CN101534836B - Parp抑制剂在制备治疗肥胖症的药物中的用途 - Google Patents
Parp抑制剂在制备治疗肥胖症的药物中的用途 Download PDFInfo
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- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
本发明涉及治疗脂肪酸合成相关疾病的方法,包括向需要的患者施用有效量的PARP抑制剂或其代谢物以抑制脂肪酸合成,其中所述脂肪酸合成相关疾病是肥胖、糖尿病或心血管疾病。本发明还涉及治疗对象的癌症的方法,包括:(i)确定来自对象的样品中的脂肪酸水平,和(ii)施用有效量的PARP抑制剂或其代谢物以抑制对象中的脂肪酸合成,其中所述施用是基于所述脂肪酸水平,从而治疗对象的癌症。本发明进一步涉及通过向需要的患者施用有效量的PARP抑制剂或其代谢物以抑制脂肪酸合成而治疗Her-2相关癌症的方法。
Description
交叉引用
本申请要求2006年9月5日提交的美国临时申请60/842489的优先权,该文献通过引用全部引入本申请。
背景技术
脂肪酸合酶(FAS)是将碳水化合物转化成脂肪酸必需的酶。在正常人体中,脂肪酸合成途径由于膳食脂肪的水平足够高而下调。但是,在许多的人恶性肿瘤和它们的前期病变中,例如前列腺癌、卵巢癌和乳腺癌,组织表达高水平的脂肪酸合酶,从而产生高水平的脂肪酸。在大多数人类癌症中的FAS上调导致FAS在恶性癌症表型的形成、维持和/或强化中发挥作用和FAS可以是抗癌药物开发的靶标的观念。
世界上大约12亿人体重超重且其中至少3亿人是肥胖的。在美国,超过九千七百万成人(即超过一半)是超重的且几乎五分之一的成人是肥胖的。减少肥胖者中的脂肪酸合成可能是肥胖症的有效治疗方法。
在体外用浅蓝菌素(FAS上的β-酮脂酰合成酶反应的共价灭活剂)处理癌细胞导致细胞通过细胞凋亡而死亡,表明具有高度活跃的脂肪酸合成的癌细胞需要有功能的途径(Pizer等,(1996)Cancer Res.56,2745-2747)。但是,浅蓝菌素具有有限的体内活性。FAS显示为被Her-2/neu在转录、翻译和生物合成活性水平上调节的基因中的一个(Menedez等,(2005)Drug New Perspect,18(6),July/August)。该Her-2/neu-诱导的乳腺癌相关FAS的上调可受到抗Her-2/neu抗体(如曲妥单抗)的抑制。采用C75(脂肪酸合成的抑制剂)的研究已显示通过肿瘤组织中脂肪酸合成的抑制的抗肿瘤活性(Kuhajda等,(2000)Proc.Natl.Acad.Sci.vol.97,no.7,3450-3454)。FAS抑制剂也显示激活体重减轻途径(Loftus,T.M.等,(2000)Science 288,2379-2381)。
由于脂肪酸合成在癌症和体重增加途径中起作用,因此一直需要开发高效的脂肪酸合成抑制剂。
发明内容
本发明的一个方面涉及治疗脂肪酸合成和代谢相关疾病的方法,包括对需要的患者施用有效量的PARP抑制剂或其代谢物以抑制脂肪酸合成,其中所述脂肪酸合成相关疾病是肥胖、糖尿病或心血管疾病。
本发明的另一个方面涉及治疗对象的癌症的方法,包括:(i)确定来自对象的样品中的脂肪酸水平,和(ii)施用有效量的PARP抑制剂或其代谢物以抑制脂肪酸合成,其中施用是基于所述脂肪酸水平,从而治疗对象的癌症。
在本发明的一些实施方式中,脂肪酸是中链脂肪酸或长链脂肪酸。中链脂肪酸包括C:6-C:12。长链脂肪酸包括大于12个碳的链长度。在一些实施方式中,脂肪酸合成的抑制包括抑制葡萄糖途径的至少一种酶。在一些实施方式中,脂肪酸合成的抑制包括抑制脂肪酸生物合成途径的至少一种酶。在一些实施方式中,脂肪酸合成的抑制包括抑制至少一种选自乙酰辅酶A、丙二酰辅酶A、乙酰辅酶A羧化酶和脂肪酸合酶的酶。在一些实施方式中,脂肪酸合酶包括酰基载体蛋白、乙酰转移酶、丙二酰转移酶、3-酮-酰基-ACP合成酶、3-酮酰基-ACP还原酶、3-羟基-酰基-ACP脱水酶和烯酰基-ACP还原酶。在一些实施方式中,脂肪酸合成的抑制包括抑制脂肪酸合酶的至少一种酶。在一些实施方式中,脂肪酸合成的抑制包括抑制从葡萄糖合成乙酰辅酶A。在一些实施方式中,脂肪酸合成的抑制包括抑制从乙酰辅酶A合成脂肪酸。
在本发明前述方面的一些实施方式中,长链脂肪酸为C:14-C:30。在一些实施方式中,长链脂肪酸为C:14、C:16、C:18、C:18-1、C:20、C:22或C:24。在一些实施方式中,抑制通过分析葡萄糖途径或脂肪酸生物合成途径的代谢物或分子流确定。在一些实施方式中,代谢物选自葡萄糖、糖原、乳酸、CO2、脂肪酸、乙酰辅酶A、RNA核糖和DNA脱氧核糖。在一些实施方式中,代谢物为用于分析而进行了化学衍生化。在一些实施方式中,分析包括质谱分析。在一些实施方式中,质谱分析是质量同位体分布分析(mass isotopomer distributionanalysis)。在一些实施方式中,脂肪酸水平是上调的。
在本发明前述方面的一些实施方式中,PARP抑制剂或其代谢物是式I的化合物、其药学上可接受的盐或其前药:
式I
其中,R1、R2、R3、R4和R5独立地选自氢、羟基、任选取代的胺、羧基、酯、亚硝基、硝基、卤素、任选取代的(C1-C6)烷基、任选取代的(C1-C6)烷氧基、任选取代的(C3-C7)环烷基、任选取代的(C3-C7)杂环基、任选取代的芳基和含硫的基团。在一些实施方式中,含硫的基团是-SR6,其中R6选自氢、C1-C6酰基、任选取代的(C1-C6)烷基、任选取代的(C3-C7)环烷基、任选取代的(C3-C7)杂环基和任选取代的芳基。
在本发明前述方面的一些优选实施方式中,PARP抑制剂或其代谢物是式II的化合物、其药学上可接受的盐或其前药:
式II
其中,R1、R3、R4和R5独立地选自氢、羟基、任选取代的胺、羧基、酯、亚硝基、硝基、卤素、任选取代的(C1-C6)烷基、任选取代的(C1-C6)烷氧基、任选取代的(C3-C7)环烷基、任选取代的(C3-C7)杂环基、任选取代的芳基和-SR6;R2是硝基或亚硝基;且其中R1、R3、R4和R5取代基中的至少两个总是为氢;其中R6为-SR6,其中R6选自氢、C1-C6酰基、任选取代的(C1-C6)烷基、任选取代的(C3-C7)环烷基、任选取代的(C3-C7)杂环基和任选取代的芳基及任选的取代基。在一些实施方式中,R6为任选取代的(C1-C6)烷基,其为S-连接的半胱氨酸结构的残基,该半胱氨酸结构可以是单半胱氨酸氨基酸或可以形成包含半胱氨酸的二肽、三肽、四肽、五肽或更高级肽的一部分。
在本发明前述方面的一些优选实施方式中,PARP抑制剂是式III的化合物、其药学上可接受的盐、其代谢物或前药:
式III。
在本发明前述方面的一些实施方式中,癌症选自结肠腺癌、食管腺癌、肝细胞肝癌、鳞状细胞癌、胰腺腺癌、胰岛细胞瘤、直肠腺癌、胃肠道基质瘤、胃腺癌、肾上腺皮质癌、滤泡性癌、乳头状癌、乳腺癌、导管癌、小叶癌、导管内癌、粘液癌、叶状肿瘤、卵巢腺癌、子宫内膜腺癌、颗粒细胞瘤、粘液性囊腺癌、子宫颈腺癌、外阴鳞状细胞癌、基底细胞癌、前列腺腺癌、骨巨细胞瘤、骨肉瘤、喉癌、肺腺癌、肾癌、膀胱癌、韦尔姆瘤(Wilm’s tumor)和淋巴瘤。
在本发明前述方面的一些实施方式中,治疗选自口服给药、经粘膜给药、口腔给药、鼻腔给药、吸入、肠胃外给药、静脉内给药、皮下给药、肌肉内给药、舌下给药、透皮给药和直肠给药。
在本发明前述方面的一些实施方式中,来自对象的样品选自肿瘤组织、头发、血液、细胞、组织、器官、脑组织、血液、血清、痰、唾液、血浆、乳头吸出物(nipple aspirant)、滑液、脑脊液、汗水、尿、粪便物、胰液、小梁液(trabecular fluid)、脑脊液、泪水、支气管灌洗液、拭子、支气管吸出物(bronchial aspirant)、精液、前列腺液、脑室液(precervicular fluid)、阴道分泌物和射精前液(pre-ejaculate)。
本发明的再另一个方面涉及一种监测PARP抑制剂或其代谢物在疾病治疗中的疗效的方法,包括(i)对患者施用有效量的PARP抑制剂或其代谢物以抑制脂肪酸合成;(ii)比较来自患者的分别第一和第二样品中的第一和第二脂肪酸水平,其中第一水平和第一样品在施用PARP抑制剂或其代谢物之前获得,而第二水平和第二样品在施用PARP抑制剂或其代谢物之后获得;和(iii)基于比较结果确定在患者中所述PARP抑制剂或其代谢物在疾病治疗中的疗效。
在本发明前述方面的一些实施方式中,脂肪酸合成的抑制包括抑制葡萄糖途径或脂肪酸生物合成途径的至少一种酶。在一些实施方式中,当第二样品中的第二脂肪酸水平低于第一样品中的第一脂肪酸水平时,PARP抑制剂或其代谢物是有治疗效果的。在一些实施方式中,当第二样品中的第二脂肪酸水平高于第一样品中的第一脂肪酸水平时,PARP抑制剂或其代谢物是没有治疗效果的。在一些实施方式中,第一脂肪酸水平和第二脂肪酸水平通过分析技术测定。在一些实施方式中,第一脂肪酸水平和第二脂肪酸水平通过质谱分析测定。在一些实施方式中,质谱分析是质量同位体分布分析。
在本发明前述方面的一些实施方式中,PARP抑制剂或其代谢物是式I的化合物、其药学上可接受的盐或其前药:
式I
其中,R1、R2、R3、R4和R5独立地选自氢、羟基、任选取代的胺、羧基、酯、亚硝基、硝基、卤素、任选取代的(C1-C6)烷基、任选取代的(C1-C6)烷氧基、任选取代的(C3-C7)环烷基、任选取代的(C3-C7)杂环基、任选取代的芳基和含硫的基团。在一些实施方式中,含硫的基团是-SR6,其中R6选自氢、C1-C6酰基、任选取代的(C1-C6)烷基、任选取代的(C3-C7)环烷基、任选取代的(C3-C7)杂环基和任选取代的芳基。
在本发明前述方面的一些实施方式中,PARP抑制剂或其代谢物是式II的化合物、其药学上可接受的盐或其前药:
式II
其中,R1、R3、R4和R5独立地选自氢、羟基、任选取代的胺、羧基、酯、亚硝基、硝基、卤素、任选取代的(C1-C6)烷基、任选取代的(C1-C6)烷氧基、任选取代的(C3-C7)环烷基、任选取代的(C3-C7)杂环基、任选取代的芳基和-SR6;R2是硝基或亚硝基;且其中R1、R3、R4和R5取代基中的至少两个总是为氢;其中R6为-SR6,其中R6选自氢、C1-C6酰基、任选取代的(C1-C6)烷基、任选取代的(C3-C7)环烷基、任选取代的(C3-C7)杂环基和任选取代的芳基及任选的取代基。在一些实施方式中,R6为任选取代的(C1-C6)烷基,其为S-连接的半胱氨酸结构的残基,该半胱氨酸结构可以是单半胱氨酸氨基酸或可以形成包含半胱氨酸的二肽、三肽、四肽、五肽或更高级肽的一部分。
在本发明前述方面的一些实施方式中,PARP抑制剂是式III的化合物、其药学上可接受的盐或其前药:
式III。
在本发明前述方面的一些实施方式中,疾病是癌症、心血管疾病、糖尿病和肥胖。在一些实施方式中,施用选自口服给药、经粘膜给药、口腔给药、鼻腔给药、吸入、肠胃外给药、静脉内给药、皮下给药、肌肉内给药、舌下给药、透皮给药和直肠给药。在一些实施方式中,第一样品中的第一脂肪酸水平从患者的病史确定。
本发明的另一方面涉及一种治疗Her-2相关癌症的方法,包括对需要的患者施用有效量的PARP抑制剂或其代谢物,其中所述PARP抑制剂或其代谢物抑制脂肪酸合成。本发明的再另一方面涉及治疗对象的Her-2相关癌症的方法,包括:(i)确定来自对象的样品中Her-2表达的水平,和(ii)对对象施用有效量的PARP抑制剂或其代谢物以抑制脂肪酸合成,其中施用是基于Her-2表达水平的确定,从而治疗对象的Her-2相关癌症。
在本发明前述方面的一些实施方式中,脂肪酸合成的抑制包括抑制葡萄糖途径或脂肪酸生物合成途径的至少一种酶。在一些实施方式中,脂肪酸合成的抑制包括抑制脂肪酸合酶的至少一种酶,其中该酶选自酰基载体蛋白、乙酰转移酶、丙二酰转移酶、3-酮-酰基-ACP合成酶、3-酮酰基-ACP还原酶、3-羟基-酰基-ACP脱水酶和烯酰基-ACP还原酶。在一些实施方式中,Her-2表达水平是上调的。
在本发明前述方面的一些实施方式中,PARP抑制剂或其代谢物是式II的化合物、其药学上可接受的盐或其前药:
式II
其中,R1、R3、R4和R5独立地选自氢、羟基、任选取代的胺、羧基、酯、亚硝基、硝基、卤素、任选取代的(C1-C6)烷基、任选取代的(C1-C6)烷氧基、任选取代的(C3-C7)环烷基、任选取代的(C3-C7)杂环基、任选取代的芳基和-SR6;R2是硝基或亚硝基;且其中R1、R3、R4和R5取代基中的至少两个总是为氢;其中R6为-SR6,其中R6选自氢、C1-C6酰基、任选取代的(C1-C6)烷基、任选取代的(C3-C7)环烷基、任选取代的(C3-C7)杂环基和任选取代的芳基及任选的取代基。在一些实施方式中,R6为任选取代的(C1-C6)烷基,其为S-连接的半胱氨酸结构的残基,该半胱氨酸结构可以是单半胱氨酸氨基酸或可以形成包含半胱氨酸的二肽、三肽、四肽、五肽或更高级肽的一部分。
在本发明前述方面的一些优选实施方式中,PARP抑制剂是式III的化合物、其药学上可接受的盐或其前药:
式III。
在本发明前述方面的一些实施方式中,治疗选自口服给药、经粘膜给药、口腔给药、鼻腔给药、吸入、肠胃外给药、静脉内给药、皮下给药、肌肉内给药、舌下给药、透皮给药和直肠给药。在一些实施方式中,样品包括癌细胞。在一些实施方式中,该方法进一步包括施用Her-2抗体。在一些实施方式中,该方法进一步包括手术、放射治疗、化疗、基因治疗、免疫治疗或其组合。
本发明的再另一个方面涉及一种治疗代谢疾病的方法,包括对需要的患者施用有效量的式II的化合物、其药学上可接受的盐或其前药:
式II
其中,R1、R3、R4和R5独立地选自氢、羟基、任选取代的胺、羧基、酯、亚硝基、硝基、卤素、任选取代的(C1-C6)烷基、任选取代的(C1-C6)烷氧基、任选取代的(C3-C7)环烷基、任选取代的(C3-C7)杂环基、任选取代的芳基和-SR6;R2是硝基或亚硝基;且其中R1、R3、R4和R5取代基中的至少两个总是为氢;其中R6是-SR6,其中R6选自氢、C1-C6酰基、任选取代的(C1-C6)烷基、任选取代的(C3-C7)环烷基、任选取代的(C3-C7)杂环基和任选取代的芳基及任选的取代基。在一些实施方式中,R6为任选取代的(C1-C6)烷基,其为S-连接的半胱氨酸结构的残基,该半胱氨酸结构可以是单半胱氨酸氨基酸或可以形成包含半胱氨酸的二肽、三肽、四肽、五肽或更高级肽的一部分。在一些优选的实施方式中,式II的化合物、药学上可接受的盐或其前药抑制脂肪酸合成,从而治疗对象的代谢疾病。
本发明的再另一个方面涉及一种治疗对象的癌症的方法,包括:(i)确定来自对象的样品中的脂肪酸水平;(ii)对对象施用有效量的式II的化合物、其药学上可接受的盐或其前药,其中施用是基于脂肪酸水平的确定,其中式II的化合物、其药学上可接受的盐或其前药包括:
式II
其中,R1、R3、R4和R5独立地选自氢、羟基、任选取代的胺、羧基、酯、亚硝基、硝基、卤素、任选取代的(C1-C6)烷基、任选取代的(C1-C6)烷氧基、任选取代的(C3-C7)环烷基、任选取代的(C3-C7)杂环基、任选取代的芳基和-SR6;R2是硝基或亚硝基;且其中R1、R3、R4和R5取代基中的至少两个总是为氢;其中R6是-SR6,其中R6选自氢、C1-C6酰基、任选取代的(C1-C6)烷基、任选取代的(C3-C7)环烷基、任选取代的(C3-C7)杂环基和任选取代的芳基及任选的取代基。在一些实施方式中,R6为任选取代的(C1-C6)烷基,其为S-连接的半胱氨酸结构的残基,该半胱氨酸结构可以是单半胱氨酸氨基酸或可以形成包含半胱氨酸的二肽、三肽、四肽、五肽或更高级肽的一部分。在一些优选的实施方式中,式II的化合物、药学上可接受的盐或其前药抑制脂肪酸合成,从而治疗对象的癌症。
在本发明前述方面的一些实施方式中,脂肪酸合成的抑制包括抑制葡萄糖途径或脂肪酸生物合成途径的至少一种酶。在一些实施方式中,脂肪酸合成的抑制包括抑制脂肪酸合酶的至少一种酶,其中该酶选自酰基载体蛋白、乙酰转移酶、丙二酰转移酶、3-酮-酰基-ACP合成酶、3-酮酰基-ACP还原酶、3-羟基-酰基-ACP脱水酶和烯酰基-ACP还原酶。在一些实施方式中,式II的化合物、药学上可接受的盐或其前药包括式III的化合物或其代谢物:
式III。
在本发明前述方面的一些实施方式中,治疗选自口服给药、经粘膜给药、口腔给药、鼻腔给药、吸入、肠胃外给药、静脉内给药、皮下给药、肌肉内给药、舌下给药、透皮给药和直肠给药。在一些实施方式中,代谢疾病是心血管疾病、糖尿病或肥胖。在一些实施方式中,癌症是,例如Her-2相关癌症、结肠腺癌、食管腺癌、肝细胞肝癌、鳞状细胞癌、胰腺腺癌、胰岛细胞瘤、直肠腺癌、胃肠道基质瘤、胃腺癌、肾上腺皮质癌、滤泡性癌、乳头状癌、乳腺癌、导管癌、小叶癌、导管内癌、粘液癌、叶状肿瘤、卵巢腺癌、子宫内膜腺癌、颗粒细胞瘤、粘液性囊腺癌、子宫颈腺癌、外阴鳞状细胞癌、基底细胞癌、前列腺腺癌、骨巨细胞瘤、骨肉瘤、喉癌、肺腺癌、肾癌、膀胱癌、韦尔姆瘤和淋巴瘤。
通过引证引入
本说明书中提到的所有公开出版物和专利申请在此通过引证引入,就如各公开出版物和专利申请具体地和个别地说明通过引证引入一样。
附图简要说明
本发明的新特征在所附的权利要求中详细地阐明。参照下面给出示例性实施方式的详细说明和附图将获得对本发明的特征和优势的更好的理解,在这些实施方式中利用了本发明的原理。附图中:
图1显示了葡萄糖途径的代谢流(metabolic flux)。
图2显示了葡萄糖途径的戊糖循环和无效循环。
图3A和3B表明3μM和10μM的3-硝基-4-碘苯甲酰胺抑制Hela细胞中肉豆蔻酸的合成。
图4A和4B表明3μM和10μM的3-硝基-4-碘苯甲酰胺抑制Hela细胞中棕榈酸的合成。
图5A和5B表明3μM和10μM的3-硝基-4-碘苯甲酰胺抑制Hela细胞中硬脂酸的合成。
图6A和6B表明3μM和10μM的3-硝基-4-碘苯甲酰胺抑制Hela细胞中油酸的合成。
图7A和7B表明3μM和10μM的3-硝基-4-碘苯甲酰胺抑制Hela细胞中C:22脂肪酸的合成。
图8A和8B表明3μM和10μM的3-硝基-4-碘苯甲酰胺抑制Hela细胞中C:24脂肪酸的合成。
图9A和9B表明3μM和10μM的3-硝基-4-碘苯甲酰胺抑制OVCAR-3细胞中花生酸的合成。
图10A和10B表明3μM和10μM的3-硝基-4-碘苯甲酰胺抑制OVCAR-3细胞中C:22脂肪酸的合成。
图11A和11B表明3μM和10μM的3-硝基-4-碘苯甲酰胺抑制OVCAR-3细胞中C:24脂肪酸的合成。
具体实施方式
定义
术语“芳基”指的是任选取代的仅含碳原子的单环或二环芳香环。该术语还包括与单环环烷基或单环环杂烷基稠合的苯基,其中连接点是在芳香部分上。芳基的例子包括,例如苯基、萘基、茚满基、茚基、四氢萘基、2,3-二氢苯并呋喃基、1,4-苯并二噁烷基(benzodioxanyl)等等。
术语“杂环基”指的是任选取代的含有至少一个杂原子(碳以外的原子,如N、O和S)的单环或二环芳香环,各环含有大约5个到大约6个原子。杂环基的例子包括,例如吡咯基、异噁唑基、异噻唑基、吡唑基、吡啶基、噁唑基、噁二唑基、噻二唑基、噻唑基、咪唑基、三唑基、四唑基、呋喃基、三嗪基、噻吩基、嘧啶基、哒嗪基、吡嗪基、苯并噁唑基、苯并噻唑基、苯并咪唑基、苯并呋喃基、苯并噻吩基(benzothiophenyl)、呋喃(2,3-b)吡啶基、喹啉基、吲哚基、异喹啉基等等。
术语“抑制”或其语法上的同义词(如“抑制性的”)并不意味着需要完全降低所考虑的生物活性,如脂肪酸的合成。这一降低优选为降低了在不存在抑制效应时(例如在不存在抑制剂如本发明公开的PARA抑制剂时)分子活性的至少约50%、至少约75%、至少约90%,且更优选为至少约95%。最优选地,该术语指的是脂肪酸合成的可观察的或可测量的降低。在治疗的情况下,抑制作用优选地足以对所治疗的状态产生治疗和/或预防效果。
这里使用的术语“药学上可接受的盐”意思是保持本发明的化合物的生物学有效性和性能的那些盐,其在生物学上或其它方面不是不合需要的。
这里使用的术语“对象”或其语法上的同义词指的是健康的或者患有或怀疑患有疾病的温血动物,如哺乳动物。优选地,“对象”指的是人。
这里使用的术语“治疗”或其语法上的同义词意思是实现治疗效果和/或预防效果。治疗效果意思是进行治疗的基础病症的根除或缓解。治疗效果还通过一种或多种与基础病症相关的生理症状的根除或缓解而获得,从而在患者中观察到改善,尽管事实是患者可能仍受到基础病症的折磨。对于预防效果,可以对具有发生特定疾病的风险的患者,或者对尽管可能还没有诊断出疾病但报告有这一疾病的一种或多种生理学症状的患者施用该组合物。
定义
“硝基苯甲酰胺前体化合物”意思是式(Ia)化合物及其药学上可接受的盐、溶剂合物、异构体、互变异构体、代谢物、类似物或前药,
其中,R1、R2、R3、R4和R5独立地选自氢、羟基、氨基、硝基、碘、(C1-C6)烷基、(C1-C6)烷氧基、(C3-C7)环烷基和苯基,其中R1、R2、R3、R4和R5五个取代基中的至少两个总是为氢,五个取代基中的至少一个总是为硝基,且位置与硝基相邻的至少一个取代基总是为碘。R1、R2、R3、R4和R5也可以是如氯、氟或溴的卤素。“前体化合物”是经历生成代谢化合物的一种或多种化学或生物化学过程(例如,在细胞中或在生物体中)的化合物。术语“前体”、“前体化合物”、“苯甲酰胺前体”或“硝基苯甲酰胺前体”在这里可互换使用。
“代谢物”意思是通过生成结构上与起始化合物不同的产物的任何体外或体内代谢过程产生的化合物。换言之,术语“代谢物”包括硝基苯甲酰胺代谢化合物。代谢物可以包括相对于前体化合物(例如在式(Ia)中所示的前体化合物)存在于任何位置的不同数目或类型的取代基。另外,代谢物可以在相对于这里所描述的化合物存在于任何位置的取代基的类型数目上发生变化。另外,术语“代谢物”、“代谢化合物”、“苯甲酰胺代谢化合物”或“硝基苯甲酰胺代谢化合物”在这里可互换使用。
“手术”意思是对人或其它哺乳动物的身体进行的包括用手或手和仪器一起的有序行为以产生治愈、治疗或诊断效果的任何治疗或诊断过程。
“放射治疗”意思是将患者暴露于高能射线,包括但不限于X射线、伽马射线和中子辐射。这一类型的治疗包括,但不限于外照射疗法、内照射疗法、植入物放射疗法、近距放射疗法、全身放射疗法和放射疗法(radiotherapy)。
“化疗”意思是通过各种方法(包括静脉内、口服、肌肉内、腹膜内、膀胱内、皮下、透皮、口腔或吸入,或者栓剂的形式)向癌症患者施用一种或多种抗癌药物和/或其它物质。化疗可以在手术之前进行以使大的肿瘤缩小,随后通过手术过程切除,或者在手术或放射治疗之后进行以防止体内任何残留的癌细胞的生长。
术语“有效量”或“药学有效量”指的是无毒的但足以提供希望的生物的、治疗的和/或预防的结果的物质量。该结果可以是疾病的征兆、症状或诱因的减少和/或减轻,或者任何其它希望的生物系统的改变。例如,用于治疗用途的“有效量”是产生临床上疾病的显著减轻所需的如这里所公开的硝基苯甲酰胺代谢化合物本身或包含这里的硝基苯甲酰胺代谢化合物的组合物的量。在任何个别情况中的合适的有效量可以由本领域普通技术人员使用常规的试验确定。
术语“PARP抑制剂或其代谢物”包括其本身为PARP抑制剂的化合物以及这些化合物的活性代谢物。在一些实施方式中,所述PARP抑制剂的代谢物本身为PARP抑制剂,无论是否分离。在一些实施方式中,所述PARP抑制剂的代谢物被分离和纯化到至少50%、至少55%、至少60%、至少70%、至少75%、至少80%、至少90%、至少92%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%、至少99.5%、至少99.9%的纯度或更纯,之后与一种或多种药学上可接受的成分混合以制备如这里更详细地描述的药学上可接受的剂型。PARP抑制剂的代谢物是这里更详细地描述的PARP抑制剂“前体化合物”或“前体”的经代谢的形式。
“药学上可接受的”或“药理学上可接受的”意思是一种物质在生物学上或其它方面不是不合需要的,即该物质可以施用于个体而不引起任何不希望的生物学效应或不以有害的方式与包含该物质的组合物中的任何成分发生相互作用。
术语“治疗”及这里使用的其语法上的同义词包括实现治疗效果和/或预防效果。治疗效果意思是进行治疗的基础病症的根除或缓解。例如,在癌症患者中,治疗效果包括基础癌症的根除或缓解。治疗效果还通过一种或多种与基础病症相关的生理症状的根除或缓解而获得,从而在患者中观察到改善,尽管事实是患者可能仍受到基础病症的折磨。对于预防效果,可以在具有发生癌症的风险的患者身上,或者尽管可能还没有诊断出这些状态,但报告有这些状态的一种或多种生理学症状的患者身上实行本发明的方法,或者对这些患者施用本发明的组合物。
这里使用的“BA”意思是4-碘-3-硝基苯甲酰胺;“BNO”意思是4-碘-3-亚硝基苯甲酰胺;“BNHOH”意思是4-碘-3-羟氨基苯甲酰胺。
硝基苯甲酰胺代谢化合物
本发明中使用的PARA抑制剂(前体化合物)是式Ia的化合物及其药学上可接受的盐、溶剂合物、异构体、互变异构体、代谢物、类似物或前药
其中,R1、R2、R3、R4和R5独立地选自氢、羟基、氨基、硝基、碘、(C1-C6)烷基、(C1-C6)烷氧基、(C3-C7)环烷基和苯基,其中R1、R2、R3、R4和R5五个取代基中的至少两个总是为氢,五个取代基中的至少一个总是为硝基,且位置与硝基相邻的至少一个取代基总是为碘。R1、R2、R3、R4和R5也可以是如氯、氟或溴取代基的卤素。
优选的(PARP抑制剂)式Ia前体化合物是
4-碘-3-硝基苯甲酰胺
(BA)
可用于本发明中的PARP抑制剂代谢物是式(IIa)的化合物及其药学上可接受的盐、溶剂合物、异构体、互变异构体、代谢物、类似物或前药:
其中,或者(1)R1、R2、R3、R4和R5取代基中的至少一个总是为含硫的取代基,且R1、R2、R3、R4和R5中其它的取代基独立地选自氢、羟基、氨基、硝基、碘、溴、氟、氯、(C1-C6)烷基、(C1-C6)烷氧基、(C3-C7)环烷基和苯基,其中R1、R2、R3、R4和R5五个取代基中的至少两个总是为氢;或者(2)R1、R2、R3、R4和R5取代基中的至少一个不为含硫的取代基且五个取代基R1、R2、R3、R4和R5中的至少一个总是为碘,且其中所述碘总是与为硝基、亚硝基、羟氨基、羟基或氨基的R1、R2、R3、R4或R5基团相邻。在一些实施方式中,(2)中的化合物中碘基总是与为亚硝基、羟氨基、羟基或氨基的R1、R2、R3、R4或R5基团相邻。在一些实施方式中,(2)中的化合物中碘基总是与为亚硝基、羟氨基或氨基的R1、R2、R3、R4或R5基团相邻。在一些实施方式中,含硫的取代基是-SR6,其中R6选自氢、C1-C6酰基、任选取代的(C1-C6)烷基、任选取代的(C3-C7)环烷基、任选取代的(C3-C7)杂环基和任选取代的芳基。
下面的成分为式IIa包含的一些优选的PARP抑制剂代谢化合物,各由以下化学式表示:
R6选自氢、烷基(C1-C8)、烷氧基(C1-C8)、异喹啉酮、吲哚、噻唑、噁唑、噁二唑、噻吩或苯基
尽管不限于任何一种特定的机理,下面提供经由硝基还原酶或谷胱甘肽结合机制的MS292代谢的实例:
硝基还原酶机制
BA谷胱甘肽结合和代谢:
本发明提供前述硝基苯甲酰胺代谢化合物用于治疗其它乳腺癌(包括乳腺的导管癌)、其它形式的白血病(包括外周血中的急性早幼粒细胞白血病)、卵巢癌、肺癌、膀胱癌、前列腺癌、胰腺癌和子宫颈癌以及这里描述的其它癌症类型的用途。
已报道硝基苯甲酰胺代谢化合物对恶性癌细胞具有选择性细胞毒性,但对非恶性癌细胞没有。参见Rice等,Proc.Natl.USA 89:7703-7707(1992)。在一种实施方式中,本发明的方法中采用的硝基苯甲酰胺代谢化合物对肿瘤细胞比对非肿瘤细胞可以表现出更高的选择性毒性。
本发明的一个方面提供通过施用有效量的聚(ADP)核糖聚合酶(PARP)抑制剂治疗脂肪酸合成相关疾病的方法,其中PARP抑制剂抑制脂肪酸合成。脂肪酸合成相关疾病包括,但不限于癌症、糖尿病、肥胖、尼曼-皮克病、高歇氏病、异染性脑白质营养不良、弥漫性体血管角质瘤、透明膜病、泰-萨克斯病、桑德霍夫病、克拉伯病、岩藻糖苷沉积症、硫脂沉积症(sulfatide lipodosis)和Farber脂肪肉芽肿病(Farber′s lipogranulomatosis)。脂肪酸合成相关疾病包括脂肪酸代谢异常的疾病。
脂肪酸合成还涉及炎症(主要的是关节、皮肤和眼睛的炎症)、生殖功能(包括引产术)、抑制胃酸分泌、通过血管舒张或收缩调节血压和抑制或激活血小板聚集和血栓形成。在一些优选的实施方式中,脂肪酸合成相关疾病包括肥胖、糖尿病或心血管疾病。
本发明的另一方面涉及通过施用有效量的PARP抑制剂或其代谢物治疗对象的癌症的方法,其中PARP抑制剂或其代谢物抑制脂肪酸合成。该方法特别涉及通过确定对象的样品中的脂肪酸水平和施用有效量的PARP抑制剂或其代谢物以抑制脂肪酸合成而治疗对象的癌症的方法,其中施用是基于所述脂肪酸水平,从而治疗对象的癌症。
测试样品可以如从来源获得的原样直接使用或在进行预处理以改变样品的特性后使用。样品可以源自任何生物来源,如组织或提取物(包括细胞)和生理液体,例如,举例来说,全血、血浆、血清、唾液、接目镜液(ocular lens fluid)、脑脊液、汗水、尿、奶水、腹水(ascotsfluid)、滑液、腹膜液等等。样品从动物或人体获得,优选从人体获得。样品可以在使用前进行处理,如从血液制备血浆、稀释粘稠流体等等。处理样品的方法可以包括过滤、蒸馏、提取、浓缩、灭活干扰性组分、加入试剂等等。
通常,在正常人体中,脂肪酸生物合成途径是下调的且身体中的大部分脂肪酸来自于膳食脂肪。但是,在患有癌症的人体中,脂肪酸生物合成途径是上调的,从而导致肿瘤组织中的脂肪酸水平升高。在各种癌症中上调的脂肪酸合成表明脂肪酸合成提供了肿瘤生长的有利条件。脂肪酸合成的抑制可以导致膜脂的耗竭,这可以引起细胞死亡(Khaddar等,Proc.Natl.Acad.Sci.1994,vol.91,p.6379-6383)。本发明提供用有效量的PARP抑制剂或其代谢物治疗癌症的方法,其中PARP抑制剂或其代谢物抑制脂肪酸合成。各种癌症包括,但不限于膀胱、乳腺、结肠、直肠、前列腺、卵巢、唾液腺、皮肤附件、胆管、宫颈内膜、外宫颈、阴道、食道、鼻咽、口咽或生殖细胞起源的那些癌症,胃、子宫内膜、肾、肝和肺的癌或腺癌,黑色素瘤和间皮瘤。
在本发明的一些实施方式中,该方法包括通过施用有效量的PARP抑制剂或其代谢物治疗Her-2相关癌症,其中PARP抑制剂或其代谢物抑制脂肪酸合成。不意图限制本发明的范围,脂肪酸合酶(FAS)催化的脂肪酸的从头(de novo)生物合成可能通过其特定地调节Her-2/neu(erB-2)癌基因的表达和活性的能力而有助于癌症表型(Menendez JA等,Drug News Perspect.2005,18(6),375-85;MenendezJA等,J.Cell Biochem.2005,94(5),857-63)。PARP抑制剂或其代谢物对脂肪酸合成的抑制可以导致Her-2相关癌症的治疗。
在本发明的一些实施方式中,治疗Her-2相关癌症的方法包括确定来自对象的样品中Her-2表达的水平和对对象施用有效量的PARP抑制剂或其代谢物以抑制脂肪酸合成,其中施用是基于来自对象的样品中Her-2表达水平的确定。在一些优选的实施方式中,样品包括肿瘤细胞。如果样品中Her-2表达水平较高,则患者用有效量的PARP抑制剂或其代谢物进行治疗。并不限制本发明的范围,PARP抑制剂或其代谢物抑制脂肪酸合成并因此治疗Her-2相关癌症。在一些实施方式中,PARP抑制剂或其代谢物通过抑制葡萄糖途径或脂肪酸生物合成途径的一种或多种酶而抑制脂肪酸合成。在一些实施方式中,PARP抑制剂或其代谢物与Her-2抗体联合施用。Her-2抗体的一个例子是赫赛汀(herceptin)。
在本发明的一些优选的实施方式中,该方法包括通过施用有效量的PARP抑制剂或其代谢物治疗肥胖症,其中PARP抑制剂或其代谢物抑制脂肪酸合成。肥胖是在成人中正变得更加普遍,且迅速地在儿童和青少年中增长的一种主要的健康问题。肥胖已经与大范围的生理、情绪和社会经济问题相关联。本发明的用于减轻肥胖的方法可应用于人和其它动物,包括脊椎动物,特别是哺乳类动物。动物包括家禽、猪、牛、羊和其它动物,其中减少脂肪聚积而不降低肌肉质量对于兽医学健康或经济原因来说可能是理想的。可以出于兽医学健康的原因按照本发明的方法对狗、猫、马和其它动物施用PARP抑制剂。
在本发明的一些优选的实施方式中,该方法包括通过施用有效量的PARP抑制剂或其代谢物治疗心血管疾病,其中PARP抑制剂或其代谢物抑制脂肪酸合成。在一些人中,过量的身体脂肪导致患血管疾病(包括心脏病和中风)的风险增加。储存在腹内沉积物中的脂肪增加可能与动脉粥样硬化心血管病(ASCVD)的危险因素相关并可能引起动脉粥样硬化心血管病。ASCVD的危险因素包括:高血压、血液中的胆固醇特别是LDL-胆固醇水平升高、糖尿病和高血糖症。具有高血压的人可能发生葡萄糖耐量减低(一种糖尿病前的状况)。
在一些优选的实施方式中,该方法包括通过施用有效量的PARP抑制剂或其代谢物治疗糖尿病,其中PARP抑制剂或其代谢物抑制脂肪酸合成。患有糖尿病的患者可能具有几种脂异常中的任一种。患有糖尿病的患者中常见的脂特征包括甘油三酯、低密度脂蛋白(LDL)和极低密度脂蛋白(VLDL)的水平升高,以及低于正常水平的高密度脂蛋白(HDL)。这些因素的综合效应导致动脉粥样硬化和血栓症的生成。其它疾病包括,但不限于高胰岛素血症、胰岛素抵抗、心肌梗死、脂肪肝、多囊卵巢综合征、血色素沉着症、非酒精性脂肪性肝炎、糖尿病性肾病等。
尽管优选在用PARP抑制剂或其代谢物进行治疗前确定对象中的脂肪酸水平,但有经验的医生可以认识到,这种确定并不总是必需的。在癌症患者使用PARP抑制剂或其代谢物治疗后肿瘤负荷的降低将证明治疗前肿瘤中较高水平脂肪酸的存在。在癌症患者可以成功地通过本发明的方法治疗的情况下,对象中脂肪酸水平的独立确定可能不是必需的。对通常发现表达升高水平的脂肪酸的癌症类型的这种经验治疗也在本发明的范围内。
本发明的另一方面涉及监测PARP抑制剂或其代谢物在疾病治疗中的疗效的方法,包括对患者施用有效量的PARP抑制剂或其代谢物以抑制脂肪酸合成;比较来自患者的第一和第二样品中的第一和第二脂肪酸水平,其中第一水平和第一样品在施用PARP抑制剂或其代谢物之前获得,而第二水平和第二样品在施用PARP抑制剂或其代谢物之后获得;和基于比较结果确定PARP抑制剂或其代谢物在患者中的疾病治疗疗效。
第一样品的第一脂肪酸水平可以恰好在对患者施用PARP抑制剂或其代谢物之前测定或者可以在对患者施用PARP抑制剂或其代谢物之前数天、数周、数月或数年之前获得。第一样品的第一脂肪酸水平可以从患者的病史获得。可能发现第二样品的第二脂肪酸水平低于第一样品的第一脂肪酸水平,从而表明患者中的脂肪酸合成受到PARP抑制剂或其代谢物的抑制并因此表明PARP抑制剂或其代谢物的疗效。可能发现第二样品的第二脂肪酸水平高于第一样品的第一脂肪酸水平,从而表明PARP抑制剂或其代谢物的较低疗效。这种PARP抑制剂或其代谢物疗效的监测可用于调节剂量和对患者的给药方案进行个性化调整。这种监测也可以用于临床试验中。
本发明的方法中的脂肪酸合成抑制可以包括抑制葡萄糖途径或脂肪酸生物合成途径的一种或多种酶。并不限制本发明的范围,这里公开了葡萄糖途径或脂肪酸生物合成途径中涉及到的各种步骤和酶。任何一个或多个步骤和/或酶可以受到本发明的PARP抑制剂或其代谢物的抑制。
葡萄糖途径
葡萄糖的氧化称作糖酵解,其中葡萄糖被氧化为乳酸或丙酮酸。在有氧条件下,大多数组织中的产物是丙酮酸且该途径称为有氧糖酵解。当氧耗尽时,例如在长时间的剧烈运动过程中,在许多组织中的主要糖酵解产物是乳酸,且该过程称为无氧糖酵解。糖酵解的途径可以看作由两个单独的阶段组成。在第一阶段中,2当量的ATP用于将葡萄糖转化为果糖1,6-二磷酸(F1,6BP)。在第二阶段中F1,6BP降解为丙酮酸,产生4当量的ATP和2当量的NADH(参见图1和2)。
ATP-依赖的葡萄糖磷酸化以形成葡萄糖6-磷酸(G6P)是糖酵解的第一个反应,且被称作己糖激酶的组织特异性的同工酶催化。已知己糖激酶有四种哺乳动物同工酶(I-IV型),IV型同工酶通常称作葡萄糖激酶。葡萄糖激酶是在肝细胞中发现的该酶的形式。己糖激酶和葡萄糖激酶活性的调节也是不同的。己糖激酶I、II和III受到产物(G6P)蓄积的变构抑制,而葡萄糖激酶则不。尽管在需要葡萄糖对外周组织提供能量时帮助外周葡萄糖利用,后者也进一步确保在葡萄糖过量期间葡萄糖的肝蓄积。
糖酵解的第二个反应是异构化,其中G6P转化为果糖6-磷酸(F6P)。催化该反应的酶是磷酸己糖异构酶(也称作磷酸葡糖异构酶)。糖酵解的下一个反应包括利用第二个ATP将F6P转化为果糖1,6-二磷酸(F1,6BP)。该反应由6-磷酸果糖-1-激酶催化,该酶更多的称为磷酸果糖激酶-1或PFK-1。由于水解酶(果糖1,6-二磷酸酶,F-1,6-BPase)的普遍存在,果糖单元很容易沿相反的(糖异生的)方向流动。在同一细胞区域中存在这两种酶提供了代谢无效循环的例子,其中如果不受控制的话,将迅速地耗尽细胞能量储存。但是,这两种酶的活性受到高度的调节,从而PFK-1被认为是糖酵解的限速酶,F-1,6-BPase被认为是糖异生的限速酶。
醛缩酶催化F1,6BP水解成两个3-碳产物:二羟丙酮磷酸(DHAP)和甘油醛3-磷酸(G3P)。醛缩酶反应很容易沿相反的方向进行,而被用于糖酵解和糖异生作用。醛缩酶反应的两个产物很容易在丙糖磷酸异构酶催化的反应中保持平衡。糖酵解的后续反应利用G3P作为底物,因此醛缩酶反应通过质量作用原理沿糖酵解方向推进。
葡萄糖代谢的第二阶段特征是产生ATP和NADH的产能糖分解反应。在这些反应的第一个中,甘油醛3-P脱氢酶(G3PDH)催化G3P的NAD+-依赖氧化反应而氧化成1,3-二磷酸甘油酸(1,3BPG)和NADH。G3PDH反应是可逆的,相同的酶在糖异生作用中催化逆向反应。
1,3BPG的高能磷酸用于通过磷酸甘油酸激酶形成ATP和3-磷酸甘油酸(3PG)。与磷酸甘油酸激酶相关的是重要的红细胞反应,通过二磷酸甘油酸变位酶形成2,3-二磷酸甘油酸(2,3BPG)。2,3BPG是血红蛋白对氧的亲和力的重要调节剂。2,3-二磷酸甘油酸磷酸酶将2,3BPG降解为3-磷酸甘油酸,糖酵解的正常中间体。因此每个丙糖通过2,3BPG支路时该支路消耗1当量的ATP。
糖酵解的其它反应旨在通过甘油酸磷酸酶变位酶将3PG转化成2PG,且烯醇酶催化2PG转化成磷酸烯醇丙酮酸(PEP)。有氧糖酵解的最终反应是由高度调节的丙酮酸激酶(PK)催化的。在该放能反应中,PEP的高能磷酸化合物保存为ATP。PEP丧失磷酸导致产生不稳定的烯醇式丙酮酸,其自动发生异构变成更稳定的酮式丙酮酸。在无氧条件下和在有氧条件的红细胞中,丙酮酸通过乳酸脱氢酶(LDH)被转化成乳酸,且乳酸输送到细胞外进入血液循环中。
在有氧条件下,大多数细胞中的丙酮酸进一步通过TCA循环代谢。丙酮酸在TCA循环中优先氧化成CO2和H2O。当输送到线粒体中时,丙酮酸遇到两种主要的代谢酶:丙酮酸羧化酶(一种糖异生酶)和丙酮酸脱氢酶(PDH),PDH复合体的第一个酶。当能荷较低时,CoA不进行酰化,丙酮酸羧化酶失活,且丙酮酸优先通过PDH复合体和TCA循环的酶代谢成CO2和H2O。PDH复合体由多份的3种独立的酶组成:丙酮酸脱氢酶(20-30份)、二氢硫辛酸转乙酰酶(60份)和二氢硫辛酸脱氢酶(6份)。该复合酶还需要5种不同的辅酶:CoA、NAD+、FAD+、硫辛酸和硫胺素焦磷酸(TPP)。PDH复合体反应的净结果是:
丙酮酸+CoA+NAD+→CO2+乙酰-CoA+NADH+H+
PDH复合体反应用于将糖酵解、糖异生和脂肪酸合成的代谢途径相互连接到TCA循环上。
脂肪酸生物合成途径
脂肪酸使用底物乙酰CoA、丙二酰CoA和NADPH通过脂肪酸合酶(FAS)合成。因此,脂肪酸合成途径通常被认为包括四种酶,FAS和三种产生其底物的酶:乙酰CoA羧化酶(ACC)、苹果酸酶和柠檬酸裂合酶。可以将底物送入该途径中的其它酶,如通过己糖单磷酸支路产生NADPH的酶,也可以影响脂肪酸合成的速率,并因此在细胞中其依赖于内源合成的脂肪酸。这些酶中任何酶的表达或活性的抑制可能影响依赖于内源合成的脂肪酸的癌细胞的生长。
丙二酰-CoA的合成是脂肪酸合成的第一步,催化该反应的酶,乙酰-CoA羧化酶(ACC),是调节脂肪酸合成的部位。与将CO2转移到底物上的其它酶一样,ACC需要生物素辅因子。从乙酰-CoA和丙二酰-CoA合成脂肪酸通过脂肪酸合酶(FAS)完成。该活性酶是相同亚单元的二聚体。
脂肪酸合成的所有反应通过FAS的多种酶活性完成。如脂肪氧化反应一样,脂肪合成涉及四种酶活性。它们是β-酮-ACP合成酶、β-酮-ACP还原酶、3-OH酰基-ACP脱水酶和烯醇-CoA还原酶。两种还原反应需要NADPH氧化成NADP+。FAS合成的最初的脂肪酸是棕榈酸。
棕榈酸是16:0的脂肪酸,即16个碳且没有不饱和位。然后棕榈酸从酶上释放且随后可以经历单独的延长和/或不饱和作用以产生其它的脂肪酸分子。脂肪酸的延长和/或不饱和作用在线粒体和内质网(微粒体膜)中都发生。这些过程的主要位置是在内质网(ER)膜中。延长涉及酰基-CoA基团与丙二酰-CoA的缩合。所获得的产物延长了两个碳(在FAS反应中从丙二酰-CoA释放CO2),其经历还原、脱水和还原而产生饱和脂肪酸。延长作用的还原反应需要作为辅因子的NADPH,正如FAS催化的类似反应一样。线粒体的延长作用涉及乙酰-CoA单元且是氧化的逆转,除了最后的还原利用NADPH而不是FADH2作为辅因子。
去饱和作用在ER膜以及在哺乳动物细胞中发生,并涉及4种广泛特异性的脂肪酰基-CoA去饱和酶(包含非血红素铁的酶)。这些酶在C4、C5、C6或C9处引入非饱和化。在去饱和化期间从氧化的脂肪酸转移来的电子从去饱和酶转移到细胞色素b5,然后转移到NADH-细胞色素b5还原酶。一些饱和脂肪酸包括,但不限于,月桂酸(C:12)、肉豆蔻酸(C:14)、棕榈酸(C:16)、硬脂酸(C:18)、油酸(C:18-1)、花生酸(C:20)、C:22和C:24。一些不饱和酸包括,但不限于,二十二碳六烯酸、二十碳五烯酸、花生四烯酸、油酸和芥酸。
分析技术
对象的样品中脂肪酸水平的确定或用PARP抑制剂或其代谢物治疗后脂肪酸合成的抑制的确定可以采用本领域中已知的各种检测技术,包括,但不限于酶分析、质谱分析如气相色谱/质谱(GC/MS)、质量选择性检测分析(MSD)、化学离子化和选择性离子监测(SIM)、质量同位体分布分析、高效液相色谱(HPLC)或核磁共振(NMR)。
在对象用有效量的PARP抑制剂或其代谢物治疗后脂肪酸抑制的确定可以包括分析来自对象的样品中的葡萄糖或脂肪酸生物合成途径的各种代谢物或分子流。该确定可以包括与参比样品的一个或多个对比。参比样品通常从同一对象或从没有该疾病(如正常对象)或作为患者的不同对象获得。参比样品可以从一个对象、多个对象获得或者可以通过合成产生。确定也可以包括确认数据与数据库的比较。本发明的一个实施方式涉及确定患有疾病(如癌症)的对象中的脂肪酸水平并使其与正常对象的脂肪酸水平联系起来。如果在患有疾病的对象中脂肪酸水平上调,则该对象用抑制脂肪酸合成的有效量的PARP抑制剂或其代谢物治疗。
在一些实施方式中,比较脂肪酸水平的步骤通过软件算法进行。优选地,产生的数据转变成计算机可读的形式;且运行算法以按照用户输入的参数对数据分类,用于检测代表患病患者中的脂肪酸水平和正常对象中的脂肪酸水平的信号。
可以在本发明的方法中分析的葡萄糖或脂肪酸生物合成途径的代谢物包括,但不限于,脂肪酸或其代谢物、酶、葡萄糖、谷氨酸、糖原、乳酸、CO2、乙酰Co-A、RNA核糖和DNA脱氧核糖。葡萄糖或脂肪酸生物合成途径的分子流包括,但不限于从培养基摄取葡萄糖、从葡萄糖产生乳酸(无氧糖酵解)、通过TCA循环从葡萄糖释放13CO2、TCA循环回补流(anaplerotic flux)、糖原合成、脂肪酸从头合成、延长、去饱和和乙酰-CoA合成、及戊糖循环-通过氧化和非氧化反应的RNA和DNA核糖合成。代谢物可以在提取后和分析前进行化学衍生化。分析技术是本领域中公知的且在本发明的范围内。
分析技术包括活性分析或染色、采用抗体的免疫分析、测定酶mRNA(如FAS mRNA)的分析等等。参与葡萄糖途径或脂肪酸生物合成途径的酶的表达可以使用如免疫组织化学分析、胞质酶免疫分析或放射免疫分析、核酸探针与mRNA靶的原位杂交或酶活性的直接测定的分析方法在通过如活体检查、切除术或针抽吸的过程获得的肿瘤组样品中直接测定。酶的表达可以使用任何合适的分析方法用从对象获得的生物液体样品(如血液、尿、血清、淋巴、唾液、精液、腹水或特别是血浆)间接测定。优选的分析包括免疫分析或放射免疫分析。
在一些实施方式中,PARP抑制剂或其代谢物对于细胞、组织或生物体的疗效可以通过分析施用有效量的PARP抑制剂或其代谢物后细胞、组织或生物体中的多种代谢物(如脂肪酸)而测定。通过这种方法,可以对PARP抑制剂或其代谢物对脂肪酸合成的抑制进行监测。
在本发明的一些优选的实施方式中,葡萄糖途径或脂肪酸生物合成途径的代谢物或分子流通过质量同位体分布分析(MIDA)进行分析。在一些实施方式中,对所有或一部分细胞、组织或生物体中的多种代谢物的分子流率进行分析。一种或多种同位素标记的代谢物或代谢物前体在足以使一种或多种同位素标记进入细胞、组织或生物体的多种代谢物中的时间内施用于细胞、组织或生物体。从细胞、组织或生物体收集培养基或细胞沉淀。代表细胞沉淀或培养基中单个代谢物的离子的多个质量同位体组线(mass isotopomeric envelopes)通过质谱鉴定。另外,在对应于各鉴定的代谢物的同位素组线内离子的相对和绝对质量同位体丰度通过质谱鉴定。这些相对和绝对质量同位体丰度使得能够计算各鉴定的代谢物的合成或去除的速率,因而多种代谢物的分子流率得到确定。在一些实施方式中,代谢物可以在加入到质谱仪中之前进行衍生化。衍生化可以是本领域中已知的任何方法,如生物化学降解代谢物或化学改变代谢物。
同位素标记包括特定的存在于生物分子中的元素的重同位素,如2H、13C、15N、18O、35S、34S,或者可以包含存在于生物分子中的元素的其它同位素,如3H、14C、35S、125I、131I。同位素标记的代谢物包括,但不限于2H2O、15NH3、13CO2、H13CO3、2H-标记的氨基酸、13C-标记的氨基酸、15N-标记的氨基酸、18O-标记的氨基酸、33S或34S-标记的氨基酸、3H2O、3H-标记的氨基酸、14C-标记的氨基酸、14CO2和H14CO2等。
代谢流评价涉及揭示体内生物化学反应的稳态速率。关于代谢流的知识有助于代谢途径的优化以获得目标代谢产物的高产率。当在两种代谢物之间存在一种以上替代途径时,使用13C-标记的底物是定量细胞的胞内流的方法。在本发明中,[1,2-13C2]-D-葡萄糖用于培养基中作为葡萄糖的唯一来源。示踪方法是基于测量同位体分布,即具有其相对丰度的代谢物的不同13C-同位素形式。通过比较测量的同位体分布和使用各替代途径时预期的分布,可以推导出关于途径间流分布的信息。
有两种确定原子的位置同位体分布的方法:核磁共振(NMR)和质谱(MS)。MS可以与液相(LC-MS)或气相(GC-MS)色谱分离方法联合。这些方法也可以组合以获得更多的关于位置同位体分布的信息并因此也获得关于流的信息。在本发明的一些优选的实施方式中,原子的同位体分布和代谢物流通过质谱确定。可以使用的质谱方法是带有电子冲击(EI)离子化和全扫描模式的GC-MS。代谢分子的质量同位体由于高能量而同时在电离箱中碎裂,且在谱中观察到一系列的碎片离子。当使用GC-串联质谱方法(GC-MS/MS)时,可以选择和碎裂(子离子扫描)目标同位体离子以得到额外的信息。许多分析的代谢物是极性的,因而可能需要衍生化以将代谢物转化成具有足够的挥发性以进行GC-MS分析。在同位体分布计算中,也考虑来自衍生(dramatizing)试剂的原子。通过LC-MS方法,当电喷射离子化(ESI)用于分析极性代谢物时,通常不需要衍生化。
可从串联质谱数据确定的同位体分布的范围可能取决于两个方面:第一,可能需要使相应的峰足以可靠地检测的质量同位体频率。第二,可能需要足够的分子碎裂。为了完全确定各同位体的丰度,对于每一对碳原子可能需要恰好出现其中一个碳的碎片。
用PARP抑制剂或其代谢物进行治疗
适用于本发明中的化合物是抑制脂肪酸合成的化合物。优选抑制剂(及其代谢物)是PARP抑制剂。这里提供的化合物对脂肪酸合成的抑制可能包括抑制葡萄糖途径或脂肪酸生物合成途径的一种或多种酶。本发明的优选PARP抑制剂是式I的化合物、其药学上可接受的盐或其前药:
式I
其中,R1、R2、R3、R4和R5独立地选自氢、羟基、任选取代的胺、羧基、酯、亚硝基、硝基、卤素、任选取代的(C1-C6)烷基、任选取代的(C1-C6)烷氧基、任选取代的(C3-C7)环烷基、任选取代的(C3-C7)杂环基、任选取代的芳基和含硫的基团。在一些实施方式中,含硫的基团是-SR6,其中R6选自氢、C1-C6酰基、任选取代的(C1-C6)烷基、任选取代的(C3-C7)环烷基、任选取代的(C3-C7)杂环基和任选取代的芳基。
另一优选的PARP抑制剂是式II的化合物、其药学上可接受的盐或其前药:
式II
其中,R1、R3、R4和R5独立地选自氢、羟基、任选取代的胺、羧基、酯、亚硝基、硝基、卤素、任选取代的(C1-C6)烷基、任选取代的(C1-C6)烷氧基、任选取代的(C3-C7)环烷基、任选取代的(C3-C7)杂环基、任选取代的芳基和-SR6;R2是硝基或亚硝基;且其中R1、R3、R4和R5取代基中的至少两个总是为氢;其中R6为-SR6,其中R6选自氢、C1-C6酰基、任选取代的(C1-C6)烷基、任选取代的(C3-C7)环烷基、任选取代的(C3-C7)杂环基和任选取代的芳基及任选的取代基。在一些实施方式中,R6是任选取代的(C1-C6)烷基,其为S-连接的半胱氨酸结构的残基,该半胱氨酸结构可以是单半胱氨酸氨基酸或可以形成包含半胱氨酸的二肽、三肽、四肽、五肽或更高级肽的一部分。
一种优选的PARP抑制剂是式III的3-硝基-4-碘苯甲酰胺、其药学上可接受的盐或其前药:
式III。
本发明的一些实施方式涉及治疗代谢疾病的方法,包括对需要的患者施用有效量的式II的化合物、其药学上可接受的盐或其前药:
式II
其中,R1、R3、R4和R5独立地选自氢、羟基、任选取代的胺、羧基、酯、亚硝基、硝基、卤素、任选取代的(C1-C6)烷基、任选取代的(C1-C6)烷氧基、任选取代的(C3-C7)环烷基、任选取代的(C3-C7)杂环基、任选取代的芳基和-SR6;R2是硝基或亚硝基;且其中R1、R3、R4和R5取代基中的至少两个总是为氢;其中R6是-SR6,其中R6选自氢、C1-C6酰基、任选取代的(C1-C6)烷基、任选取代的(C3-C7)环烷基、任选取代的(C3-C7)杂环基和任选取代的芳基及任选的取代基;且其中式II的化合物、其药学上可接受的盐或其前盐抑制脂肪酸合成,从而治疗对象的代谢病。在一些实施方式中,R6为任选取代的(C1-C6)烷基,其为S-连接的半胱氨酸结构的残基,该半胱氨酸结构可以是单半胱氨酸氨基酸或可以形成包含半胱氨酸的二肽、三肽、四肽、五肽或更高级肽的一部分。
本发明进一步包括式I化合物的代谢物的用途。用于本发明的一些代谢物为式(IIa)的化合物及其药学上可接受的盐、溶剂合物、异构体、互变异构体、代谢物、类似物或前药:
其中,或者(1)R1、R2、R3、R4和R5取代基中的至少一个总是为含硫的取代基,且R1、R2、R3、R4和R5中其它的取代基独立地选自氢、羟基、氨基、硝基、碘、溴、氟、氯、(C1-C6)烷基、(C1-C6)烷氧基、(C3-C7)环烷基和苯基,其中R1、R2、R3、R4和R5五个取代基中的至少两个总是为氢;或者(2)R1、R2、R3、R4和R5取代基中的至少一个不为含硫的取代基且五个取代基R1、R2、R3、R4和R5中的至少一个总是为碘,且其中所述碘总是与为硝基、亚硝基、羟氨基、羟基或氨基的R1、R2、R3、R4或R5基团相邻。在一些实施方式中,(2)中的化合物中碘基总是与为亚硝基、羟氨基、羟基或氨基的R1、R2、R3、R4或R5基团相邻。在一些实施方式中,(2)中的化合物中碘基总是与为亚硝基、羟氨基或氨基的R1、R2、R3、R4或R5基团相邻。
下面的成分为优选的代谢化合物,各由以下化学式表示:
R6选自氢、烷基(C1-C8)、烷氧基(C1-C8)、异喹啉酮、吲哚、噻唑、噁唑、噁二唑、噻吩或苯基
在一些实施方式中,这里提供的化合物的代谢物可以用于本发明的方法中。例如,所述代谢物包括如名称为“Treatment of Cancer”、发明者为Ernest Kun、Jerome Mendeleyev、Carol Basbaum、HassanLemjabbar-Alaoui和Valeria Ossovskaya的2006年9月5日提交的代理人卷号为28825-729.101的美国申请中描述的那些,该文献通过引用全部引入本申请。
本发明的一些实施方式涉及治疗对象的癌症的方法,包括确定来自对象的样品中的脂肪酸水平和对对象施用有效量的式II的化合物、其药学上可接受的盐或其前药,其中施用是基于脂肪酸水平的确定。式II的化合物、其药学上可接受的盐或其前药抑制脂肪酸合成,从而治疗对象的癌症。
典型的盐是无机离子的盐,例如,举例来说,钠、钾、钙、镁离子等等。这些盐包括与无机酸或有机酸生成的盐,如盐酸、氢溴酸、磷酸、硝酸、硫酸、甲磺酸、对甲苯磺酸、乙酸、富马酸、琥珀酸、乳酸、苦杏仁酸、苹果酸、柠檬酸、酒石酸或马来酸。另外,如果化合物包含羧基或其它酸性基团,它可以与无机碱或有机碱转化成药学上可接受的加成盐。合适的碱的例子包括氢氧化钠、氢氧化钾、氨水、环己胺、二环己基胺、乙醇胺、二乙醇胺、三乙醇胺等等。
这里描述的PARP抑制剂可以包含一个或多个不对称中心并因此产生外消旋体和外消旋混合物、单对映异构体、单个非对映异构体和非对映异构体混合物。这些化合物的所有这些同分异构体形式明显地包括在本发明中。这里描述的PARP抑制剂也可以以互变异构形式表示,它们都包括在本发明中。PARP抑制剂也可以为顺式-或反式-或E-或Z-双键同分异构体形式。这些抑制剂的所有这些同分异构体形式明显地包括在本发明中。这里描述的PARP抑制剂的所有晶形明显地包括在本发明中。PARP抑制剂也可以以其药学上可接受的盐、衍生物或前药存在。
现有本领域中已知其它PARP抑制剂且它们在本发明的范围内。PARP抑制剂已设计为苯甲酰胺的类似物,其在PARP的催化位点与天然底物NAD竞争性地结合。PARP抑制剂包括,但不限于苯酰胺类、喹诺酮类和异喹诺酮类、苯并吡喃酮类、3,5-二碘-4-(4’-甲氧基苯氧基)苯甲酸甲酯和3,5-二碘-4-(4’-甲氧基苯氧基)苯乙酮(US5,464,871、US 5,670,518、US 6,004,978、US 6,169,104、US 5,922,775、US 6,017,958、US 5,736,576和US 5,484,951,所有文献通过引用全部引入本申请)。PARP抑制剂包括多种环状苯甲酰胺类似物(即内酰胺类),其为NAD位点的强抑制剂。其它PARP抑制剂包括,但不限于苯并咪唑类和吲哚类(EP 841924、EP 1127052、US 6,100,283、US6,310,082、US 2002/156050、US 2005/054631、WO 05/012305、WO99/11628和US 2002/028815)。本领域中已知的其它PARP抑制剂也可以抑制脂肪酸合成且在本发明的范围内(2006年6月12日提交的美国申请60/804563,其通过引用全部引入本申请)。
癌症类型
本发明中的癌症包括,但不限于结肠腺癌、食管腺癌、肝细胞肝癌、鳞状细胞癌、胰腺腺癌、胰岛细胞瘤、直肠腺癌、胃肠道基质瘤、胃腺癌、肾上腺皮质癌、滤泡性癌、乳头状癌、乳腺癌、导管癌、小叶癌、导管内癌、粘液癌、叶状肿瘤、卵巢腺癌、子宫内膜腺癌、颗粒细胞瘤、粘液性囊腺癌、子宫颈腺癌、外阴鳞状细胞癌、基底细胞癌、前列腺腺癌、骨巨细胞瘤、骨肉瘤、喉癌、肺腺癌、肾癌、膀胱癌、韦尔姆瘤和淋巴瘤。
癌症的其它例子包括,但不限于肾上腺皮质癌、肛门癌、再生障碍性贫血、胆管癌、膀胱癌、骨癌、骨转移、成人CNS脑肿瘤、儿童CNS脑肿瘤、乳腺癌、血管滤泡性淋巴组织增生(Castleman病)、子宫颈癌、幼年期非霍奇金淋巴瘤、结肠直肠癌、子宫内膜癌、食道癌、尤文氏(Ewing’s)肿瘤家族、眼癌、胆囊癌、胃肠道类癌肿瘤、胃肠道基质肿瘤、妊娠性滋养层细胞病、霍奇金氏病、卡波济肉瘤、肾癌、喉和下咽癌、急性淋巴细胞性白血病、急性骨髓性白血病、儿童白血病、慢性淋巴细胞性白血病、慢性骨髓性白血病、肝癌、肺类癌瘤、非霍奇金淋巴瘤、男性乳腺癌、恶性间皮瘤、多发性骨髓瘤、骨髓发育异常综合征、鼻腔和鼻旁癌、鼻咽癌、成神经细胞瘤、口腔和口咽癌、骨肉瘤、胰腺癌、阴茎癌、垂体瘤、前列腺癌、视网膜母细胞瘤、横纹肌肉瘤、唾液腺癌、肉瘤(成人软组织癌)、黑色素皮肤癌、非黑色素皮肤癌、胃癌、睾丸癌、胸腺癌、甲状腺癌、子宫肉瘤、阴道癌、外阴癌和瓦尔登斯特伦巨球蛋白血症。
本发明提供的方法可以包括与其它疗法结合施用PARP抑制剂。对可以与本发明的组合物共同施用的疗法的选择部分地取决于所治疗的状态。例如,对于治疗急性骨髓性白血病,PARP抑制剂可以与放射治疗、单克隆抗体治疗、化疗、骨髓移植、基因治疗、免疫治疗或其组合结合使用。
Her-2相关癌症
在一个方面中,本发明提供通过施用有效量的PARP抑制剂治疗Her-2相关癌症的方法。Her-2疾病是乳腺癌的类型。以侵略性的生长和较差的预后为特征,它可以由肿瘤细胞中存在过量数目的称为HER2(人表皮生长因子受体-2)的基因引起。可以与这里公开的PARP抑制剂联合使用的疗法包括,但不限于Her-2抗体(例如赫赛汀)、抗激素类(例如,选择性雌激素受体调节剂(SERM)它莫西芬)、化疗和放射治疗、芳香酶抑制剂(例如,阿那曲唑、来曲唑和依西美坦)和抗雌激素类(例如,氟维司群(Faslodex))。
乳腺癌
在一个方面中,本发明提供治疗乳腺癌的方法,包括,但不限于乳腺导管组织中的导管癌。
原位小叶癌和原位导管癌是分别在小叶和导管中发生,但可能不扩散到环绕乳腺的脂肪组织或身体的其它区域的乳腺癌。浸润性(或扩散性)小叶和导管癌是分别在小叶和导管中发生并扩散到乳腺的脂肪组织和/或身体的其它部分的癌症。可以从本发明的方法提供的治疗中获得益处的其它癌症是髓样癌、胶样癌、小管癌和炎性乳腺癌。
在一些实施方式中,本发明提供所谓的“三阴性”乳腺癌的治疗。有几种通过典型生物标志识别的乳腺癌亚类,如雌激素受体(ER)和/或黄体酮受体(PR)阳性肿瘤、HER2-扩增肿瘤和ER/PR/HER2-阴性肿瘤。这三种亚型已经通过多种乳腺癌中的基因表达分布型可再现地识别,并表现出基底细胞样(basal-like)亚型表达分布和较差的预后。三阴性乳腺癌的特征在于ER/PR/HER2-阴性肿瘤。
卵巢癌
在另一方面中,本发明提供治疗卵巢癌的方法,包括,但不限于上皮性卵巢肿瘤、卵巢中的腺癌和已经从卵巢转移到腹腔中的腺癌。可以与本发明的PARP抑制剂联合使用的卵巢癌的治疗包括,但不限于手术、免疫治疗、化疗、激素治疗、放射治疗或其组合。一些可能的手术方法包括肿瘤减积术(debulking),及单侧或双侧卵巢切除术和/或单侧或双侧输卵管切除术。
可以在联合疗法中使用的抗癌药物包括环磷酰胺、依托泊苷、六甲蜜胺和异环磷酰胺。采用药物它莫西芬的激素治疗可以用于缩减卵巢肿瘤。放射治疗可以是外照射疗法和/或近距放射疗法。
子宫颈癌
在另一方面中,本发明提供治疗子宫颈癌的方法,包括,但不限于子宫颈上皮中的腺癌。这一癌症存在两个主要的类型:鳞状细胞癌和腺癌。某些子宫颈癌同时具有这两者的特征并被称为腺鳞癌或混合癌。
前列腺癌
在一个另外的方面中,本发明提供治疗前列腺癌的方法,包括,但不限于腺癌或已转移到骨骼的腺癌。前列腺癌在男性的环绕尿道第一部分的前列腺器官中发生。
胰腺癌
在另一方面中,本发明提供治疗胰腺癌的方法,包括,但不限于胰腺导管组织中的上皮样癌和胰腺导管中的腺癌。
可以与本发明的PARP抑制剂联合使用的治疗包括,但不限于手术、免疫治疗、放射治疗和化疗。可能的手术治疗选择包括胰末端切除或胰全切除和胰十二指肠切除术(惠普尔手术)。放射治疗可以是胰腺癌患者的选择,例如,通过体外的仪器使射线聚焦于肿瘤上的外照射放射。另一种选择是在手术过程中采用的术中电子束照射。
膀胱癌
在另一方面中,本发明提供治疗膀胱癌的方法,包括,但不限于膀胱中的移行细胞癌。膀胱癌是尿道上皮癌(移行细胞癌)或衬于膀胱内的尿道上皮细胞中的肿瘤。膀胱癌的其它情况有鳞状上皮细胞癌、腺癌和小细胞癌。尿道上皮癌的几种亚型取决于它们是否是扩散性的和它们是乳头状的还是扁平的。非扩散性的肿瘤是在尿道上皮(膀胱的最内层)中,而扩散性的肿瘤从尿道上皮扩散到膀胱的主肌肉壁的更深层中。扩散性的乳头状尿道上皮癌是分叉到膀胱的中空中心中的细长手指样突起,且还向外生长到膀胱壁中。非扩散性的乳头状尿道上皮肿瘤朝向膀胱的中心生长。尽管非扩散性的扁平尿道上皮肿瘤(也称作原位扁平癌)限制于最靠近膀胱的内部中空部分的细胞层,但扩散性的扁平尿道上皮癌侵入膀胱的更深层,特别是肌肉层。
可以与本发明的PARP抑制剂联合用于治疗膀胱癌的疗法包括手术、放射治疗、免疫治疗、化疗或其组合。一些手术选择是经尿道切除术、膀胱切除术或根治性膀胱切除术。膀胱癌的放射治疗可以包括外照射和近距放射疗法。
免疫疗法是可以用于治疗膀胱癌患者的另一种方法。一种方法是卡介苗(BCG),其中有时用于结核病疫苗的细菌通过导管直接给予膀胱。身体发动对细胞的免疫应答,从而攻击和杀死癌细胞。免疫治疗的另一方法是施用调节免疫应答的干扰素类、糖蛋白类。干扰素α经常用于治疗膀胱癌。
可以用于联合治疗膀胱癌的抗癌药物包括塞替哌、氨甲蝶呤、长春花碱、阿霉素、环磷酰胺、紫杉醇、卡铂、顺铂、异环磷酰胺、吉西他滨或其组合。
急性骨髓性白血病
在另一方面中,本发明提供治疗急性骨髓性白血病(AML)的方法,优选为外周血中的急性早幼粒细胞白血病。AML在骨髓中开始,但可以扩散到身体的其它部分,包括淋巴结、肝脏、脾脏、中枢神经系统和睾丸。AML的特征是可以持续增殖和聚集的未成熟骨髓细胞,通常是粒细胞或单核细胞。
AML可以通过与本发明的PARP抑制剂联用的其它疗法治疗。这些疗法包括,但不限于免疫治疗、放射治疗、化疗、骨髓或外周血干细胞移植或其组合。放射治疗包括外照射且可能具有副作用。可以用于治疗AML的化疗中的抗癌药物包括阿糖胞苷、蒽环类抗生素、蒽二酮、脱甲氧柔红霉素、柔红霉素、伊达比星、米托蒽醌、硫鸟嘌呤、长春新碱、泼尼松、依托泊苷或其组合。
单克隆抗体治疗可以用于治疗AML患者。为了提供杀死身体中的白血病细胞的手段,小分子或放射性化学物质可以在施用于患者之前连接到这些抗体上。结合AML细胞上的CD33的单克隆抗体,吉姆单抗奥佐米星(gemtuzumab ozogamicin),可以用于治疗不能耐受现有的化疗方案的AML患者。骨髓或外周血干细胞移植可以用于治疗AML患者。一些可能的移植方法是同种异体或自体移植。
可以通过本发明提供的方法治疗的白血病的其它类型包括,但不限于急性淋巴细胞性白血病、急性骨髓性白血病、慢性淋巴细胞性白血病、慢性骨髓性白血病、毛细胞白血病、脊髓发育不良和骨髓增生性疾病。
肺癌
在另一方面中,本发明提供治疗肺癌的方法。肺癌的常见类型是非小细胞肺癌(NSCLC),其分成鳞状细胞癌、腺癌和大细胞未分化癌。与本发明的PARP抑制剂联用的肺癌的治疗选择包括手术、免疫治疗、放射治疗、化疗、光动力学治疗或其组合。用于治疗肺癌的一些可能的手术选择是分段或楔形切除术、肺叶切除术或肺切除术。放射治疗可以是外照射疗法或近距放射疗法。
可用于治疗肺癌的化疗中的一些抗癌药物包括顺铂、卡铂、紫杉醇、多西他赛、吉西他滨、长春瑞滨、依立替康、依托泊苷、长春花碱、埃罗替尼、吉非替尼、异环磷酰胺、氨甲蝶呤或其组合。光动力学治疗(PDT)可以用于治疗肺癌患者。
皮肤癌
在另一方面中,本发明提供治疗皮肤癌的方法。有几种开始于皮肤的癌症类型。最常见的类型是基底细胞癌和鳞状细胞癌,其为非黑素瘤皮肤癌。光线性角化病为有时发展成鳞状细胞癌的皮肤状态。非黑素瘤皮肤癌很少扩散到身体的其它部分。黑色素瘤(皮肤癌中最少见的形式)更可能侵入附近组织并扩散到身体的其它部分。
可以与本发明的PARP抑制剂联用的不同类型的治疗包括,但不限于手术、放射治疗、化疗和光动力学治疗。治疗皮肤癌的一些可能的手术选择是莫氏显微手术、简单切除、电干燥法和刮除术、冷冻手术、激光手术。放射治疗可以是外照射疗法或近距放射疗法。其它类型的治疗包括生物治疗或免疫治疗、化学免疫治疗、采用氟尿嘧啶的局部化疗和光动力学治疗。
眼癌,视网膜母细胞瘤
在另一方面中,本发明提供治疗眼视网膜母细胞瘤的方法。视网膜母细胞瘤是视网膜的恶性肿瘤。该肿瘤可以仅在一只眼睛中或在两只眼睛中发生。可以与本发明的PARP抑制剂联用的治疗选择包括摘出术(摘除眼睛的手术)、放射治疗、冷冻治疗、光凝固术、免疫治疗、温热治疗和化疗。放射治疗可以是外照射疗法或近距放射疗法。
眼癌,眼内黑色素瘤
在另一方面中,本发明提供治疗眼内(眼)黑色素瘤的方法。眼内黑色素瘤是在称为葡萄膜的眼部分中发现癌细胞的疾病。葡萄膜包括虹膜、睫状体和脉络膜。眼内黑色素瘤最经常在中年人群中发生。可以与本发明的PARP抑制剂联用的治疗包括手术、免疫治疗、放射治疗和激光治疗。手术是最常见的眼内黑色素瘤治疗方法。一些可能的手术选择是虹膜切除术、虹膜小梁切除术、虹膜睫状体切除术、脉络膜切除术、摘出术和眶内容摘除术。放射治疗可以是外照射疗法或近距放射疗法。激光治疗可以是用于毁灭肿瘤的强有力的光束、温热疗法或光凝固术。
子宫内膜癌
在另一方面中,本发明提供治疗子宫内膜癌的方法。子宫内膜癌是开始于子宫内膜(子宫的内衬)中的癌症。子宫癌和子宫内膜癌的一些实例包括,但不限于腺癌、腺棘皮瘤、腺鳞状细胞癌、乳头状浆液性腺癌、透明细胞腺癌、子宫肉瘤、基质瘤、恶性混合中胚叶肿瘤和平滑肌肉瘤。
肝癌
在另一方面中,本发明提供治疗原发肝癌(在肝脏中开始的癌症)的方法。原发肝癌在成人和儿童中都可发生。可以与本发明的PARP抑制剂联用的不同类型的治疗包括手术、免疫治疗、放射治疗、化疗和经皮乙醇注射。可以使用的手术类型是冷冻手术、部分肝切除术、全肝切除术和射频消蚀(radiofrequency ablation)。放射治疗可以是外照射疗法、近距放射疗法、放射致敏剂或放射标记抗体。其它类型的治疗包括高温治疗和免疫治疗。
肾癌
在另一方面中,本发明提供治疗肾癌的方法。肾癌(也称作肾细胞癌或肾腺癌)是在肾脏的小管内衬中发现恶性细胞的疾病。可以与本发明的PARP抑制剂联用的治疗包括手术、放射治疗、化疗和免疫治疗。一些可能的治疗肾癌的手术选择是肾部分切除术、简单肾切除术和根治性肾切除术。放射治疗可以是外照射疗法或近距放射疗法。干细胞移植可用于治疗肾癌。
甲状腺癌
在另一方面中,本发明提供治疗甲状腺癌的方法。甲状腺癌是在甲状腺组织中发现癌(恶性)细胞的疾病。甲状腺癌的四种主要类型是乳头状甲状腺癌、滤泡性甲状腺癌、甲状腺髓样癌和甲状腺间变癌。甲状腺癌可以通过手术、免疫治疗、放射治疗、激素治疗和化疗进行治疗。可以用于与本发明的PARP抑制剂联用的一些可能的手术选择包括,但不限于叶切除术、甲状腺近全切除术、甲状腺全切除术和淋巴结清扫术(lymph node dissection)。放射治疗可以是外照射疗法或可能需要摄入含有放射性碘的液体。激素治疗使用激素阻止癌细胞生长。在治疗甲状腺癌时,激素可以用于阻止身体产生可能使癌细胞生长的其它激素。
AIDS相关癌症
AIDS-相关淋巴瘤
在另一方面中,本发明提供治疗AIDS-相关淋巴瘤的方法。AIDS-相关淋巴瘤是在患有获得性免疫缺陷综合征(AIDS)的患者的淋巴系统中形成恶性细胞的疾病。AIDS是由攻击和削弱人体的免疫系统的人类免疫缺陷病毒(HIV)引起的。然后免疫系统不能够迎击感染和侵袭人体的疾病。患有HIV疾病的人具有发生感染、淋巴瘤和其它类型癌症的较大风险。淋巴瘤是影响淋巴系统的白细胞的癌症。淋巴瘤分成两个总的类型:霍奇金淋巴瘤和非霍奇金淋巴瘤。霍奇金淋巴瘤和非霍奇金淋巴瘤都可以在AIDS患者中发生,但非霍奇金淋巴瘤更常见。当患有AIDS的人具有非霍奇金淋巴瘤时,这称为AIDS-相关淋巴瘤。非霍奇金淋巴瘤可以是进展缓慢的(生长迟缓的)或侵袭性的(生长快速的)。AIDS-相关淋巴瘤通常是侵袭性的。AIDS-相关淋巴瘤的三种主要类型是弥漫性大B-细胞淋巴瘤、B-细胞免疫母细胞淋巴瘤和小无裂细胞淋巴瘤。
高效抗逆转录病毒疗法(HAART)用于减缓HIV的进展。也使用防止和治疗(可能是严重的)感染的药品。AIDS-相关淋巴瘤可以通过化疗、免疫治疗、放射治疗和伴随干细胞移植的高剂量化疗进行治疗。放射治疗可以是外照射疗法或近距放射疗法。AIDS-相关淋巴瘤可以通过单克隆抗体疗法进行治疗。
卡波济肉瘤
在一个方面中,本发明提供治疗卡波济肉瘤的方法。卡波济肉瘤是在皮肤或内衬于口、鼻和肛门的粘膜下的组织中发现癌细胞的疾病。卡波济肉瘤可以在服用免疫抑制剂的人中发生。在患有获得性免疫缺陷综合征(AIDS)的患者中的卡波济肉瘤被称为流行性卡波济肉瘤。卡波济肉瘤可以用手术、化疗、放射治疗和免疫疗法治疗。外照射疗法是卡波济肉瘤的常用治疗方法。可以用于与本发明的PARP抑制剂联用的治疗包括,但不限于局部切除术、电干燥法和刮除术、及冷冻疗法。
病毒诱导的癌症
在另一方面中,本发明提供治疗病毒诱导的癌症的方法。主要的病毒-恶性肿瘤系统包括乙型肝炎病毒(HBV)、丙型肝炎病毒(HCV)和肝细胞癌;1型人嗜T淋巴细胞病毒(HTLV-1)和成体T-细胞白血病/淋巴瘤;和人乳头状瘤病毒(HPV)和子宫颈癌。
病毒诱导的肝细胞癌
HBV和HCV两种病毒与肝细胞癌或肝癌都通过引起细胞死亡和随后的再生经由肝脏中的慢性复制而发挥作用。可以用于与本发明的PARP抑制剂联用的治疗包括,但不限于手术、免疫疗法、放射疗法、化疗和经皮乙醇注射。可以使用的手术的类型是冷冻手术、部分肝切除术、全肝切除术和射频消蚀。放射治疗可以是外照射疗法、近距放射疗法、放射致敏剂或放射标记抗体。其它类型的治疗包括高温治疗和免疫治疗。
病毒诱导的成体T-细胞白血病/淋巴瘤
成体T-细胞白血病是血液和骨髓的癌症。可以用于与本发明的PARP抑制剂联用的成体T-细胞白血病/淋巴瘤的治疗包括,但不限于放射治疗、免疫治疗和化疗。放射治疗可以是外照射疗法或近距放射疗法。治疗成体T-细胞白血病/淋巴瘤的其它方法包括免疫治疗和具有干细胞移植的高剂量化疗。
病毒诱导的子宫颈癌
子宫颈被人乳头状瘤病毒(HPV)感染是子宫颈癌的原因。可以用于与本发明的PARP抑制剂联用的治疗包括,但不限于手术、免疫治疗、放射治疗和化疗。可以使用的手术的类型是宫颈锥形切除术、全子宫切除术、双侧输卵管卵巢切除术、子宫根治术、盆腔廓清术、冷冻手术、激光手术和环形电外科切除术(loop electrosurgical excisionprocedure)。放射治疗可以是外照射疗法或近距放射疗法。
CNS癌症
脑和脊髓肿瘤是在作为中枢神经系统(CNS)主要部分的颅骨或骨质脊柱内部发现的组织的非正常生长。良性肿瘤是非癌性的,而恶性肿瘤是癌性的。源于脑或脊髓的肿瘤被称为原发肿瘤。原发肿瘤可以由特定的遗传疾病(例如,神经纤维瘤病、结节性硬化症)引起或由于暴露于辐射或致癌化学物质而引起。
成人中的原发脑肿瘤来自于被称为星形细胞的脑细胞,星形细胞构成血脑屏障并有助于中枢神经系统的营养。这些肿瘤被称为神经胶质瘤(星形细胞瘤、间变星形细胞瘤或多形性成胶质细胞瘤)。这些肿瘤中的一些包括,但不限于少突神经胶质细胞瘤、室管膜瘤、脑脊膜瘤、淋巴瘤、神经鞘瘤和成神经管细胞瘤。
CNS的神经上皮肿瘤
星形细胞肿瘤,如星形细胞瘤;间变(恶性)星形细胞瘤,如大脑半球的、间脑的、眼的、脑干的、小脑的;多形性成胶质细胞瘤;毛细胞性星形细胞瘤,如大脑半球的、间脑的、眼的、脑干的、小脑的;室管膜下的巨细胞星形细胞瘤;和多形性黄色瘤型星形细胞瘤。少突神经胶质肿瘤,如少突神经胶质细胞瘤和间变(恶性)少突神经胶质细胞瘤。室管膜细胞肿瘤,如室管膜瘤、间变性室管膜瘤、粘液乳头形室管膜瘤和亚室管膜瘤(subependymoma)。混合神经胶质瘤,如混合性少突星形细胞瘤、间变(恶性)少突星形细胞瘤和其它的(例如,室管膜星形细胞瘤)。起源不确定的神经上皮肿瘤,如极性成胶质细胞瘤、星形母细胞瘤和大脑胶质瘤病。脉络丛的肿瘤,如脉络丛乳头状瘤和脉络丛癌(间变性脉络丛乳头状瘤)。神经细胞和混合神经细胞神经胶质肿瘤,如神经节细胞瘤;小脑发育不良性神经节细胞瘤(Lhermitte-Duclos);神经节神经胶质瘤;间变(恶性)神经节神经胶质瘤;婴儿型促纤维增生型神经节神经胶质瘤,如婴儿型促纤维增生型星形细胞瘤;中枢神经细胞瘤;胚胎发育不良性神经上皮肿瘤;嗅神经母细胞瘤(成感觉神经细胞瘤)。松果体实质(Pineal Parenchyma)肿瘤,如松果体瘤、成松果体细胞瘤和混合松果体瘤/成松果体细胞瘤。带有成神经细胞或成神经胶质细胞因素的肿瘤(胚胎性肿瘤),如髓上皮瘤;具有多能分化的原始神经外胚层肿瘤,如成神经管细胞瘤;大脑原始神经外胚层肿瘤;神经母细胞瘤;视网膜母细胞瘤和成室管膜细胞瘤。
其它CNS肿瘤
鞍区(Sellar Region)的肿瘤,如垂体腺瘤、垂体腺癌和颅咽管瘤。造血系统肿瘤,如原发恶性淋巴瘤、浆细胞瘤和粒细胞肉瘤。生殖细胞肿瘤,如生殖细胞瘤、胚胎性癌、卵黄囊瘤(内胚层窦瘤)、绒毛膜癌、畸胎瘤和混合生殖细胞肿瘤。脑脊膜的肿瘤,如脑脊膜瘤、非典型脑脊膜瘤和间变(恶性)脑脊膜瘤。脑脊膜的非脑膜上皮肿瘤,如良性间充质肿瘤;恶性间充质肿瘤;原发黑色素细胞性病变;造血系统肿瘤;和组织发生不确定的肿瘤,如成血管细胞瘤(毛细血管成血管细胞瘤)。脑神经和脊神经的肿瘤,如许旺氏细胞瘤(神经鞘瘤(neurinoma)、神经鞘瘤(neurilemoma));神经纤维瘤;恶性外周神经鞘肿瘤(恶性神经鞘瘤),如上皮样的、不同的间质或上皮分化的和黑变病的肿瘤。区域性肿瘤的局部扩展,如副神经节瘤(化学感受器瘤)、脊索瘤、chodroma、软骨肉瘤和癌。转移性肿瘤,未分类肿瘤及囊肿和肿瘤样病变,如Rathke裂囊肿、表皮样瘤、皮样囊肿、第三脑室的胶样囊肿、肠原囊肿、神经胶质囊肿、粒细胞肿瘤(迷芽瘤、垂体细胞瘤)、下丘脑神经细胞错构瘤、鼻部神经胶质异位(nasal glialherterotopia)和浆细胞肉芽肿。
可用的化学治疗剂包括,但不限于烷化剂,如环磷酰胺、异环磷酰胺、美法仑、苯丁酸氮芥、BCNU、CCNU、氮烯唑胺(Decarbazine)、甲苄肼、白消安和噻替派;抗代谢物,如甲氨蝶呤(Methotraxate)、5-氟尿嘧啶、阿糖胞苷、吉西他滨6-巯基嘌呤、6-硫鸟嘌呤、氟达拉滨和克拉屈滨;蒽环类,如柔红霉素、阿霉素、伊达比星、表柔比星和米托蒽醌;抗生素类,如博来霉素;喜树碱类,如依立替康和托泊替康;紫杉烷类,如紫杉醇和多西他赛;及铂类,如顺铂、卡铂和奥沙利铂。
PNS癌症
外周神经系统由从脑和脊髓分枝的神经组成。这些神经形成CNS和身体部分之间的通讯网络。外周神经系统进一步细分成躯体神经系统和植物性神经系统。躯体神经系统由到达皮肤和肌肉并参与意识活动的神经组成。植物性神经系统由将CNS连接到脏器(如心脏、胃和肠)的神经组成。它介导非意识活动。
听神经瘤是从平衡神经(也称为第八脑神经或前庭蜗神经)产生的良性纤维性生长。恶性外周神经鞘瘤(MPNST)是良性软组织瘤(如神经纤维瘤和神经鞘瘤)的恶性对应体。它最常见于深部软组织中,通常在神经干的极近处。最常见的位置包括坐骨神经、臂丛和骶丛(sarcalplexus)。
MPNST可以分成具有上皮样的、间充质的或腺性的特征的三个主要类别。MPNST中的一些包括,但不限于带软骨分化的皮下恶性上皮样神经鞘瘤、腺性的恶性神经鞘瘤、带神经束膜分化的恶性外周神经鞘瘤、带杆状特征的皮下上皮样恶性神经鞘瘤、表皮的上皮样MPNST、蝾螈瘤(带成横纹肌细胞分化的MPNST)、带成横纹肌细胞分化的神经鞘瘤。稀有MPNST病例包含多种肉瘤性组织类型,特别是骨肉瘤、软骨肉瘤和血管肉瘤。这些肿瘤有时不能与软组织的恶性间质瘤区分开。
其它类型的PNS癌症包括,但不限于恶性纤维性细胞瘤、恶性纤维性组织细胞瘤、恶性脑脊膜瘤、恶性间皮瘤和恶性混合苗勒氏肿瘤。
口腔和口咽癌症
口腔癌症包括,但不限于下咽癌、喉癌、鼻咽癌和口咽癌。
胃癌
有三种主要类型的胃癌:淋巴瘤、胃基质瘤和类癌瘤。淋巴瘤是有时在胃壁中发现的免疫系统组织的癌症。胃基质瘤从胃壁的组织发生。类癌瘤是胃的激素产生细胞的肿瘤。
睾丸癌
睾丸癌是通常在年轻男性的一个或两个睾丸中发生的癌症。睾丸的癌症在被称为生殖细胞的特定细胞中发生。在男性中发生的生殖细胞肿瘤(GCT)的两个主要类型是精原细胞瘤(60%)和非精原细胞瘤(40%)。肿瘤也可以在睾丸的支持和激素产生组织或基质中发生。这类肿瘤被称为性腺基质细胞瘤。两个主要类型是睾丸间质细胞瘤和睾丸支持细胞瘤。继发睾丸瘤是在另一器官中开始,然后扩散到睾丸的肿瘤。淋巴瘤是继发睾丸瘤。
胸腺癌
胸腺是位于胸腔上/前部中的小器官,从喉基部延伸到心脏前部。胸腺包含两种主要类型的细胞,胸腺上皮细胞和淋巴细胞。胸腺上皮细胞可以是胸腺瘤和胸腺癌的起源。淋巴细胞(不论是在胸腺中还是在淋巴结中)可以变成恶性的并发展成被称为霍奇金氏病和非霍奇金淋巴瘤的癌症。胸腺癌包括嗜银(Kulchitsky)细胞或神经内分泌细胞,其通常释放特定的激素。这些细胞可以引起被称为类癌或类癌瘤的癌症。
可以与本发明的PARP抑制剂联用的治疗包括,但不限于手术、免疫治法、化疗、放射治法、化疗和放射治疗的组合或生物学治疗。已经用于胸腺瘤和胸腺癌治疗的抗癌药物为阿霉素(亚德里亚霉素)、顺铂、异环磷酰胺和皮质激素类(泼尼松)。
营养和代谢障碍
营养和代谢障碍的例子包括,但不限于尿崩症、Fabry病、脂肪酸代谢障碍、半乳糖血症、戈谢病、葡萄糖-6-磷酸脱氧酶(G6PD)、戊二酸尿、赫尔勒-沙利氏综合征(hurler-scheie)、Hunter综合征、低磷酸盐血症、I细胞、克拉伯病、乳酸性酸中毒、长链3羟酰基CoA脱氢酶缺失(LCHAD)、溶酶体贮积症、甘露糖苷贮积症、槭糖尿病、Maroteaux-Lamy综合征、异染性脑白质营养不良、线粒体病、Morquio病、黏多糖贮积症、脑神经新陈代谢病(neuro-metabolic)、尼曼-皮克病、有机酸血症、嘌呤、苯丙酮酸尿(PKU)、庞佩氏病、假hurler病、丙酮酸脱氢酶缺失、桑德霍夫病、桑菲利波综合征、席耶氏综合征、Sly综合征、泰-萨克斯病、三甲基胺尿症(臭鱼症)、尿素循环状态、维生素D缺乏佝偻病、肌肉代谢病、遗传性代谢障碍、酸-碱失衡、酸中毒、碱中毒、尿黑酸尿、α-甘露糖苷贮积症、淀粉样变性、贫血症、铁质缺乏、抗坏血酸缺乏、维生素缺乏症、脚气病、生物素酰胺酶缺乏症、缺乏糖蛋白综合征、肉碱障碍、胱氨酸贮积症、胱氨酸尿、法布里病、脂肪酸氧化障碍、岩藻糖苷贮积症、半乳糖血症、戈谢病、吉尔伯特氏综合征、葡萄糖磷酸脱氧酶缺失、戊二酸血症、糖原贮积症、哈特纳普病、血色素沉积症、含铁血黄素沉着症、肝豆状核变性、组氨酸血症、同型胱氨酸尿症、高胆红素血症、高钙血症、高胰岛素血症、高钾血症、高脂血症、高草酸尿、维生素A过多症、低钙血症、低血糖症、低钾血症、低钠血症、低磷酸酯酶症(hypophosphotasia)、胰岛素抵抗、碘缺乏、铁过载、黄疸,慢性先天性的、利氏病、莱施-奈恩综合征、亮氨酸代谢障碍、溶酶体贮积症、镁缺乏、枫糖尿症、MELAS综合征、Menkes卷发综合征、代谢综合征X、粘脂贮积病、粘多糖贮积症(mucopolysacchabridosis)、尼曼-皮克病、肥胖症、鸟氨酸氨甲酰基转移酶缺乏病、骨软化症、糙皮病、过氧物酶体病、卟啉症、红细胞生成的、斑岩(porphyries)、假戈谢病、雷夫叙姆病、急性脑病综合征、佝偻病、桑德霍夫病、丹吉尔病、泰-萨克斯病、四氢生物蝶呤缺乏、三甲基胺尿症(臭鱼症)、酪氨酸血症、尿素循环障碍、水-电解质失衡、韦尼克脑病、维生素A缺乏、维生素B12缺乏、维生素B缺乏、沃尔曼病和泽韦格综合征。
在一些优选的实施方式中,代谢疾病包括糖尿病和肥胖症。
使用方法
适用于本发明中的化合物是抑制脂肪酸合成的化合物。优选地该抑制剂是PARP抑制剂。在用有效量的PARP抑制剂治疗之前和/或之后对脂肪酸水平的分析具有各种治疗和诊断应用。临床应用包括,例如疾病的检测、区分疾病状态以为诊断提供信息、疗法的选择(如用有效量的PARP抑制剂进行治疗)、治疗反应的预测、疾病分期、病程的鉴定、PARP抑制剂疗效的预测、患者轨迹的监测(例如,发病之前)、PARP抑制剂副反应的预测、治疗相关效力和毒性的监测及复发的检测。对象的脂肪酸水平的鉴定也可以用于为PARP抑制剂治疗的对象选择疗法和个性化给药方案。
对象的脂肪酸水平的鉴定和随后有效量PARP抑制剂的治疗可用于使得能够或有助于治疗药剂的药物开发过程。脂肪酸水平的鉴定可以用于选择加入到PARP抑制剂的临床试验中的对象。脂肪酸水平的进一步鉴定可以指明进行临床试验的治疗的对象的疾病状态,并显示PARP抑制剂治疗过程中状态的变化。脂肪酸水平的鉴定可以表明PARP抑制剂治疗的效力,并可用于按照其对于各种疗法的反应对对象分类。脂肪酸水平的鉴定也可以用于为PARP抑制剂治疗的对象选择个性化给药方案。
在一些实施方式中,患者、卫生保健提供者(如医生和护士)或卫生保健管理者基于来自对象的样品中的脂肪酸水平选择有效量的PARP抑制剂对对象的治疗。该方法可用于评价随时间的治疗效力。例如,生物样品可以随着患者用PARP抑制剂进行治疗在一段时间内获得。不同样品中的脂肪酸水平可以彼此比较以确定疗效。另外,这里描述的方法可以用于比较不同疾病疗法(包括用PARP抑制剂进行治疗)的效力和/或不同群体(例如,种族、家族历史等)对一种或多种治疗的反应。
制剂和药物组合物
本发明提供的方法可以包括与其它疗法联合施用有效量的如这里提供的抑制剂。可以与本发明的组合物共同施用的疗法的选择将部分依赖于进行治疗的状态。例如,对于治疗急性骨髓性白血病,本发明一些实施方式的化合物可用于与放射治疗、单克隆抗体治疗、化疗、骨髓移植或其组合联用。
放射致敏剂可以与治疗有效量的PARP抑制剂结合施用,其中PARP抑制剂可以促进放射致敏剂加入到靶细胞中或PARP抑制剂可控制到靶细胞的治疗药物、营养物和/或氧流。类似地,化学致敏剂也已知增加癌细胞对化学治疗化合物的毒性作用的敏感性。可以与PARP抑制剂结合使用的示例性化学药物包括,但不限于阿霉素、喜树碱、氮烯唑胺、卡铂、顺铂、柔红霉素、多西他奇、亚德里亚霉素、干扰素(α、β、γ)、白介素2、伊立替康、紫杉醇、链脲菌素、替莫唑胺、托泊替康及其治疗有效的类似物和衍生物。另外,可以与PARP抑制剂结合使用的其它治疗剂包括,但不限于5-氟尿嘧啶、甲酰四氢叶酸、5’-氨基-5’-脱氧胸苷、氧、卡波金(carbogen)、红细胞输血、全氟化碳(例如,Fluosol-DA)、2,3-DPG、BW12C、钙通道阻断剂、己酮可可碱(pentoxyfylline)、血管生成抑制化合物、肼苯哒嗪和L-BSO。
已知放射致敏剂提高癌细胞对电磁辐射的毒性作用的敏感性。许多癌症治疗方案目前采用X-射线的电磁辐射活化的放射致敏剂。X-射线活化的放射致敏剂的例子包括,但不限于以下物质:甲硝唑、米索硝唑、去甲基醚醇硝唑、哌莫硝唑、依他硝唑、尼莫唑、丝裂霉素C、RSU 1069、SR 4233、EO9、RB 6145、烟酰胺、5-溴脱氧尿苷(BUdR)、5-碘脱氧尿苷(IUdR)、溴脱氧胞苷、氟脱氧尿苷(FudR)、羟基脲、顺铂及其治疗有效的类似物和衍生物。
肿瘤的光动力学治疗(PDT)采用可见光作为敏化剂的放射活化剂。光动力学放射致敏剂的例子包括,但不限于以下物质:血卟啉衍生物、光卟啉、苯卟啉衍生物、NPe6、锡初卟啉SnET2、pheoborbide、细菌叶绿素、酞菁染料、锌酞菁染料及其治疗有效的类似物和衍生物。
这里公开的治疗方法可以通过口服给药、经粘膜给药、口腔给药、鼻腔给药、吸入、肠胃外给药、静脉内给药、皮下给药、肌肉内给药、舌下给药、透皮给药和直肠给药。
非侵入性给药包括(1)以软膏或乳膏的形式局部涂覆到皮肤上;(2)直接局部涂覆到口咽组织上;(3)口服;(4)作为气溶胶鼻腔给药;(5)以栓剂、乳膏或泡沫形式在阴道内应用抑制剂;(6)直接涂覆到子宫颈上;(7)通过栓剂、冲洗或其它合适的形式直肠施用;(8)膀胱冲洗;和(9)对肺施用抑制剂的气溶胶化制剂。
用于本发明方法的PARP抑制剂的药物组合物包括以治疗或预防有效量包含活性成分的组合物。特定应用有效的实际量尤其取决于治疗的状态和给药途径。有效量的确定在本领域技术人员的能力范围内。药物组合物包含PARP抑制剂、一种或多种药学上可接受的载体、稀释剂或赋形剂和任选的其它治疗药物。该组合物可以配制成持续或延迟释放形式。
在一些实施方式中,PARP抑制剂可以以凝胶、油膏、溶液、浸渍绷带、脂质体或生物可降解的微胶囊形式区域地或局部地施用。用于局部涂覆的组合物或剂型可以包括溶液、洗剂、油膏、乳膏、凝胶、栓剂、喷雾剂、气雾剂、悬浮液、扑粉、浸渍绷带和敷料、脂质体、生物可降解聚合物和人工皮肤。制备前述组合物的典型的药物载体包括藻酸盐、羧甲基纤维素、甲基纤维素、琼脂糖、果胶、明胶、胶原、植物油、矿物油、硬脂酸、硬脂醇、矿脂、聚乙二醇、聚山梨醇酯、聚乳酸、聚乙二醇酯、聚酸酐、磷脂、聚乙烯吡咯烷酮等等。
组合物可通过注射、局部地、经口地、透皮地、经直肠地或通过吸入施用。施用治疗药物的口服形式可以包括粉末、片剂、胶囊、溶液或乳液。有效量可以以单剂量或相隔适宜的时间间隔(如数小时)的一系列剂量施用。药物组合物可以使用一种或多种生理可接受的载体(包括赋形剂和有助于将活性化合物加工成可作为药物使用的制剂的辅剂)以常规方式配制。合适的制剂依赖于选择的给药途径。用于制备本发明的药剂的药物组合物的合适技术是本领域中公知的。
可以理解,活性物质的合适剂型及包含活性化合物的组合物可以在患者之间变化。确定最佳剂型一般包括使治疗效果的水平与本发明的治疗的任何风险或有害的副作用平衡。选择的剂量水平取决于多种因素,包括,但不限于特定PARP抑制剂的活性、给药途径、给药时间、化合物的排泄率、治疗的持续时间、其它组合使用的药物、化合物和/或材料、及患者的年龄、性别、体重、状态、总体健康和先前的病史。化合物的量和给药途径最终由医生决定,虽然一般地说,剂量将在作用部位达到获得希望的效果而不引起实质性的有害副作用的局部浓度。
体内施用可以以单剂量连续地或间断地(例如,按适当的间隔以分离的剂量)在整个治疗过程中实行。确定最有效的施用手段和剂量的方法是本领域技术人员公知的并随用于治疗的剂型、治疗目的、治疗的靶细胞和治疗的对象发生变化。单次或多次施用可以通过由治疗医生选择剂量水平和模式完成。
实施例
实施例I
目的:本研究涉及分析3-硝基-4-碘苯甲酰胺(式III的化合物)对使用[1,2-13C2]-D-葡萄糖作为唯一葡萄糖源培养的OVCAR-3细胞和Hela细胞的代谢物流的体外效应。该分析包括将代谢物流与细胞生长改变效应相联系,分析抗增殖作用的机理并分析潜在的毒性、选择性和效力。目标代谢物包括葡萄糖(培养基和粒糖原)、乳酸(培养基)、13CO2(培养基)、C:14(肉豆蔻酸)、C:16(棕榈酸)、C:18(硬脂酸)、C:18-1(油酸)、C:20、C:22、C:24(细胞沉淀)、脂肪酸的乙酰-CoA合成(细胞沉淀)、及RNA核糖和DNA脱氧核糖(细胞沉淀)。目标流包括从培养基摄取葡萄糖、从葡萄糖产生乳酸(无氧糖酵解)、通过TCA循环由葡萄糖释放I3CO2、糖原合成、脂肪酸的从头合成、延长、去饱和和乙酰-CoA合成及戊糖循环-通过氧化和非氧化反应的RNA和DNA核糖合成。
材料和方法:具有>99%的纯度和每个位置具有>99%的同位素富集的用于该代谢物分布研究的示踪剂(稳定的同位素[1,2-13C2]-D-葡萄糖)从Cambridge Isotope Laboratories,Inc.(Andover,Massachusetts)购买。
细胞和细胞培养:OVCAR3和Hela细胞购自美国典型培养物保藏中心(ATCC)。细胞按照从ATCC获得的说明进行培养。细胞在37℃、5%的CO2和95%的湿度下孵育并在从ATCC收到细胞后和在用于该研究之前使用0.25%的胰蛋白酶(Gibco/BRL)传代不超过十次。
75%铺满培养的细胞在含[1,2-13C2]-D-葡萄糖的培养基(100mg/dl的总浓度=5mM,50%同位素富集-即一半未标记的葡萄糖,一半用稳定同位素13C示踪剂标记)中孵育。细胞以每个T75培养瓶106个细胞的密度接种且3-硝基-4-碘苯甲酰胺以0.3-3μM的浓度加入培养基中。对照培养物仅用溶剂(vehicle)处理。用于本研究的3-硝基-4-碘苯甲酰胺的剂量基于表明该药物在葡萄糖存在或不存在的情况下有效地控制人细胞中糖原磷酸化酶活性的体外试验进行选择(Andersen B等,2002,Biochem J.367:443-450)。培养基中的葡萄糖和乳酸水平使用Cobas Mira化学分析仪(Roche Diagnostics,Pleasanton,CA,USA)测量。
RNA核糖稳定同位素研究:RNA核糖在细胞提取物的Trizol纯化后通过细胞RNA的酸水解分离。总RNA量在一式三份的培养物中通过光谱光度的测定评价。在质谱分析之前,核糖使用吡啶中的羟胺与乙酸酐(Supelco,Bellefonte,PA)衍生化成其醛腈乙酸酯(aldonitrileacetate)形式。离子簇在m/z256(核糖的1-5碳)(化学离子化,CI)及m/z217(核糖的3-5碳)和m/z242(核糖的1-4碳)(电冲击离子化,EI)附近监测以确定核糖中13C的摩尔富集和位置分布。按照惯例,通过质谱测量的12C-化合物的基本质量(与其衍生化剂一起)给定为m0(Boros LG等,2002,Drug Discov.Today 7:364-372)。
从RNA回收的用单13C原子在第一碳位置(m1)标记的核糖分子用于测量通过葡萄糖经G6PD途径的直接氧化产生的核糖部分。用13C在最先的两个碳位置(m2)标记的核糖分子用于测量通过转酮醇酶产生的部分。在第四和第五碳位置双标记(m2和m4)的核糖分子用于测量通过丙糖磷酸异构酶和转酮醇酶产生的摩尔分数。
乳酸:在用HCl酸化后通过氯乙烯从细胞培养基(0.2ml)中提取乳酸。乳酸衍生化成其丙胺-七氟丁酸酯形式且监测m/z328(乳酸的1-3碳)(化学离子化,CI)以检测m1(通过PC的循环乳酸)和m2(通过Embden-Meyerhof-Parnas途径产生的乳酸)用于估计戊糖循环活性(Lee WN等,1998,Am JPhysiol 274:E843-E851)。记录OVCAR3和Hela细胞释放的乳酸产生的m1/m2比率以确定响应于3-硝基-4-碘苯甲酰胺处理的相对于无氧糖酵解的戊糖循环活性。
谷氨酸:来自葡萄糖的谷氨酸标记分布适用于确定相对于TCA循环中合成代谢葡萄糖利用的葡萄糖氧化,也称作回补流。组织培养基首先用6%高氯酸处理且上清液通过3cm3 Dowex-50(H+)柱。氨基酸用15ml的2N氢氧化铵洗脱。为进一步分离谷氨酸和谷氨酰胺,氨基酸混合物通过3cm3 Dowex-1(乙酸盐)柱,然后用15ml的0.5N乙酸收集。来自培养基的谷氨酸部分转化成其三氟乙酰丁基酯(TAB)。在EI条件下,TAB-谷氨酸的离子化产生两个碎片,m/z198和m/z152,对应于谷氨酸的C2-C5和C2-C4(Lee WN等.1996,DevelopmentalNeuroscience 18:469-477)。在4-5碳位置上标记的谷氨酸指示丙酮酸脱氢酶活性,而在2-3碳位置上标记的谷氨酸指示使葡萄糖碳进入TCA循环的丙酮酸羧化酶活性。TCA循环合成代谢葡萄糖利用基于谷氨酸的m1/m2比率计算(Leimer KR等,1977,J.Chromatography141:121-144)。
脂肪酸:棕榈酸、硬脂酸、胆固醇和油酸在30%KOH和100%乙醇对细胞沉淀进行皂化后使用石油醚提取。脂肪酸使用0.5N的甲醇-HCl转化成其甲基化衍生物。棕榈酸、硬脂酸和油酸分别在m/z270,m/z 298和m/z264进行监测,如通过不同同位体的质量同位体分布分析(MIDA)所确定的,使反映新脂部分的合成、延长和去饱和的13C标记的乙酰单元发生富集(Lee WN,等,1998,J.Biol.Chem.273:20929-20934;Lee WN等,1995,Anal Biochem 226:100-112)。
气相色谱/质谱(GC/MS):质谱数据在连接到HP6890气相色谱上的HP5973质量选择检测器上获得。设置如下:GC入口温度250℃,输送线280℃,MS源230℃,MS Quad 150℃。HP-5毛细柱(30m长,250μm直径,0.25μm膜厚)用于葡萄糖、核糖和乳酸分析。转酮醇酶在戊糖循环的非氧化分支中具有最高的代谢控制系数(Sabate L等,1995,Mol.Cell Biochem.142:9-17;Comin-Anduix B等,2001,Eur.J.Biochem.268:4177-4182)。可是应该注意到,除其它的酶外,转酮醇酶和转醛醇酶都可以参与人体细胞中的非氧化戊糖循环代谢。
数据分析和统计方法:对于在每项试验中的各种条件,每个试验采用三重细胞培养完成,且试验重复一次。质谱分析通过自动进样器三次独立地自动注射1μl样品完成,且仅接受标准样品误差小于标准化峰强度的1%时的结果。统计分析采用不配对样品的Student′s t-检验进行。99%置信区间的双侧显著性(μ+/-2.58δ),p<0.01表明在对照和3-硝基-4-碘苯甲酰胺中葡萄糖碳代谢具有显著性差异。
结果:在Hela细胞中成功地进行了示踪剂处理,且所有培养物的示踪剂标记的葡萄糖部分在0.0分时在总葡萄糖的45%-55%之间。示踪剂孵育20小时、48小时和72小时足以产生Hela细胞特异的代谢物标记分布。Hela细胞响应于3-硝基-4-碘苯甲酰胺的葡萄糖代谢具有差异。效应是剂量-响应性的,且与由葡萄糖从头合成中链和长链脂肪酸的减少保持很大的一致。花生酸(C:20)的从头合成被3-硝基-4-碘苯甲酰胺的抑制作用减弱。从葡萄糖富集乙酰-CoA用于花生酸合成在3-硝基-4-碘苯甲酰胺处理的Hela培养物中较高。
葡萄糖在TCA循环中氧化成CO2和ATP不受3-硝基-4-碘苯甲酰胺的影响。从葡萄糖到长链饱和脂肪酸(C:20-C:24)的乙酰-CoA贡献存在剂量依赖的提高。3-硝基-4-碘苯甲酰胺在Hela细胞中是代谢活性化合物。中链到长链脂肪酸(C:14-C:18)的从头合成随着从葡萄糖对乙酰-CoA合成的贡献降低而减少。3-硝基-4-碘苯甲酰胺通过限制脂肪酸的从头合成作为其在Hela细胞中抗增殖作用的基础机制而减少细胞膜形成。3-硝基-4-碘苯甲酰胺增加从葡萄糖形成的乙酰-CoA以用于形成花生酸,因此它可以刺激前列腺素合成。3-硝基-4-碘苯甲酰胺对细胞能量产生、核酸更新和糖原合成没有毒性效应。3-硝基-4-碘苯甲酰胺对底物(葡萄糖)摄取和活化(磷酸化)没有抑制效应。
在OVCAR-3细胞中成功地进行了示踪剂处理,且所有培养物的示踪剂标记的葡萄糖部分在0.0分时在总葡萄糖的45%-55%之间。示踪剂孵育72小时足以产生Hela细胞特异的代谢物标记分布。OVCAR-3细胞响应于3-硝基-4-碘苯甲酰胺的葡萄糖代谢具有显著差异。该效应是剂量-响应性的,且与由葡萄糖从头合成中链和长链脂肪酸的减少以及葡萄糖的乙酰-CoA合成的减少保持很大的一致。
OVCAR-3细胞中中链到长链脂肪酸(C:14-C:18)的从头合成被3-硝基-4-碘苯甲酰胺的抑制作用减弱。在OVCAR-3细胞中脂肪酸的从头合成相对较低(<30%)。醛缩酶和丙糖磷酸异构酶在DNA合成期间是活性的,且转酮醇酶以及G6PDH是3-硝基-4-碘苯甲酰胺处理的目标酶。通过直接途径的糖原合成和裂解受到3-硝基-4-碘苯甲酰胺的抑制。
从葡萄糖到长链饱和脂肪酸(C:20-C:24)的乙酰-CoA贡献存在剂量依赖性的提高。3-硝基-4-碘苯甲酰胺在OVCAR-3细胞中是代谢活性化合物。中链到长链脂肪酸(C:14-C:18)的从头合成略微增加,从葡萄糖合成乙酰-CoA没有显著的改变。3-硝基-4-碘苯甲酰胺通过限制长链脂肪酸(C:20-C:24)的从头合成作为其在OVCAR-3细胞中抗增殖作用的基础机制而减少细胞膜形成。3-硝基-4-碘苯甲酰胺还抑制用于DNA脱氧核糖合成和直接糖原合成的G6PDH和转酮醇酶流。3-硝基-4-碘苯甲酰胺对细胞能量产生和核酸RNA更新没有毒性效应。这些研究的结果显示于图3A、3B(72小时时13C-标记的肉豆蔻酸(C:14))、4A、4B(72小时时13C-标记的棕榈酸(C:16))、5A、5B(72小时时13C-标记的硬脂酸(C:18))、6A、6B(72小时时13C-标记的油酸(C:18-1))、7A、7B(72小时时13C-标记的C:22脂肪酸)、8A、8B(72小时时13C-标记的C:24脂肪酸)、9A、9B(72小时时13C-标记的花生酸(C:20))、10A、10B(72小时时13C-标记的C:22脂肪酸)和11A、11B(72小时时13C-标记的C:24脂肪酸)。在各种情况中,“A”图显示掺入细胞沉淀中的脂肪酸量,而“B”图显示来自葡萄糖的13乙酰CoA富集(左)和新的脂肪酸合成部分(右)。这些结果表明PARP-1抑制剂3-硝基-4-碘苯甲酰胺在细胞中抑制脂肪酸合成。
尽管这里显示和描述的本发明的优选实施方式,但本领域技术人员很清楚,这些实施方式仅以举例的方式提出。本领域技术人员可以想到许多的变形、变化和替换而不脱离本发明的范围。应当理解,可以在本发明的实施中采用这里描述的本发明实施方式的各种改变形式。下面的权利要求限定本发明的范围且本发明包括这些权利要求的范围内的方法和结构及它们的等同物。
Claims (12)
2.如权利要求1所述的用途,其中所述化合物抑制脂肪酸合成。
3.如权利要求2所述的用途,其中所述抑制的脂肪酸是中链脂肪酸或长链脂肪酸。
4.如权利要求2所述的用途,其中所述脂肪酸合成的抑制包括抑制葡萄糖途径的至少一种酶。
5.如权利要求2所述的用途,其中所述脂肪酸合成的抑制包括抑制脂肪酸生物合成途径的至少一种酶。
6.如权利要求2所述的用途,其中所述脂肪酸合成的抑制包括抑制选自乙酰辅酶A羧化酶和脂肪酸合酶的至少一种酶。
7.如权利要求2所述的用途,其中所述脂肪酸合成的抑制包括抑制脂肪酸合酶的至少一种酶。
8.如权利要求7所述的用途,其中所述脂肪酸合酶包括酰基载体蛋白、乙酰转移酶、丙二酰转移酶、3-酮-酰基-ACP合成酶、3-酮酰基-ACP还原酶、3-羟基-酰基-ACP脱水酶和烯酰基-ACP还原酶。
9.如权利要求2所述的用途,其中所述脂肪酸合成的抑制包括抑制从葡萄糖合成乙酰辅酶A。
10.如权利要求2所述的用途,其中所述脂肪酸合成的抑制包括抑制从乙酰辅酶A合成所述脂肪酸。
12.如权利要求3所述的用途,其中所述长链脂肪酸是C:14-C:30。
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AU2007292306A1 (en) | 2008-03-13 |
CA2662337A1 (en) | 2008-03-13 |
IL197350A0 (en) | 2009-12-24 |
WO2008030891A2 (en) | 2008-03-13 |
WO2008030891A3 (en) | 2008-08-21 |
US7994222B2 (en) | 2011-08-09 |
US20120004260A1 (en) | 2012-01-05 |
EP2061479A2 (en) | 2009-05-27 |
JP2010502731A (ja) | 2010-01-28 |
US20080103208A1 (en) | 2008-05-01 |
EP2061479A4 (en) | 2010-08-04 |
CN102379884A (zh) | 2012-03-21 |
CN101534836A (zh) | 2009-09-16 |
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