标准误差限的平均值。P<0.05(双样本t检验;对照对VPA和塞来昔布处理的以及单药治疗对组合治疗处理的动物)。
图5b显示用VPA和塞来昔布单独处理后以及用两种药物组合处理后的APCmin小鼠(家族性腺瘤性息肉病(一种导致结肠癌发生的遗传性疾病)的动物模型)的肝提取物中的前列腺素水平。在这里可以看出两种药物将前列腺素的水平降至相似的程度。同时使用两种药物的组合治疗导致前列腺素分泌增加的降低。这种前列腺素分泌的抑制的加强是加和性的,再次论证了观察到的腺瘤生长降低的协同作用不能仅仅通过干扰前列腺素分泌的抑制来解释,而是必定归因于VPA的双重活性,(i)作为HDAC酶的抑制剂,以及(ii)其能够下调Cox-2的表达,并随后降低前列腺素的水平。
所示为两只(对照组)、四只(VPA组)以及五只(塞来昔布和组合的组)动物的平均值以及标准偏差。
详细地说,分别不处理或者用VPA或塞来昔布或两种药物一起处理七至十六周龄的性别相配的(sexmatched)杂合C57BL/6J-APCmin/+小鼠(Jackson Laboratories,Bar Harbor,Maine)。用PBS注射(腹膜内)对照动物。注射(腹膜内)VPA的钠盐等渗水溶液4周(2×400mg/kg/天),而将塞来昔布以1250ppm(0.12%)随食物随意喂给动物4周。所述组合组接受两个单独处理组VPA组和塞来昔布组的相同剂量4周。处死动物时,纵向地打开整个肠道并将其固定于10%磷酸盐缓冲的甲醛中24小时,之后在50%乙醇中进行乙醇固定三天。在0.1%亚甲蓝中染色1分钟以提高息肉对比度,之后由两个对小鼠接受处理不知情的独立的观察者在解剖显微镜下测定息肉的数目和尺寸。
如所述的,在肝组织中离体评定环加氧酶的活性(Reuter et al.,2002;BMC Cancer 2:19)。简要地说,在最后一次给予载体或药物后3小时对小鼠实施安乐死,并且获得肝组织(~100mg)样品。然后将该样品放入含有1ml磷酸钠缓冲液(10mM,pH 7.4)的微量离心管中,并用剪刀细细地切碎15秒。然后将样品于37°在振荡水浴中孵育20分钟。在孵育之后,以9000×g离心30秒并收集该上清液。将上清液瞬时冷冻在液氮中,并储存在-80℃用于之后前列腺素E2含量的测定。使用市售的竞争性酶免疫试样(Cayman Chemical),在1∶20稀释上清液后一式两份测定PGE2的浓度。
实施例4
在胶原诱导的类风湿性关节炎(CIA)治疗模型中,HDAC抑制剂降低了临床严重程度的评分。
已知Cox-2对于炎症过程是关键的(Dubois R.et al.,FASEB J 12,1063-1073(1998))。它被炎症介质TNF-α快速上调和COX酶产生的前列腺素进一步抑制免疫监视。因此,COX酶的抑制及随后前列腺素产生的降低最终导致炎性症状的减轻,并因此利用其减轻的效果。然而,它不能有效地影响炎症过程的起因。近年来,对炎性疾病的病因疗法的寻找导致了设计靶向TNF-α作为关键炎症介质的新治疗。
最近,发现HDAC抑制剂显示出抗炎活性(也参见图1,其中HDAC抑制剂下调炎性细胞因子的表达,包括TNF-α)。因此,可以提出,可以将HDAC抑制剂与起抗炎作用的Cox抑制剂进行组合从而实现新的治疗选择,其结合两种抑制原理以在治疗炎性疾病时实现累加乃至协同的治疗效果。这里,特别地以及如上所述的,HDAC抑制剂的双重机制即它们的HDAC抑制活性以及它们下调Cox-2表达的能力、以及因此随后降低前列腺素的水平,有助于该假定的成立。
为了评估HDAC抑制剂体内抑制可溶性TNF-α分泌的能力,使用在3H1小鼠中的急性LPS诱导的炎症模型。在腹膜内注射LPS 1小时前,使用测试物质腹膜内注射所述小鼠。在LPS刺激1小时后取出血样,使用TNF-αELISA试样测定血清中的TNF-α水平。如图6(下图)所示,与对照小鼠相比,VPA和G2M-707预处理导致血清中TNF-α的绝对水平60%的降低。
该实验清楚地显示,HDAC抑制剂是体内TNF-α水平的强效抑制剂,并且可以用于治疗对Cox-2和TNF-α水平降低产生应答的炎性疾病。
详细地说,在每只小鼠用50μg的LPS(Sigma)诱导炎症之前1小时,用VPA(400mg/kg/天,n=8)、G2M-701(1mg/小鼠/天,n=4)、G2M-707(1mg/小鼠/天,n=4)或者用200μl PBS(对照,n=8)处理小鼠。LPS处理1小时后,通过心脏穿刺取血并分离血清。使用来自BenderMedSystems的TNF-αsandwich ELISA模块检测所述血清。如制造商的说明书所述的进行该分析。使用ABTS作为底物,并用96孔板读数器在405nm波长处完成测量。给出405nm处的绝对OD水平。
为了评估在治疗性体内炎症模型中HDAC抑制剂的抗炎效力,我们将VPA和G2M-707应用于患有晚期胶原诱导的关节炎(CIA)的小鼠。
图6(上图)显示出,在这种类风湿性关节炎(RA)的模型中用VPA或G2M-707处理的结果。与对照组比较,两种药物有效地降低了临床严重程度评分(总评分),并且在该处理过程中维持功效。泼尼松龙(一种临床用于RA的皮质甾体药物)用作本研究的阳性对照。
每个数据点分别代表9只(VPA组)、8只(G2M-707组)或4只(泼尼松龙组)动物的平均值。P<0,05(双样本t检验;对照对VPA处理以及对照对泼尼松龙处理的动物)。
详细地说,在该治疗性CIA模型中,用CFA中的100μg鸡II型胶原(Chondrex)免疫7周龄的DBA/1雌性小鼠。免疫后21至28天,开始发生关节炎,并且在6周后,发生率达到93%。在未处理的动物中,该严重程度为中度至高度,并且平均得分达到10.3(最高得分为15)。使用已建立的评分系统监视所述小鼠每天的关节炎征兆。在关节炎的第一次征兆出现时,该受影响的小鼠划为处理组。用载体对照或者VPA以2×400mg/kg/天腹膜内或者G2M-707以2×1mg/小鼠/天腹膜内或者泼尼松龙以2×20mg/kg/天(腹膜内)处理所述小鼠15天。基于每只爪的外观评估关节炎的临床严重程度,并且主观地分级为0至4。将每个肢的评分加和,得到最大严重程度评分为16。该评分系统如下:0,无关节炎;1,爪变红并且一只或两只趾肿胀;2,整个爪轻度至中度肿胀;3,整个爪广泛地肿胀;4,整个爪极端肿胀并且开始关节强直。发病后,对该动物每周进行3次评分。
Claims (30)
1.组蛋白脱乙酰酶抑制剂与NSAID组合用于制造治疗或预防疾病的药物的用途,所述疾病的特征在于在受其影响的组织中组蛋白脱乙酰酶HDAC-2被上调。
2.根据权利要求1的用途,其中受所述疾病影响的组织的至少部分(a)具有在APC基因中的至少一种突变,或者(b)具有在β-联蛋白基因中的至少一种突变,该突变导致获得β-联蛋白的功能、或者β-联蛋白的稳定或提高的半衰期,或者(c)表现出c-myc的上调或提高的功能,和/或(d)表现出导致HDAC-2上调的Wnt途径的突变或变化。
3.权利要求1或2的用途,其中所述疾病为导致癌症、癌症诱因病症或炎性病症的遗传病况。
4.权利要求1至3任一项的用途,其中所述遗传病况为家族性腺瘤性息肉病。
5.权利要求1至4任一项的用途,其中所述NSAID为环加氧酶抑制剂。
6.权利要求1至5任一项的用途,其中所述NSAID为环加氧酶-2抑制剂。
7.权利要求1至6任一项的用途,其中所述NSAID选自水杨酸酯/盐,芳基链烷酸,2-芳基丙酸,N-芳基邻氨基苯甲酸,昔康类如美洛昔康和吡罗昔康,昔布类如塞来昔布、伐地昔布、罗美昔布、依托考昔和洛芬昔布,磺苯胺,吲哚美辛,舒林酸,阿司匹林,氟比洛芬,布洛芬,萘普生药物及其衍生物。
8.根据权利要求1至7任一项的用途,其中所述组蛋白脱乙酰酶抑制剂是式I的化合物或者其药学上可接受的盐,
其中R1和R2独立地为直链的或支链的,饱和的或不饱和的,任选地包含一个或几个杂原子并且可被取代的脂肪族C3-25烃链,R3为羟基、卤素、烷氧基或任选地烷基化的氨基基团。
9.根据权利要求8的用途,其中R1和R2独立地为直链的或支链的C3-25烃链,其任选地包含一个双键或三键。
10.根据权利要求1至9任一项的用途,其中所述组蛋白脱乙酰酶抑制剂为丙戊酸或其药学上可接受的盐。
11.根据权利要求1至7任一项的用途,其中所述组蛋白脱乙酰酶抑制剂选自异羟肟酸衍生物、苯甲酰胺、pyroxamides及其衍生物、具有HDAC抑制活性的微生物代谢物、脂肪酸及其衍生物、环状四肽、肽化合物、HDAC第III类抑制剂以及SIRT抑制剂或其药学上可接受的盐。
12.根据权利要求1至7任一项的用途,其中所述组蛋白脱乙酰酶抑制剂选自异羟肟酸衍生物(如NVP-LAQ824、LBH-589、曲古抑菌素A(TSA)、N-辛二酰基苯胺异羟肟酸、CBHA、G2M-701、G2M-702、G2M-707、Pyroxamide、Scriptaid、CI-994、CG-1521、Chlamydocin、联芳异羟肟酸酯/盐、A-161906、双环芳基-N-羟基甲酰胺、PXD-101、磺酰胺异羟肟酸)、TPX-HA类似物(CHAP)、Oxamflatin、Trapoxin、Depudecin、Apidicin、苯甲酰胺、(如MS-27-275和MGCD0103)丁酸及其衍生物、Pivanex(丁酸新戊酰氧基甲酯)、trapoxin A、酯肽(FK-228)以及相关的肽化合物、Tacedinaline以及MG2856或其药学上可接受的盐。
13.权利要求1至12的用途,其中所述疾病为雌激素受体依赖的乳癌、雌激素受体非依赖的乳癌、激素受体依赖的前列腺癌、激素受体非依赖的前列腺癌、脑癌、肾癌、结肠癌、结肠直肠癌、胰腺癌、膀胱癌、食道癌、胃癌、泌尿生殖器癌、胃肠癌、子宫癌、卵巢癌、星形细胞瘤、神经胶质瘤、皮肤癌、鳞状细胞癌、角化棘皮瘤、鲍恩病、皮肤T细胞淋巴瘤、黑素瘤、基底细胞癌、光化性角化病;ichtiosis;痤疮、寻常痤疮、肉瘤、卡波西肉瘤、骨肉瘤、头颈癌、小细胞肺癌、非小细胞肺癌、白血病、淋巴瘤和/或其它血细胞癌症。
14.权利要求1至12任一项的用途,其中所述疾病为甲状腺抵抗综合征、糖尿病、地中海贫血、硬化、原虫感染、类风湿性关节炎、类风湿性脊椎炎、所有形式的风湿病、骨关节炎、痛风性关节炎、多发性硬化、胰岛素依赖型糖尿病、非胰岛素依赖型糖尿病、哮喘、鼻炎、葡萄膜炎、红斑狼疮、溃疡性结肠炎、克罗恩病、炎性肠病、慢性腹泻、银屑病、特应性皮炎、骨病、纤维增生性疾病、动脉粥样硬化、再生障碍性贫血、迪格奥尔格综合征、格雷夫斯病、癫痫、癫痫持续状态、阿尔茨海默病、抑郁症、精神分裂症、分裂情感性障碍、躁狂症、中风、心境不协调精神病症状、双相障碍、情感障碍、脑膜炎、肌营养不良、多发性硬化、躁动、心脏肥大、心力衰竭、再灌注损伤和/或肥胖。
15.根据权利要求1至14任一项的用途,其中所述药物通过基于静脉内、肌肉内、皮下、局部、口服、鼻部、腹膜内或者栓剂的施用方式应用。
16.根据权利要求1至15任一项的用途,其中所述不同的药物化合物以两种独立药物的形式分开地施用或者以在单一应用单元中含有两种药物的施用方式施用。
17.一种药物组合物,其包含丙戊酸或其药学上可接受的盐、塞来昔布以及至少一种药学上可接受的赋形剂或稀释剂。
18.一种药盒,其包含作为第一组分的丙戊酸或其药学上可接受的盐,以及作为第二组分的塞来昔布。
19.一种药物组合物,其包含丙戊酸或其药学上可接受的盐、舒林酸以及至少一种药学上可接受的赋形剂或稀释剂。
20.一种药盒,其包含作为第一组分的丙戊酸或其药学上可接受的盐,以及作为第二组分的舒林酸。
21.一种药物组合物,其包含丙戊酸或其药学上可接受的盐、阿司匹林以及至少一种药学上可接受的赋形剂或稀释剂。
22.一种药盒,其包含作为第一组分的丙戊酸或其药学上可接受的盐,以及作为第二组分的阿司匹林。
23.一种药物组合物,其包含丙戊酸或其药学上可接受的盐、布洛芬以及至少一种药学上可接受的赋形剂或稀释剂。
24.一种药盒,其包含作为第一组分的丙戊酸或其药学上可接受的盐,以及作为第二组分的布洛芬。
25.一种药物组合物,其包含丙戊酸或其药学上可接受的盐、灭酸以及至少一种药学上可接受的赋形剂或稀释剂。
26.一种药盒,其包含作为第一组分的丙戊酸或其药学上可接受的盐、以及作为第二组分的灭酸。
27.一种药物组合物,其包含丙戊酸或其药学上可接受的盐、吡罗昔康以及至少一种药学上可接受的赋形剂或稀释剂。
28.一种药盒,其包含作为第一组分的丙戊酸或其药学上可接受的盐,以及作为第二组分的吡罗昔康。
29.一种药物组合物,其包含PXD101或其药学上可接受的盐、塞来昔布以及至少一种药学上可接受的赋形剂或稀释剂。
30.一种药盒,其包含作为第一组分的PXD101或其药学上可接受的盐,以及作为第二组分的塞来昔布。
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EP3439649B1 (en) | 2016-04-08 | 2023-11-15 | Cereno Scientific AB | Delayed release pharmaceutical formulations comprising valproic acid, and uses thereof |
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US6110955A (en) * | 1997-03-11 | 2000-08-29 | Beacon Laboratories, Inc. | Metabolically stabilized oxyalkylene esters and uses thereof |
US20020103110A1 (en) * | 2001-01-26 | 2002-08-01 | Spitzer A. Robert | System and method for rectal administration of medication for treatment of migraines |
CA2461373A1 (en) * | 2001-11-06 | 2003-05-15 | Novartis Ag | Cyclooxygenase-2 inhibitor/histone deacetylase inhibitor combination |
JP2005525345A (ja) * | 2002-02-15 | 2005-08-25 | スローン−ケッタリング・インスティテュート・フォー・キャンサー・リサーチ | Trx媒介性疾患を処置する方法 |
SE0300098D0 (sv) * | 2003-01-15 | 2003-01-15 | Forskarpatent I Syd Ab | Use of cyclin D1 inhibitors |
US20050070524A1 (en) * | 2003-06-06 | 2005-03-31 | Pharmacia Corporation | Compositions of a cyclooxygenase-2 selective inhibitor and an anticonvulsant agent for the treatment of central nervous system disorders |
EP1491188A1 (en) * | 2003-06-25 | 2004-12-29 | G2M Cancer Drugs AG | Topical use of valproic acid for the prevention or treatment of skin disorders |
WO2005013958A1 (en) * | 2003-08-07 | 2005-02-17 | Novartis Ag | Histone deacetylase inhibitors as immunosuppressants |
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- 2006-06-14 AU AU2006272118A patent/AU2006272118A1/en not_active Abandoned
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- 2006-06-14 BR BRPI0613402-5A patent/BRPI0613402A2/pt not_active IP Right Cessation
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WO2010148572A1 (en) * | 2009-06-26 | 2010-12-29 | Asan Laboratories Co., Ltd. | Method for treating or ameliorating mucocutaneous or ocular toxicities |
CN102458473A (zh) * | 2009-06-26 | 2012-05-16 | 英属开曼群岛商安盛开发药物股份有限公司 | 治疗或减缓粘膜皮肤或眼睛毒性的方法 |
AU2009348848B2 (en) * | 2009-06-26 | 2012-10-25 | Sunny Pharmtech, Inc. | Method for treating or ameliorating mucocutaneous or ocular toxicities |
CN102526732A (zh) * | 2011-12-20 | 2012-07-04 | 同济大学 | 靶向调节组蛋白乙酰化水平的药物在制备用于预防或治疗自身免疫性疾病的药物中的用途 |
CN104152407A (zh) * | 2014-06-24 | 2014-11-19 | 天津医科大学口腔医院 | 组蛋白去乙酰化酶抑制剂在制备牙源性干细胞的成骨分化制剂中的应用 |
CN110945016A (zh) * | 2017-05-24 | 2020-03-31 | 特拉斯福特普拉斯公司 | 用于治疗炎性疾病的肽化合物、缀合化合物及其用途 |
CN110013556A (zh) * | 2018-01-05 | 2019-07-16 | 华上生技医药股份有限公司 | 用于调节肿瘤微环境和免疫疗法的药物组合和方法 |
CN110882250A (zh) * | 2018-09-07 | 2020-03-17 | 上海市计划生育科学研究所 | 一种化合物在治疗弱精症中的用途 |
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US20080207724A1 (en) | 2008-08-28 |
EP1904107A2 (en) | 2008-04-02 |
CA2614770A1 (en) | 2007-01-25 |
WO2007009539A3 (en) | 2007-09-07 |
MX2008000686A (es) | 2008-03-19 |
AU2006272118A1 (en) | 2007-01-25 |
BRPI0613402A2 (pt) | 2011-01-11 |
EP1743654A1 (en) | 2007-01-17 |
WO2007009539A2 (en) | 2007-01-25 |
JP2009501168A (ja) | 2009-01-15 |
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