CN101917976A - 二硫化物化疗药及其应用方法 - Google Patents
二硫化物化疗药及其应用方法 Download PDFInfo
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- CN101917976A CN101917976A CN2008801255886A CN200880125588A CN101917976A CN 101917976 A CN101917976 A CN 101917976A CN 2008801255886 A CN2008801255886 A CN 2008801255886A CN 200880125588 A CN200880125588 A CN 200880125588A CN 101917976 A CN101917976 A CN 101917976A
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Abstract
本发明提供了用于治疗癌症的组合物和方法。
Description
本申请要求保护在35U.S.C.§119(e)下、于2007年11月20日申请的美国临时专利申请号60/989,383的优先权。上述申请通过引用结合到本文中。
依照35U.S.C.§202(c),公认美国政府对所述本发明具有某些权利,本发明是部分使用来自国立卫生院(National Institutes of Health)的基金进行的,基金号CA109604。
发明领域
本发明涉及二硫化物化疗药及其使用方法。
发明背景
在本说明书全文中引用了若干出版物和专利文件,以便描述本发明所属领域的现有技术水平。这些引用各自通过引用结合到本文中,如同全文引用一样。
辐射和化疗药对人类肿瘤、尤其是实体瘤的治疗是有效的。然而,在初始治疗中存活的癌细胞对后续治疗变得具有耐受性。这种对后续治疗的耐受性正是这些患者缺乏更好的总体存活的主要原因。也已经知道低氧在癌症治疗结果中起到主要作用。绝大多数人类实体瘤都表现出低氧。遗憾的是,与含氧量正常的肿瘤细胞相比,含氧量低的肿瘤细胞对放疗和化疗更具有耐受性,而且认为这些含氧量低的细胞对疾病复发而言是重要的贡献者(参见例如Teicher等(1990)Cancer Res.,50:3339-3344;Grau和Overgaard(1988)Radiother.Oncol.13:301-309)。若干研究已经证明,实体瘤的含氧量低的细胞也缺乏葡萄糖。
由含氧量低的癌细胞和含氧量正常的癌细胞这两者组成的缺葡萄糖的癌细胞对化疗药具有更强耐受性(Cui等(2007)Cancer Res.,67:3345-55)。葡萄糖消耗在大多数实体瘤中是常见的,因为更高的代谢活性和由于无组织的血管系统而导致的灌注缺乏。也据信它诱导针对应激的耐受性。一些实验室近来的兴趣热点在于了解葡萄糖缺乏对癌细胞的影响,因为相信在实体瘤、尤其是含氧量低的肿瘤中葡萄糖的总体稳定状态水平更低(Aronen等(2000)Clin.Cancer Res.,6:2189-200;Rajendran等(2004)Clin.Cancer Res.,10:2245-52;Schroeder等(2005)Cancer Res.,65:5163-71)。已经提出,葡萄糖水平的降低可能是因为癌细胞代谢活性更高(Schroeder等(2005)Cancer Res.,65:5163-71)。由无组织的血管系统所致的局部缺血条件也可能是导致实体瘤中葡萄糖水平更低的原因(Schroeder等(2005)Cancer Res.,65:5163-71)。若干近期研究已经在体外观察到葡萄糖缺乏对癌细胞的影响(Yun等(2005)J.Biol.Chem.,280:9963-9972;Katol等(2002)Oncogene,21:6082-6090;Ryoo等(2006)Biol.Pharm.Bull.,29:817-820)。这些研究指出若干分子机制可能涉及缺葡萄糖肿瘤细胞的存活。这些研究已经证明了以缺葡萄糖的癌细胞作为靶标的重要性,因为它诱导能使其存活并对治疗的反应更低的存活分子,尽管缺乏葡萄糖。
葡萄糖-6-磷酸脱氢酶(G6PD)是氧化型戊糖磷酸循环(oxidative pentose phosphate cycle,OPPC)的第一个酶而且是限速酶。作为OPPC底物的葡萄糖是OPPC介导的氧化剂/二硫化物的解毒作用所需的。氧化型戊糖磷酸循环利用葡萄糖作为底物来产生还原剂。当暴露给氧化剂/二硫化物时,这些还原剂可用于维持哺乳动物细胞中还原型谷胱甘肽的体内稳态。谷胱甘肽是一种由甘氨酸、半胱氨酸和谷氨酸组成的三肽。在正常条件下,哺乳动物细胞中的还原型GSH至多比氧化型GSH(GSSG)高100倍。然而,由氧化剂/二硫化物产生的氧化型GSH对癌细胞是有害的。
发明概述
依照本发明的一方面,提供在有需要的患者中治疗癌症的方法。在一个实施方案中,所述方法包括给予包含至少一种含有二硫化物的化合物和药学上可接受的载体的组合物。所述含有二硫化物的化合物可选自羟乙基二硫化物(HEDS)、巯基丙酰基甘氨酸(MPG)的二硫化物(甘氨酸丙酰基二硫化物)、MPG和ME的二硫化物、2-巯基乙烷磺酸盐(美司钠(mesna))的二硫化物、MPG和美司钠的二硫化物、以及ME和美司钠的二硫化物。在另一个实施方案中,所述癌细胞是含氧量低的、含氧量正常的、缺葡萄糖的、葡萄糖正常的、和/或对辐射和/或化疗药具有耐受性的癌细胞。
依照另一方面,提供在有需要的患者中治疗癌症的方法,其中所述癌症包括含氧量低的癌细胞。在一个实施方案中,所述方法包括给予至少一种含有二硫化物的化合物,并任选给予至少一种化疗药、含氧量低的毒素和/或辐射。在一个具体的实施方案中,所述化疗药选自拓扑异构酶II抑制剂和铂配合物。在另一个实施方案中,所述含氧量低的毒素选自替拉扎明、AQ4N、5-硝基咪唑、尼莫唑、依他硝唑、丝裂霉素C类似物E09、2-硝基咪唑CI-1010和其它含氧量低的特异性生物反应性药物。在又一个实施方案中,所述含有二硫化物的化合物可与至少一种化疗药、低氧药物(hypoxic agent)和/或辐射序贯和/或同时给予。
依照另一方面,提供在有需要的患者中治疗癌症的方法,其中所述癌症包括缺葡萄糖的含氧量正常的癌细胞。在一个实施方案中,所述方法包括给予至少一种含有二硫化物的化合物,并任选给予至少一种化疗药和/或辐射。在一个具体的实施方案中,所述化疗药选自拓扑异构酶II抑制剂和铂配合物。在又一个实施方案中,所述含有二硫化物的化合物与至少一种化疗药和/或辐射序贯和/或同时给予。
也提供在有需要的患者中治疗癌症的方法,其中所述癌症包括具有正常葡萄糖的含氧量正常的癌细胞。在一个实施方案中,所述方法包括给予至少一种含有二硫化物的化合物并任选至少一种葡萄糖-6-磷酸脱氢酶(G6PD)抑制剂和/或至少一种化疗药、低氧毒素(hypoxictoxin)和/或辐射。G6PD抑制剂可选自脱氢表雄酮(DHEA)、硫酸DHEA、2-脱氧葡萄糖、卤代DHEA、表雄酮、异氟烷、七氟烷、地西泮和G6PD靶向的siRNA/shRNA分子。
依照本发明的另一方面,提供用于治疗癌症的组合物。在一个具体的实施方案中,所述组合物包含至少一种含有二硫化物的化合物和至少一种药学上可接受的载体。在一个具体的实施方案中,所述组合物还包含至少一种化疗药。在另一个实施方案中,所述组合物包含至少一种含有二硫化物的化合物、至少一种低氧毒素和至少一种药学上可接受的载体。所述组合物还可包含至少一种葡萄糖-6-磷酸脱氢酶(G6PD)抑制剂。在一个具体的实施方案中,所述组合物包含MPG的二硫化物、至少一种药学上可接受的载体和任选的至少一种其它含有二硫化物的化合物。
附图简述
图1是显示存在或不存在葡萄糖和不同量的HEDS时,辐射敏感型人类结肠癌细胞的存活的图。
图2是显示存在或不存在葡萄糖和不同量的HEDS时,暴露于4Gyγ辐射的辐射敏感型人类结肠癌细胞的存活的图。
图3是显示存在或不存在葡萄糖和不同量的HEDS时,辐射耐受型人类结肠癌细胞的存活的图。
图4是显示存在或不存在葡萄糖和不同量的HEDS时,暴露于4Gyγ辐射的辐射耐受型人类结肠癌细胞的存活的图。
图5是提供对于存在或不存在葡萄糖时的辐射敏感型人类结肠癌细胞,作为HEDS浓度的函数的巯基乙醇的量的图。
图6是提供对于存在或不存在葡萄糖时的辐射耐受型人类结肠癌细胞,作为HEDS浓度的函数的巯基乙醇的量的图。
图7是显示对于存在或不存在葡萄糖时的辐射敏感型人类结肠癌细胞,作为HEDS浓度的函数的胞内硫醇(thiol)的量的图。
图8是显示对于存在或不存在葡萄糖时的辐射耐受型人类结肠癌细胞,作为HEDS浓度的函数的胞内硫醇的量的图。
图9是在对照大鼠和用HEDS、依托泊苷或HEDS和依托泊苷治疗大鼠中,乳瘤异种移植物随时间的体积图。
图10是在人类结肠癌细胞中,作为葡萄糖浓度的函数的HEDS解毒图(基于巯基乙醇浓度)。
图11是显示不同浓度葡萄糖下人类结肠癌细胞中硫醇的胞内浓度的图。
图12是显示在用HEDS和不同浓度葡萄糖治疗的人类结肠癌细胞中硫醇的胞内浓度的图。
图13是在乳瘤异种移植物大鼠模型中肿瘤体积随时间的倍增图。对具有小肿瘤(约139mm3)的大鼠或者不给予治疗(对照)或者给予MPG二硫化物40mg/Kg/天。
图14是在乳瘤异种移植物大鼠模型中肿瘤体积随时间的倍增图。对具有大肿瘤(约2837mm3)的大鼠或者不给予治疗(对照)或者给予MPG二硫化物40mg/Kg/天。
图15是在乳瘤异种移植物大鼠模型中肿瘤体积随时间的倍增图。对具有大肿瘤(约2837mm3)的大鼠用顺铂(2mg/Kg体重)或用用顺铂(2mg/Kg体重)和MPG二硫化物40mg/Kg/天来治疗。
图16是存在或不存在葡萄糖时,在不同癌细胞中的HEDS解毒图(基于巯基乙醇浓度)。
图17是显示存在或不存在葡萄糖和不同量的HEDS时,暴露于4Gyγ辐射的人类前列腺癌细胞的存活的图。
图18是显示存在或不存在葡萄糖和不同量的HEDS时,暴露于4Gyγ辐射的人类乳癌细胞的存活的图。
发明详述
如下所述,已经确定,当缺葡萄糖时,辐射耐受型p53突变型HT29结肠癌细胞对辐射变得更具有耐受性。这增加了可靶向缺葡萄糖的癌细胞的鉴别试剂的重要性。依据本发明,已经确定,对氧化型戊糖磷酸循环缺陷型细胞具有专一性的氧化剂/二硫化物可用于靶向实体瘤中不同类型的癌细胞,例如含氧量低的癌细胞、缺葡萄糖的癌细胞、含氧量正常的癌细胞和含有葡萄糖的癌细胞。该方法提高了辐射和化疗药的功效,因为它靶向所有缺葡萄糖的癌细胞,包括含氧量低的癌细胞和非含氧量低的癌细胞。依据本发明,也提供了新的氧化剂,其对缺葡萄糖的含氧量低的和非含氧量低的细胞以及氧化型戊糖循环缺陷型癌细胞具有专一性。的确,葡萄糖的缺乏介导胞内代谢活性,所述胞内代谢活性导致胞内一种这样的氧化剂/二硫化物的积累(其通过GSH消耗而引起氧化应激,导致细胞死亡),并导致人类癌细胞对辐射和化疗药的反应的改善。
依照本发明,提供治疗癌症的方法。所述方法包括将至少一种含有二硫化物的化合物给予有需要的患者。在一个实施方案中,将所述含有二硫化物的化合物给予含氧量低的癌细胞和/或缺葡萄糖的癌细胞,并任选与至少一种化疗药、低氧毒素和/或辐射(例如电离辐射)联用。在一个具体的实施方案中,所述化疗药包括至少一种拓扑异构酶II抑制剂和/或铂配合物。在另一个实施方案中,所述低氧毒素包括选自以下的至少一种:替拉扎明、AQ4N、5-硝基咪唑、尼莫唑、依他硝唑、丝裂霉素C类似物E09、2-硝基咪唑CI-1010和其它低氧特异性生物反应性药物。所述含有二硫化物的化合物可与至少一种化疗药、低氧毒素、药物和/或辐射序贯(例如在之前或之后)和/或同时给予。
在另一个实施方案中,可通过给予至少一种葡萄糖-6-磷酸脱氢酶(G6PD)抑制剂和至少一种含有二硫化物的化合物,使含氧量正常的癌细胞对至少一种化疗药和/或辐射敏感。因此,本发明包括在有需要的患者中治疗癌症的方法,其中所述癌症包括含氧量正常的细胞,所述方法包括给予至少一种G6PD抑制剂和至少一种含有二硫化物的化合物,任选在至少一种化疗药和/或辐射之前给予和/或同时给予。在一个具体的实施方案中,所述化疗药包括至少一种拓扑异构酶II抑制剂和/或铂配合物。
含有二硫化物的化合物是容易得到的(参见例如Sigma Aldrich2006-2007产品目录)。在一个实施方案中,所述含有二硫化物的化合物是二烷基二硫化物(例如包含至少一个硫原子的低级烷基二硫化物)或二芳基二硫化物,其中二硫化物的结构单元(member)可以相同(对称二硫化物)或不同(不对称二硫化物)。在另一个实施方案中,所述含有二硫化物的化合物是包含硫胺的二硫化物,例如但不限于硫胺二硫化物、硫胺丙基二硫化物和硫胺四氢呋喃基二硫化物。在另一个实施方案中,示例性的含有二硫化物的化合物包括但不限于:羟乙基二硫化物(HEDS;一种巯基乙醇(ME)的二硫化物)、巯基丙酰基甘氨酸(MPG)的二硫化物、MPG和低级烷基的二硫化物、MPG和ME的二硫化物、美司钠(2-巯基乙烷磺酸盐)的二硫化物、MPG和美司钠的二硫化物以及ME和美司钠的二硫化物。在一个具体的实施方案中,所述含有二硫化物的化合物是MPG的二硫化物。
本发明还包括至少一种如上所述的药物(例如一种或多种含有二硫化物的化合物、一种或多种G6PD抑制剂、一种或多种化疗药、一种或多种低氧毒素等)和至少一种药学上可接受的载体的组合物。在一个具体的实施方案中,本发明的组合物可给予有需要的患者,用于治疗或预防癌症。
可用本发明方案治疗的癌症包括但不限于:前列腺癌、直肠结肠癌、结肠癌、胰腺癌、宫颈癌、胃癌、子宫内膜癌、脑癌、肝癌、膀胱癌、卵巢癌、睾丸癌、头颈部癌、皮肤癌(包括黑素瘤和基底瘤(basal carcinoma))、间皮内层癌(mesothelial lining)、白细胞癌(包括淋巴瘤和白血病)、食道癌、乳癌、肌肉癌、结缔组织癌、肺癌(包括小细胞肺癌和非小细胞肺癌)、肾上腺癌、甲状腺癌、肾癌或骨癌;成胶质细胞瘤、间皮瘤、肾细胞癌、胃癌、肉瘤、绒毛膜癌、皮肤基底细胞癌和睾丸精原细胞瘤。在一个具体的实施方案中,所述癌症是实体瘤。
葡萄糖-6-磷酸脱氢酶(G6PD)抑制剂包括但不限于:脱氢表雄酮(DHEA)、硫酸DHEA、2-脱氧葡萄糖、卤代DHEA、表雄酮、异氟烷、七氟烷、地西泮和siRNA/shRNA分子(参见例如(Park等(2005)Mol.Cell Biol.,25:5146-57;Ho等(2006)Cytometry Part A,69A:1054-1061;WO/2006/083051;WO/2007/117048;Lamberton等(2003)Mol.Biotech.24:111-119;Invitrogen(Carlsbad,CA);Santa Cruz Biotechnologies(Santa Cruz,CA);和OriGene Technologies(Rockville,MD))。
定义
本文所用的术语“烷基”包括含有约1-20个碳、尤其是约1-10个碳、更尤其是约1-5个碳(即低级烷基)的直链、支链和环状烃。烷基的烃链中可以间插一个或多个氧原子、氮原子或硫原子(尤其是约1-3个杂原子、更尤其是1个杂原子)并且可以是不饱和的(含有一个或多个双键或三键)。烷基可任选被取代(例如用以下基团取代:卤基、烷基、卤代烷基、烷氧基、烷硫基、羟基、甲氧基、羧基、氧代基、环氧基、烷氧基羰基、烷基羰基氧基、氨基、氨基甲酰基、脲、烷基脲、芳基、醚、酯、硫酯、腈、硝基、酰胺、羰基、羧酸基、磺酸基和硫醇)。在一个优选的实施方案中,本发明的烷基包含至少一个硫原子。
本文所用的术语“芳基”是指在环部分含有约6-10个碳的单环和双环芳族基团。芳基可通过合适碳原子被任选取代。芳基可以是杂芳基(包含至少一个硫、氧或氮杂原子环结构单元的环系)。
“药学上可接受的”是指被美国联邦政府或州政府法定部门批准的。“药学上可接受的”药剂列于美国药典或其它公认的药典中,用于动物、尤其是人类。
“载体”是指与本发明活性试剂一起给予的例如稀释剂、佐剂、赋形剂、助剂或溶媒。这类药物载体可以是无菌液体,例如水和油,包括石油、动物、植物或合成来源的那些,例如花生油、大豆油、矿物油、芝麻油等。水或盐水溶液和葡萄糖水溶液和甘油溶液优选用作载体,尤其是用于注射用溶液剂。合适的药物载体描述于E.W.Martin “Remington’s Pharmaceutical Sciences″。
本文所用的术语“含氧量低的”是指与正常细胞或组织相比而言,细胞或组织中氧或氧张力水平较低。当O2浓度低于在它们特定细胞或组织中的正常氧水平时,则细胞或组织就是含氧量低的。术语“含氧量低的肿瘤细胞”或“含氧量低的癌细胞”是指与相应正常细胞或组织相比,肿瘤细胞或组织具有更低水平的氧或氧张力。本文所用的术语“含氧量正常的”是指目标细胞和/或组织的正常氧浓度。
本文所用的术语“缺葡萄糖的”是指与正常细胞或组织相比而言,细胞或组织中的葡萄糖水平较低。当在特定细胞或组织中,葡萄糖浓度低于在正常葡萄糖水平时,则这些细胞或组织就是缺葡萄糖的。术语“缺葡萄糖的癌细胞”是指与相应的正常细胞或组织相比而言,具有较低葡萄糖水平的肿瘤细胞或组织。本文所用的术语“正常葡萄糖”是指目标细胞和/或组织的正常葡萄糖浓度。
化疗药是表现出抗癌活性和/或是对细胞有害的化合物(例如毒素)。合适的化疗药包括但不限于:毒素(例如皂草毒蛋白、蓖麻毒蛋白、相思豆毒蛋白、溴化乙锭、白喉(diptheria)毒素、假单胞菌外毒素和以上所列举的其它);烷化剂(例如氮芥例如苯丁酸氮芥、环磷酰胺、异环磷酰胺、氮芥、美法仑和乌拉莫司汀;氮杂丙烷例如塞替派;甲烷磺酸酯例如白消安;亚硝基脲例如卡莫司汀、洛莫司汀和链佐星;铂配合物;生物还原性烷化剂例如丝裂霉素、丙卡巴肼、达卡巴嗪和六甲蜜胺);DNA链断裂剂(例如博来霉素);拓扑异构酶II抑制剂;DNA小沟结合剂(例如普卡霉素(plicamydin));抗代谢物(例如叶酸拮抗剂例如甲氨蝶呤和三甲曲沙;嘧啶拮抗剂例如氟尿嘧啶、氟脱氧尿苷、CB3717、阿扎胞苷、阿糖胞苷和氟尿苷;嘌呤拮抗剂例如巯基嘌呤、6-硫鸟嘌呤、氟达拉滨、喷司他丁;天冬酰胺酶;和核糖核苷酸还原酶抑制剂例如羟基脲);微管蛋白相互作用剂(例如长春新碱、长春碱和紫杉醇(Taxol));激素药物(例如雌激素;缀合的雌激素;乙炔基雌二醇;二乙基己烯雌酚;氯烯雌酚(chlortrianisen);双烯雌酚(idenestrol);孕酮例如己酸羟孕酮、甲羟孕酮和甲地孕酮;和雄激素例如睾酮、丙酸睾酮、氟甲睾酮和甲睾酮);肾上腺皮质类固醇(例如泼尼松、地塞米松、甲泼尼龙和泼尼松龙);黄体生成素-释放剂或促性腺激素-释放激素拮抗剂(例如醋酸亮丙立德和醋酸戈舍瑞林);吲哚胺2,3-加双氧酶抑制剂(例如1-甲基-色氨酸);和抗激素抗原(例如他莫昔芬、抗雄激素药物例如氟他胺;和抗肾上腺药物例如米托坦和氨基格鲁米特)。铂配合物包括但不限于:顺铂(顺-二氯化二胺铂(II))、卡铂(二氨(1,1-环丁烷二羧酸)-铂(II))、四铂(奥马铂;四氯(1,2-环己烷二胺-N,N′)-铂(IV))、thioplatin(二(O-乙基二硫代碳酸)合铂(II))、沙铂、奈达铂、奥沙利铂、庚铂、异丙铂、反铂、洛铂、顺-胺二氯(2-甲基吡啶)铂、JM 118(顺-氨二氯(环己胺)铂(II))、JM 149(顺-氨二氯(环己胺)-反-二氢氧代铂(IV))、JM216(二-乙酸-顺-氨二氯(环己胺)铂(IV))、JM335(反-氨二氯(环己胺)二氢氧代铂(IV))和(反,反,反)二-mu-(己烷-1,6-二胺)-mu-[二胺-铂(II)]二[二胺(氯)铂(II)]四氯化物。拓扑异构酶II抑制剂包括但不限于:安吖啶、美诺立尔、氨萘非特、放线菌素D、柔红霉素、N,N-二苄基道诺霉素、椭圆玫瑰树碱、道诺霉素、吡唑并吖啶、伊达比星、米托蒽醌、m-AMSA、比生群、多柔比星(阿霉素)、脱氧多柔比星、依托泊苷(VP-16)、磷酸依托泊苷、oxanthrazole、柔红霉素苯腙、表柔比星、博来霉素和替尼泊苷(VM-26)。
术语“电离辐射”是指常规用于肿瘤治疗的辐射。辐射,无论是单次给予大剂量还是重复给予较小剂量,通常都会引起水电离,因此形成反应性氧物质。电离辐射包括但不限于x射线、电子束、γ射线等。本文所用的术语“高剂量辐射”是指超过0.5Gy或可治疗性使用以杀伤细胞的任何剂量。
“低氧毒素”包括但不限于:替拉扎明、AQ4N、5-硝基咪唑、尼莫唑、依他硝唑、丝裂霉素C类似物E09、2-硝基咪唑CI-1010和其它低氧特异性生物反应性药物。
本文所用的术语“致敏”是指药物使细胞(例如肿瘤细胞)对化疗药和/或辐射的敏感性增加的能力。辐射致敏剂能增加癌细胞对辐射的毒性效果的敏感性。
治疗药
可将依照本发明方法给予患者的化合物掺入到单一药物组合物中,如果合适的话。或者,可将单一化合物掺入到用于给予患者分离的药物组合物中,然后可包含在药盒内。在另一个实施方案中,药物组合物的成分彼此不同(例如含有二硫化物的化合物是并非化疗药的不同化合物)。
本发明的药物组合物可包含适于通过任何给药途径或通过直接给予/注射到肿瘤和/或周围区域来递送抑制剂的药学上可接受的载体,所述给药途径例如但不限于:局部、口服、直肠,通过静脉内、肌内、腹膜内注射。
医生在考虑了患者年龄、性别、体重、总体身体状况和具体病症及其严重程度之后,可决定所给予药物制剂的剂量和给药方案。医生也可考虑药物的给予途径,与药物联用的药物载体,以及药物的生物活性。
以下给出实施例,以便更好地说明本发明的某些实施方案。它们不得视为以任何方式限制本发明。
实施例I
可通过以下文献所述方法来合成本发明二硫化物例如MPG二硫化物:Hunter等(2006)J.Org.Chem.,71:8268-8271;Bao和Shimizu(2003)Tetrahedron,59:9655-9659;Sanz等(2002)Synthesis 856-858等。简而言之,可在二甲亚砜存在下,通过二氯二氧化钼(VI)(dichlorodioxomolybdenum)催化,将单硫醇(mono thiol)转化为二硫化物,合成对称的二硫化物。可在1-氯苯并三唑存在下,通过将两种不同单硫醇转化为不对称的二硫化物,合成不对称的二硫化物。
实施例II
葡萄糖消耗在大多数实体瘤中是常见的,因为更高的代谢活性和由于无组织的血管系统而导致的灌注缺乏。据信葡萄糖缺乏诱导针对应激和治疗的耐受性。葡萄糖缺乏在已呈辐射耐受的p53突变型癌细胞中诱导辐射耐受性。
研究使用HEDS(一种氧化剂/二硫化物)来增加辐射敏感型人类结肠癌细胞和辐射耐受型人类结肠癌细胞针对γ辐射的反应。在含葡萄糖的培养基中,癌细胞在将HEDS解毒成为巯基乙醇(ME)中表现出HEDS浓度依赖性增加。作为培养基中葡萄糖消耗的结果,胞内葡萄糖消耗导致这些癌细胞不能将HEDS解毒成为ME。此外,HEDS降低了缺葡萄糖的癌细胞中谷胱甘肽(GSH)水平。
图1、图2、图3和图4表明,HEDS与辐射联用能显著降低辐射敏感型人类结肠癌细胞(HCT116)和辐射耐受型(HT29)人类结肠癌细胞的存活。克隆生成测定(clonogenic assay)显示,在葡萄糖存在下,单用HEDS对这些细胞具有很少/没有细胞毒效果(图1和3)。在葡萄糖不存在时,更高浓度HEDS单用可降低HCT116存活达75%,但对辐射耐受型HT29细胞却没有明显效果(图1和3)。HEDS与辐射的联合治疗显示,在葡萄糖不存在时,HEDS介导辐射敏感型癌细胞(图2)和辐射耐受型(图4)癌细胞这两者对辐射的敏感性。
在图1中,使辐射敏感型人类结肠癌细胞HCT116缺乏葡萄糖4小时,然后用不同浓度HEDS治疗3小时。洗涤细胞并补充新鲜生长培养基。按照得到不超过200个集落的浓度接种细胞,进行集落测定。将每个实验重复至少3次,除非小于所绘制的点,否则显示其误差(Each experiment was repeated at least three times with errors as shown unless smaller than points plotted)。
对于图2,使HCT116细胞缺乏葡萄糖达4小时,用不同浓度HEDS治疗1小时,然后暴露给4Gy辐射。辐射后2小时,洗涤细胞并补充新鲜生长培养基。然后如上文对图1所述,进行集落测定。
对于图3,使辐射耐受型人类结肠癌细胞HT29缺乏葡萄糖达4小时,然后用不同浓度HEDS治疗3小时。洗涤细胞并补充新鲜生长培养基。对于图4,使HT29细胞缺乏葡萄糖达4小时,在4Gy辐射之前用不同浓度HEDS治疗1小时。辐射2小时后,洗涤细胞并补充新鲜生长培养基。按照得到不超过200个集落的浓度接种细胞,进行集落测定。每个实验重复至少3次,除非小于所绘制的点,否则显示其误差。洗涤细胞并补充新鲜生长培养基。
缺葡萄糖的癌细胞中HEDS解毒作用的缺乏,是造成人类结肠癌细胞对辐射具有更好反应的原因,如图2和图4所示。
图5和图6显示HEDS在缺葡萄糖的人类癌细胞中不能有效转化为巯基乙醇(ME),这种转化是解毒过程。这些图显示与葡萄糖一起孵育的细胞能够产生多达3000μM的无毒ME。无葡萄糖的细胞在将HEDS转化成无毒ME的过程中的效率要低6倍。葡萄糖,作为氧化型戊糖磷酸循环中将HEDS转化为ME所需底物,是HEDS的有效解毒所必需的。在辐射敏感型结肠癌细胞(HCT116)和辐射耐受型(HT29)结肠癌细胞中都观察到该现象。
对于图5和6,通过使细胞缺乏葡萄糖达4小时,使人类结肠癌细胞HCT116和HT29分别对HEDS进行解毒/生物还原(bioreduction)。然后,将所述细胞用HEDS治疗3小时并将0.5ml胞外培养基从培养皿中移至含有0.5ml磺基水杨酸(SSA)裂解缓冲液的微量离心管中。在Fisher 59A(Pittsburgh,PA)微量离心机中对样品进行高速离心,上清液用于通过DTNB反应性巯基乙醇(ME)测定来定量测定生物还原。每个实验重复至少3次,除非小于所绘制的点,否则显示其误差。
图7和图8显示仅在葡萄糖不存在时,在辐射敏感型人类结肠癌细胞(HCT116)和辐射耐受型人类结肠癌细胞(HT29)这两者中HEDS降低胞内硫醇。这些图证明,具有葡萄糖的细胞能通过维持胞内硫醇而应付HEDS治疗。相比之下,在HEDS治疗之后,在缺葡萄糖细胞中,胞内硫醇降至低达对照的40%。在辐射敏感型结肠癌细胞(HCT116)和辐射耐受型结肠癌细胞(HT29)这两者中都观察到该现象。
通过首先使细胞缺乏葡萄糖达4小时,测定人类结肠癌细胞HCT116和HT29中HEDS对胞内硫醇的消耗。HEDS治疗后3小时,用细胞清洗液洗涤结合的细胞并用1ml磺基水杨酸(SSA)裂解缓冲液裂解细胞。然后,在Fisher 59A微量离心机中对样品进行高速离心,上清液用于使用Ellman氏试剂的胞内硫醇定量测定。每个实验重复至少3次,除非小于所绘制的点,否则显示其误差。
图1-8所示结果清楚表明,通过改变缺葡萄糖的癌细胞的硫醇状况,HEDS改善了人类癌细胞对DNA损伤剂的反应。
实施例III
也研究了使用HEDS(一种氧化剂/二硫化物)来增强肿瘤异种移植物对拓扑异构酶II抑制剂依托泊苷的反应。图9表明HEDS治疗能增强大鼠中肿瘤异种移植物对依托泊苷(一种拓扑异构酶II抑制剂,其也可通过诱导DNA损伤而杀伤细胞)的反应(至少提高50%反应)。在肿瘤大小为约8x8mm的大鼠中,测定HEDS(0和10mg/kg/天)对于肿瘤针对依托泊苷(12mg/Kg/天)的反应的影响。以0mg/kg和10mg/kg经IP注射给予溶于生理盐水的HEDS。HEDS给予后1小时,经IP将依托泊苷给予这些大鼠。一连3天持续进行这样的治疗。每周2次测量肿瘤生长,共2周。结果表明,与单独使用依托泊苷相比,当使用HEDS和依托泊苷治疗时,肿瘤反应提高50%。
用HEDS所观察到的这种反应提高的现象与下述现象是一致的:癌细胞在低葡萄糖浓度(1-3mM)下时(与生理浓度的葡萄糖(5mM)相比)不能在体外有效使HEDS解毒而导致胞内硫醇消耗(另见图10-12)。这些体外和体内结果表明,生理浓度(5mM)的葡萄糖可以容易地使HEDS解毒(图10和11),但葡萄糖少于3mM的肿瘤则会受到HEDS的影响(图10和12)。
对于图10,通过将细胞与不同浓度的葡萄糖孵育4小时,测定人类结肠癌细胞HCT116的葡萄糖浓度依赖性的HEDS解毒/生物还原。HEDS治疗后3小时,将0.5ml胞外培养基从培养皿中移至含有0.5ml磺基水杨酸(SSA)裂解缓冲液的微量离心管中。在Fisher 59A微量离心机中对样品进行高速离心,上清液用于通过DTNB反应性巯基乙醇(ME)测定来定量测定生物还原。每个实验重复至少3次,除非小于所绘制的点,否则显示其误差。
对于HCT116细胞中胞内硫醇的评价,将细胞与不同浓度的葡萄糖一起孵育4小时。对于图12,将细胞用HEDS治疗3小时。治疗之后,用细胞清洗液洗涤结合的细胞并用1ml磺基水杨酸(SSA)裂解缓冲液裂解细胞。在Fisher 59A微量离心机中对样品进行高速离心,上清液用于使用Ellman氏试剂的胞内硫醇定量测定。每个实验重复至少3次,除非小于所绘制的点,否则显示其误差。
实施例IV
除了HEDS之外,还测试了MPG二硫化物。MPG二硫化物的结构是:
该化合物由Biosynthesis Inc.(Lewisville,Texas)采用对称的二硫化物合成方法合成。通过质谱实测的质量(348.21)与根据MPG二硫化物结构而计算的MPG二硫化物分子量(324.40)是一致的。经薄层色谱测定(洗脱液:n-BuOH∶HOAc∶H2O 4∶2∶1),化合物纯度>90%。
在大鼠乳瘤异种移植模型中测试了MPG二硫化物在改进针对顺铂的反应中的功效。针对两种不同肿瘤大小测定了MPG二硫化物。这些不同肿瘤大小是通过肿瘤在大鼠中生长6天(小肿瘤,图13)或12天(大肿瘤,图14和15)而得到的。MPG二硫化物经测定对动物无毒。
在具有小肿瘤(约139mm3)的大鼠或具有大肿瘤(约2837mm3)的大鼠中,测定了肿瘤对MPG二硫化物的反应。以40mg/Kg/天经IP注射给予溶于生理盐水的MPG二硫化物。对照动物接受盐水治疗。一连3天持续进行这样的治疗。该治疗方案在这些动物中不引起任何可观察到的副作用。各组(对照或MPG二硫化物)由至少3只动物组成。各数据点是至少3只动物的平均值,除非小于所绘制的点,否则显示其标准误差。
在肿瘤体积约为2837mm3的大鼠中,测定了由MPG二硫化物所提高的大肿瘤针对顺铂的反应。以40mg/Kg/天经IP注射给予溶于生理盐水的MPG二硫化物。MPG二硫化物给予之后1小时,经IP将顺铂(2mg/kg)给予这些大鼠。再继续2天对这些动物进行不使用顺铂而仅使用用MPG的治疗。该治疗方案在这些动物中不引起任何可观察到的副作用。各组(顺铂或MPG二硫化物加上顺铂)由至少3只动物组成。各数据点是至少3只动物的平均值,除非小于所绘制的点,否则显示其标准误差。
在13天内,所有未治疗小肿瘤大小增加几乎达200倍,从136±4.37mm3到27,300mm3(图13)。此时对这些动物实施安乐死。显然,从治疗之日的139±4.29mm3到第13天的126±119mm3(图13),MPG二硫化物本身完全抑制小肿瘤的生长。
对于较大的肿瘤,在5天内,所有未治疗肿瘤的大小都增加了几乎10倍,从2837±204mm3到25,015±2855mm3(图14)。此时对这些动物实施安乐死。用MPG二硫化物治疗的肿瘤的生长从2848±538mm3起仅增加3倍,其在治疗后5天比未治疗动物小2.5倍(图14)。肿瘤持续低速生长,在第8天达到最大尺寸为18,038±1289mm3。
单用顺铂可抑制肿瘤生长,从2948±180mm3到治疗后13天的4355±577mm3(图17)。然而,与顺铂和MPG二硫化物各自单独使用相比,这两者联用明显更好地降低了肿瘤大小(比顺铂组小38倍),使肿瘤体积从2402±218mm3降低为治疗开始之后的第13天的112±47mm3(图15)。
这些结果表明,MPG二硫化物起到了肿瘤化疗药的作用,甚至当单独给予时,尤其是对于小肿瘤(小于约500mm3)。然而,MPG二硫化物与化疗药(例如顺铂)联用能完全消除肿瘤、甚至是大肿瘤,而这是单用顺铂所不能达到的。
实施例V
除了人类结肠癌细胞(HCT116和HT29;参见实施例II)之外,也针对包括乳癌细胞和前列腺癌细胞的其它人类癌细胞,在体外测试了含有二硫化物的化合物。正如用两种人类结肠癌细胞系所观察的那样,在葡萄糖贫化培养基中,两种人类乳癌细胞系(MCF7、SKBR3)和4种前列腺癌细胞系(DU145、PC3、DU145、LnCaP)也表现出不能将HEDS转化为ME(这种转化是解毒过程)。图16显示,在葡萄糖不存在时,6种不同的人类癌细胞(HCT116、HT29、PC3、DU145、MCF7、SKBR3、LnCaP)缺乏将HEDS转化为ME的能力(给出了3次实验的平均值和标准误差)。这些结果表明,给予二硫化物化合物,例如HEDS和/或MPG二硫化物,可用于治疗各种各样的癌症,尤其是当与其它常规癌症治疗联用时。
图17和图18表明,给予HEDS也可增强其它类型的癌细胞对化疗药、尤其是DNA损伤剂的反应。图17和图18显示,在葡萄糖存在和不存在时,HEDS对乳癌细胞系(MCF7)和前列腺癌细胞系(DU145)的辐射反应的影响。结果表明,在葡萄糖不存在时,HEDS能显著增加MCF7和DU145这两者的辐射反应。这些辐射相关的结果表明,含有二硫化物的化合物可广泛用于增加癌细胞对化疗药、尤其是DNA损伤剂的反应。
尽管上文已经描述并具体举例说明了本发明的某些优选实施方案,但不得视为本发明受到这些实施方案的限制。可对其进行各种修改,只要不偏离所提交权利要求书给出的本发明范围和精神。
Claims (27)
1.在有需要的患者中治疗癌症的方法,所述方法包括将包含至少一种含有二硫化物的化合物和药学上可接受的载体的组合物给予所述患者,其中所述含有二硫化物的化合物包含由至少一个二硫键连接至第二烷基的第一低级烷基。
2.权利要求1的方法,其中所述第一低级烷基是巯基丙酰基甘氨酸(MPG)。
3.权利要求1的方法,其中所述第二烷基是低级烷基。
4.权利要求1的方法,其中所述含有二硫化物的化合物选自巯基丙酰基甘氨酸(MPG)的二硫化物、羟乙基二硫化物(HEDS)、MPG和ME的二硫化物、2-巯基乙烷磺酸盐(美司钠)的二硫化物、MPG和美司钠的二硫化物以及ME和美司钠的二硫化物。
5.权利要求4的方法,其中所述含有二硫化物的化合物是MPG的二硫化物。
6.权利要求1的方法,其中所述癌症包括选自以下的细胞:含氧量低的癌细胞、缺葡萄糖的癌细胞、以及含氧量低并且缺葡萄糖的癌细胞。
7.权利要求1的方法,所述方法还包括给予至少一种化疗药。
8.权利要求1的方法,所述方法还包括给予辐射。
9.权利要求1的方法,所述方法还包括给予至少一种低氧毒素。
10.权利要求7的方法,其中所述化疗药选自拓扑异构酶II抑制剂和铂配合物。
11.权利要求9的方法,其中所述低氧毒素选自替拉扎明、AQ4N、5-硝基咪唑、尼莫唑、依他硝唑、丝裂霉素C类似物E09、2-硝基咪唑CI-1010和其它低氧特异性生物反应性药物。
12.权利要求1的方法,其中所述癌症包括含氧量正常的癌细胞。
13.权利要求12的方法,所述方法还包括给予至少一种葡萄糖-6-磷酸脱氢酶(G6PD)抑制剂。
14.权利要求13的方法,其中所述G6PD抑制剂选自脱氢表雄酮(DHEA)、硫酸DHEA、2-脱氧葡萄糖、卤代DHEA、表雄酮、异氟烷、七氟烷、地西泮和G6PD siRNA分子。
15.包含至少一种含有二硫化物的化合物、至少一种化疗药和至少一种药学上可接受的载体的组合物,其中所述含有二硫化物的化合物包含由至少一个二硫键连接至第二烷基的第一低级烷基。
16.权利要求15的组合物,所述组合物还包含至少一种葡萄糖-6-磷酸脱氢酶(G6PD)抑制剂。
17.权利要求15的组合物,其中所述第二烷基是低级烷基。
18.权利要求15的组合物,其中所述第一低级烷基是巯基丙酰基甘氨酸(MPG)。
19.权利要求15的组合物,其中所述含有二硫化物的化合物选自羟乙基二硫化物(HEDS)、巯基丙酰基甘氨酸(MPG)的二硫化物、MPG和ME的二硫化物、2-巯基乙烷磺酸盐(美司钠)的二硫化物、MPG和美司钠的二硫化物以及ME和美司钠的二硫化物。
20.权利要求15的组合物,其中所述化疗药选自拓扑异构酶II抑制剂和铂配合物。
21.权利要求16的组合物,其中所述G6PD抑制剂选自脱氢表雄酮(DHEA)、硫酸DHEA、2-脱氧葡萄糖、卤代DHEA、表雄酮、异氟烷、七氟烷、地西泮和G6PD siRNA分子。
22.包含至少一种含有二硫化物的化合物、至少一种低氧毒素和至少一种药学上可接受的载体的组合物,其中所述含有二硫化物的化合物包含由至少一个二硫键连接至第二烷基的第一低级烷基。
23.权利要求22的组合物,其中所述第二烷基是低级烷基。
24.权利要求22的组合物,其中所述第一低级烷基是巯基丙酰基甘氨酸(MPG)。
25.权利要求22的组合物,其中所述低氧毒素选自替拉扎明、AQ4N、5-硝基咪唑、尼莫唑、依他硝唑、丝裂霉素C类似物E09、2-硝基咪唑CI-1010和其它低氧特异性生物反应性药物。
26.权利要求22的组合物,所述组合物还包含至少一种化疗药。
27.包含至少一种含有二硫化物的化合物和至少一种药学上可接受的载体的组合物,其中所述含有二硫化物的化合物是巯基丙酰基甘氨酸(MPG)的二硫化物。
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CN107217054A (zh) * | 2017-04-25 | 2017-09-29 | 中山大学肿瘤防治中心 | G6pd基因及其表达产物在治疗结直肠癌中的应用 |
CN112480097A (zh) * | 2020-11-26 | 2021-03-12 | 汕头大学医学院 | 一种靶向ets结构域蛋白的抑制剂及其应用 |
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CN107217054A (zh) * | 2017-04-25 | 2017-09-29 | 中山大学肿瘤防治中心 | G6pd基因及其表达产物在治疗结直肠癌中的应用 |
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