CN101123958A - 联合放射疗法与化学疗法的组合物和方法 - Google Patents
联合放射疗法与化学疗法的组合物和方法 Download PDFInfo
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Abstract
本发明涉及包括放射疗法和化学疗法的联合疗法。具体而言，本发明的异黄酮或其类似物与放射疗法或化学疗法联合在治疗癌症和相关疾病与病症中的用途。本发明同样涉及用于所述联合疗法的组合物和药剂及其制造方法。
Description
发明领域
本发明涉及包括放射疗法和化学疗法的联合疗法。具体而言，本发明涉及与放射疗法或化学疗法联合的异黄酮或其类似物在治疗癌症和相关疾病与病症中的用途。本发明同样涉及用于上述疗法和用途具有相同用途的组合物和药剂及其制造方法。
背景
不管其发病机理如何，癌症特征为细胞生长和生存不受控制和调节。该过程包含一系列的变化。该系列的最早期端称为恶变前期。在此阶段，细胞在形态(不规则外观、轻微未分化、肥大)、有丝分裂活性(增生)及生存(降低凋亡指数)等方面表现出一系列变化。在该系列的另一端，癌细胞表现出完全未分化外观，经历快速和反复的有丝分裂，经历导致入侵周围组织和远处组织的迁移和一极低比率的凋亡。人类和动物的癌症状态包括处于该系列这两种末端之间的任何阶段的细胞。
虽然参与癌症发病机理中的准确机理尚未明确，但一几乎为所有形式的癌症所共有的根本错误发生于负责控制生存与死亡之间的平衡的细胞机理方面。
对于任何癌性或非癌性细胞，死亡是一种正常的默认情形。死亡由两种主要机理引起：(a)死亡受体(例如Fas、TRAIL等等)，其为于每一细胞表面表达的蛋白质且其对免疫细胞或血液中的可溶性因子有应答；(b)线粒体破裂，其通常为由该细胞内产生的内部信号引发。死亡由激活称为胱天蛋白酶类的蛋白水解酶(该酶消化细胞蛋白)通过任一机理发生。经由死亡受体的死亡称为外在性细胞凋亡；经由线粒体机理的死亡称为内在性细胞凋亡。为了生存，细胞需要通过产生抗凋亡蛋白(例如C-FLIP、XIAP、Smac-DIABLO和Bax)来阻断经常存在的死亡受体引发因子。这些抗凋亡蛋白的存在有助于防止或者是通向或者是来自死亡受体或线粒体的促死亡(pro-death)信号级联途径。据认为激活鞘氨醇激酶这种受体对在细胞内产生这些抗凋亡因子起着重要作用。为了让死亡发生，细胞需要或者下调抗凋亡蛋白产生或增加其降解速率或者二者都需要。
生存同样经由细胞中生长受体主动促进。这包括诸如表皮生长因子受体、血小板衍生生长因子受体、胰岛素样生长因子受体、肿瘤坏死因子受体和成纤维细胞生长因子受体等受体。这些生长受体被自分泌、旁分泌和内分泌来源的其相应的生长因子所激活，为细胞提供不断变化的(ongoing)重要刺激，使其经由各种促生存(pro-survival)途径而生存。
癌症与这些促生存/促死亡平衡机制的任一种的功能紊乱有关。举例而言，很多癌细胞过量表达一种或多种生长受体，导致过激活促生存机制。很多上皮源癌症(例如肺癌和乳房癌)表达超出正常水平的表皮生长因子受体。在另外情形下，癌症与通过下调死亡受体表达和/或通过过量表达抗凋亡因子而破坏该死亡受体机制有关。
癌症与细胞控制机制内功能紊乱的相关性，意味着癌症的成功治疗需要或者修正这些功能紊乱或者激活能够补偿该功能紊乱系统的其它功能。此为当前大量化学疗法和放射线疗法的基础。这些不同治疗方法基本上皆为寻求或者代谢上或者物理上不可逆地损伤癌细胞以使该细胞诱发细胞凋亡。这种细胞损伤严重到可引发如下促死亡后果：上调死亡受体表达和/或上调这些死亡-受体自分泌来源的配体的表达，和/或下调抗凋亡因子的表达，和/或上调促死亡因子。来自任一种或所有这些作用的最终结果为激活由胱天蛋白酶介导的自溶蛋白水解过程。
通过许多方法可达到治疗癌症的目的。这些治疗的目标通常为或者阻断细胞分裂或者减慢细胞分裂速率(细胞郁滞(cytostasis))或引起细胞死亡(细胞毒性)。其它较少见的目标是抑制供给快速生长的癌症组织需要的所需营养物质的供应(抗血管生成)。其它较少见的目标是阻止该细胞的功能完整性以达到阻止生长率的程度(信号转导抑制)。
那些其主要作用为抗血管生成的方法包括：
(a)沙利度胺。
那些其主要作用为细胞郁滞的方法包括：
(a)拓扑异构酶抑制剂(例如托泊替康(癌康定))。
那些其主要作用为细胞毒性的方法包括：
(a)那些其作用主要通过DNA损伤来介导的方法(例如放射线、顺铂、卡铂、依托泊苷、博莱霉素、多柔比星、烷化剂)；
(b)那些其作用主要通过破坏微管来介导的方法(例如紫杉烷类、长春花类生物碱、秋水仙碱)；
(c)那些其作用主要通过抗代谢药作用来介导的方法(例如氨甲喋呤、5-氟尿嘧啶、羟基脲、阿糖胞苷)。
那些其主要作用为信号转导调节的方法包括：
(a)那些其作用主要通过抑制生长受体活性来介导的方法(例如蛋白质酪氨酸激酶抑制剂、作为生长受体激动剂的抗体、他莫昔芬、抗雄激素、抗雌激素、GnrH激动剂)；
(b)那些其作用主要通过上调死亡受体表达或活性来介导的方法(例如干扰素、Fas配体、TRAIL配体)。
对于大多数人类和动物癌症来说，当前疗法具有若干缺点。首先，它们中很多与剂量限制和不良副作用有关，这种副作用反映了此等疗法的非特异性且与对非癌性组织的损伤有关。症状包括降低骨髓功能(贫血)、胃肠道不适(恶心、呕吐)和脱发。另外的缺点是严重烧伤疼痛(放射线疗法)、失去性欲和生育力(性激素拮抗剂)和对于诸如白血病等其它癌症类型易患病的素质(放射线疗法、某些药物)。
其次，很多肿瘤对标准抗癌疗法表现出天然不敏感。在此等情形下，标准疗法在任何剂量时或者具有很少的或没有抗癌作用，或者为起到显著临床效果所需剂量毒性很大。这些肿瘤实例为肾癌和胰腺癌、黑素瘤和胆管细胞癌。这种相对不敏感的基本原理尚不明确。
第三，在那些对标准抗癌疗法表现出敏感性的肿瘤中，很多随后出现抗性。这种诱导出的抗性的基本原理据认为是过表达诸如p-糖蛋白等蛋白质，这些蛋白质为‘转运蛋白’，其将药物在发挥任何生物学作用之前从细胞中逐出。
本发明主题重点是致力于解决细胞对放射疗法的抗性或上调或促进癌细胞或肿瘤对放射线疗法增加的敏感性。
放射疗法(放射线疗法)使用高能射线(通常为X-射线)以杀死癌细胞。X-射线除具有小于100埃的极短波长外与可见放射线具有相似特性。X-射线于1895年首先发现，此后不久放射线用于医学诊断、研究和治疗癌细胞与肿瘤。在某些病例中放射疗法同样在外科手术前使用以缩小肿瘤大小。放射疗法同样能在外科手术后使用以杀死残留组织。
治疗通常为局部，意即将该高能射线对准机体内或机体上一特定位点。一般而言，癌细胞比正常细胞对放射疗法更敏感，将杀死更多这样的细胞类型。受到影响的正常细胞通常可恢复以很快修复自身。拟治疗的癌细胞本身存在的难题是对放射疗法变得不敏感。其它问题包括拟治疗的位点与诸如心脏或脊髓等要害器官接近。此时所给予的放射线的水平或剂量为既可攻击癌细胞又不损伤周围正常细胞、组织或器官的临界值。癌细胞对放射线敏感性的任何增加、敏感性的恢复或保护正常细胞均将是一极为受欢迎的效果。
因此，迫切需要开发改进的能致力于解决先天性或获得性放射线抗性或化学抗性问题的抗癌疗法和能以更安全、更好耐受的方式提供改进抗癌效果的抗癌疗法。
本发明一优选目的是提供用于治疗、改善或预防癌症的药物组合物和方法。本发明同样寻求提供将癌细胞作为治疗目标的治疗用的药物组合物和方法，这些组合物和方法在靶向功能、保护或区别正常细胞与癌细胞、改进毒性剂的递送和/或恢复具有先天性或获得性抗性的癌细胞的放射线敏感性或化学敏感性等方面提供改进的药理学活性。
发明概述
现在本申请阐述新的治疗方案和化疗组合物与化合物。本发明基于异黄烷类化合物在提高癌细胞对各式各样具有极为不同的作用方式的抗癌治疗(药物或放射线疗法)的敏感性和恢复对那些药剂和治疗方法有获得性抗性的细胞对那些相同的药剂的敏感性方面的完全意想不到的活性。更令人惊讶的是已发现异黄酮类化合物对非癌细胞和组织表现出保护作用。
本发明一方面提供一种通过用如下所示的式(I)异黄酮类化合物接触癌细胞或肿瘤来增加或恢复癌细胞或肿瘤对放射疗法的敏感性的方法。
本发明另一方面提供一种用式(I)异黄酮类化合物接触正常细胞或组织块来保护正常细胞或组织块不受放射疗法和/或化学疗法影响的方法。
本发明另一方面提供一种通过用式(I)异黄酮类化合物接触癌细胞或肿瘤来增加或恢复癌细胞或肿瘤对化学疗法的敏感性的方法。在一实施方案中，患者在其治疗方案中既接受放射疗法又接受化学疗法。在另一实施方案中该活性剂为生长受体抑制剂或死亡受体刺激剂。
通式(I)化合物为由下式代表的异黄烷类化合物：
其中
R1、R2和Z独立为氢、羟基、OR9、OC(O)R10、OS(O)R10、CHO、C(O)R10、COOH、CO2R10、CONR3R4、烷基、卤烷基、芳基烷基、烯基、炔基、芳基、杂芳基、烷基芳基、烷氧基芳基、硫代、烷硫基、氨基、烷基氨基、二烷基氨基、硝基或卤代，或
R2如前所定义，而R1和Z与其所连接的碳原子共同形成一选自下式的五元环：
R1如前所定义，而R2和Z与其所连接的碳原子共同形成一选自下式的五元环：
而
W为R1，A为氢、羟基、NR3R4或硫代基，而B选自下式：
W为R1，而A和B与其所连接的碳原子共同形成一选自下式的六元环：
W、A和B与其所连接的基团共同选自下式：
W和A与其所连接的基团共同选自下式：
而B选自下式：
其中
R3为氢、烷基、芳基烷基、烯基、芳基、氨基酸、C(O)R11(其中R11为氢、烷基、芳基、芳基烷基或氨基酸)或CO2R12(其中R12为氢、烷基、卤烷基、芳基或芳基烷基)，
R4为氢、烷基或芳基，或
R3和R4与其所连接氮共同构成吡咯烷基或哌啶基，
R5为氢、C(O)R11(其中R11如前所定义)或CO2R12(其中R12如前所定义)，
R6为氢、羟基、烷基、芳基、氨基、硫代、NR3R4、COR11(其中R11如前所定义)、CO2R12(其中R12如前所定义)或CONR3R4，
R7为氢、C(O)R11(其中R11如前所定义)、烷基、卤烷基、烯基、芳基、芳基烷基或Si(R13)3，其中每一个R13独立为氢、烷基或芳基，
R8为氢、羟基、烷氧基或烷基，
R9为烷基、卤烷基、芳基、芳基烷基、C(O)R11(其中R11如前所定义)或Si(R13)3(其中R13如前所定义)，
R10为氢、烷基、卤烷基、氨基、芳基、芳基烷基、氨基酸、烷基氨基或二烷基氨基，
画图线””代表或一单键或一双键，
T独立为氢、烷基或芳基，
X为O、NR4或S，而
Y为下式：
其中：
R14、R15和R16独立为氢、羟基、OR9、OC(O)R10、OS(O)R10、CHO、C(O)R10、COOH、CO2R10、CONR3R4、烷基、卤烷基、芳基烷基、烯基、炔基、芳基、杂芳基、硫代、烷硫基、氨基、烷基氨基、二烷基氨基、硝基或卤代，或R14、R15和R16中任两个稠合形成一环烷基、芳香或杂芳香结构，和
任选取代的化合物和其药学上可接受盐及前药。
在一优选实施方案中，在放射疗法或用第二种化疗剂治疗之前先用式(I)化合物治疗癌症患者。然而，就给予式(I)化合物和或者是放射疗法或者是给予第二种化疗剂或两者都给予而言，其涵盖可使用任何次序。
在一另外实施方案中，在观察到一癌症患者对放射疗法有抗性或者先天性或者获得性)后将式(I)化合物给予该患者。
在一另外实施方案中，在观察到一癌症患者对化疗剂有抗性(或者先天性或者获得性)后将式(I)化合物给予该患者。
本发明另一方面提供一种联合疗法，其包括将有效治疗量的式(I)化合物给予正经历放射疗法或将要经历放射疗法的受试者。在一实施方案中，在放射疗法之前给予，且可在该受试者出现放射线抗性后给予。
本发明另一方面提供一种联合疗法，其包括将有效治疗量的式(I)化合物和化疗剂给予受试者。可顺次给予或同时给予或在该受试者出现化学抗性后给予。
在一优选实施方案中，拟治疗的病症最好为显示恶性特征的癌症，但也可包括诸如恶变前损害等癌症的早期阶段(例如非典型、发育异常、上皮内瘤形成)和良性癌症。
本发明另外方面提供制造用于上述本发明方法的药物的方法和用于所述方法的药物。
除非正文中另有要求，否则遍及本说明书和下述权利要求书中的词语“包含(comprise)”和其变体例如“包含comprises”或“包括或包含(comprising)”应理解为意味着包含所述整数物或步骤或者所述组整数或步骤，但并不排除任何其它完整物或步骤或其它组完整物或步骤。
发明详述
本文所用术语“异黄烷类”、“异黄酮类”和“异黄酮”广义上可理解为包括以1，2-二苯基丙烷系统为基础、在吡喃环上有侧接苯基的稠环苯并吡喃分子。因此，通常称为异黄酮、异黄烯、异黄烷、异黄烷酮、异黄烷醇等等的这些类别的化合物本文统称为异黄酮类、异黄酮衍生物或异黄烷类化合物。
术语“烷基”可理解为意指直链和支链两种烷基基团，例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基等等。该烷基含有1到10个碳原子，优选含1到6个碳原子，更优选甲基、乙基、正丙基或异丙基。该烷基可任选由一个或多个氟、氯、溴、碘、羧基、C1-C4-烷氧羰基、C1-C4-烷基氨基-羰基、二-(C1-C4-烷基)-氨基-羰基、羟基、C1-C4-烷氧基、甲酰氧基、C1-C4-烷基-羰氧基、C1-C4-烷硫基、C3-C6-环烷基或苯基。
术语“芳基”可理解为包括苯基和萘基，且任选可由一或多个C1-C4-烷基、羟基、C1-C4-烷氧基、羰基、C1-C4-烷氧基羰基、C1-C4-烷基羰氧基或卤代取代。
术语“卤代”可理解为包括氟代、氯代、溴代和碘代，优选氟代和氯代，更优选氟代。就“卤烷基”而言应包括一卤代烷基、二卤代烷基和一直到全卤代烷基。优选的卤代烷基为三氟甲基和五氟乙基。
术语“药学上可接受盐”是指带有电荷且可与药物作用剂结合给药的有机或无机部分，举例而言，作为盐中的反-阳离子或反-阴离子。药学上可接受阳离子为本领域技术人员所知，包括但不限于钠、钾、钙、锌和季胺。药学上可接受阴离子为本领域技术人员所知，包括但不限于氯化物、乙酸盐、柠檬酸盐、碳酸氢盐和碳酸盐。
术语“药学上可接受衍生物”或“前药”是指活性化合物的衍生物，其给予受试者后能直接或间接提供母体化合物或代谢物或其自身可表现活性。前药包括在本发明范围中。
本文所用术语“治疗”、“预防”或“防止”、“改善”等等应在其最广义的方面来理解。具体而言，术语“治疗”不一定意味着动物得到治疗直至完全恢复。因此，“治疗”包括改善具体病症的症状或严重程度，或预防或降低具体病症的发展风险。
术语“放射疗法”或“放射线疗法”大致可理解为包括用影响癌细胞、肿瘤或有关机制和生物学过程的粒子和/或能量波的治疗方法或疗法。具体而言，放射线为用于放射疗法中的高能波或粒子，例如X-射线、电子、γ射线或质子。最优选的波或粒子为X-射线。
术语“化疗剂”广义上可理解为包括所有影响癌细胞、肿瘤或有关机制和生物学过程的药物、化学药品、化合物、组合物、作用剂、药物、聚合物、多肽、蛋白质等等。
优选的式(I)异黄烷类化合物选自通式(III)到(IX)，更优选选自通式(IV)到(IX)：
其中
R1、R2、R5、R6、R14、R15、W和Z如上定义，
更优选R1、R2、R14、R15、W和Z独立为氢、羟基、OR9、OC(O)R10、C(O)R10、COOH、CO2R10、烷基、卤烷基、芳基烷基、芳基、硫代、烷硫基、氨基、烷基氨基、二烷基氨基、硝基或卤代，
R5为氢、C(O)R11(其中R11为氢、烷基、芳基或氨基酸)或CO2R12(其中R12为氢、烷基或芳基)，
R6为氢、羟基、烷基、芳基、COR11(其中R11如前所定义)或CO2R12(其中R12如前所定义)，
R7为氢、C(O)R11(其中R11如前所定义)、烷基、卤烷基、烯基、芳基、卤代芳基、烷基芳基、烷氧基芳基、芳基烷基或Si(R13)3，其中每一个R13独立为氢、烷基或芳基，
R9为烷基、卤烷基、芳基烷基或C(O)R11，其中R11如前所定义，而
R10为氢、烷基、氨基、芳基、氨基酸、烷基氨基或二烷基氨基，
更优选
R1和R14独立为羟基、OR9、OC(O)R10或卤代，
R2、R15、W和Z独立为氢、羟基、OR9、OC(O)R10、C(O)R10、COOH、CO2R10、烷基、卤烷基或卤代，
R5为氢、C(O)R11(其中R11为氢或烷基)或CO2R12(其中R12为氢或烷基)，
R6为氢或羟基，
R7为氢、C(O)R11(其中R11为氢或烷基)、烷基、卤烷基、烯基、芳基、卤代芳基、烷基芳基、烷氧基芳基、芳基烷基或Si(R13)3，其中每一个R13独立为氢、烷基或芳基，
R9为烷基、芳基烷基或C(O)R11，其中R11如前所定义，而
R10为氢或烷基，
而更优选
R1和R14独立为羟基、甲氧基、苄氧基、乙酰氧基或氯代，
R2、R15、W和Z独立为氢、羟基、甲氧基、苄氧基、乙酰氧基、甲基、三氟甲基或氯代，
R5为氢或CO2R12，其中R12为氢或甲基，
R6为氢，而，
R7为氢、甲基、乙基、三氟甲基、苯基、卤代苯基、甲基苯基、乙基苯基、甲氧基苯基或苯基甲基。
尤其优选的式(I)异黄酮类化合物和其药学上可接受盐选自：
(顺式) 7 (反式) 8
在一另外的实施方案中，优选的异黄酮类化合物为通式(VI)异黄酮-3-烯(isoflav-3-ene)和异黄烷化合物，而除了下列化合物及其药学上可接受盐外，尤其要提及上面的化合物12到化合物21和化合物30：
在一本发明最优选实施方案中，异黄酮类化合物选自化合物12(脱氢雌马酚)、化合物32、化合物39、化合物45和化合物48。因此，在本说明书实施例和附图中具体提及脱氢雌马酚，然而，本文提供的下面的实施例和附图不应该理解为限制本发明内容。
以诸如金雀异黄素和异黄烯(例如脱氢雌马酚)等异黄酮为实例的异黄酮类化合物家族代表一种大有前途的新的预防和治疗癌症的化学治疗药物。这些化合物药理学作用的准确原理尚未完全明了，但结果是细胞郁滞和细胞毒性。对于该化合物家族的非常值得注意的是其显示出广泛的抗人类和动物癌症的活性和其对癌细胞的高度选择性这一事实。
我们已证明这种异黄酮类家族的化学成员(例如脱氢雌马酚)为有效的抗癌剂，其令人惊讶地对诸如顺铂和吉西他滨等化疗药物有协同作用，即使这两种标准化学毒性药物在细胞内具有完全不同的抗癌效果。
更令人惊讶的是本发明人发现：异黄酮类或衍生物增加或恢复癌细胞和肿瘤对放射线疗法作用效果的敏感性。
治疗方案可包括一次治疗或一经过若干周称为分次治疗(fractions)的疗程治疗。举例而言，分次治疗通常从星期一到星期五每天一次，例如在周末间歇性休息以帮助正常细胞恢复。实际的治疗方案将很大程度上视拟治疗的癌症类型和拟采用的放射疗法类型而定。本领域技术人员可通过考虑各种特定因素(包括患者健康状况、疾病进展情况和癌症类型)最好地确定每一个体的最合适方案。
在一优选的实施方案中，在放射疗法之前给予异黄酮或其衍生物。预治疗的作用是加强癌细胞或肿瘤对放射线作用的敏感性。为了影响目标细胞抵抗放射线的能力，放射疗法前和/或放射疗法期间应该适当地开始异黄酮类化合物预治疗。在一最宽泛的优选实施方案中，预治疗的时间和持续时间足够让给予的异黄酮类接触癌细胞或肿瘤。该时间通常可为7天或14天或直到30天。在另一优选实施方案中，异黄酮类化合物治疗在放射疗法之前6天，或之前5天或3天或2天或1天。
在其它情况下，在放射疗法的当天给予异黄酮类化合物可能很有利，其通过或者是移除细胞凋亡阻断剂或者是增加降解速率可更具有帮助细胞死亡的作用。
若该治疗包括分次治疗，则异黄酮类化合物的给药可定期发生在第一次治疗前或仅在若干次放射线治疗前或在每一次放射线治疗前。
在另一优选的实施方案中，发现给予异黄酮类化合物可恢复或至少可解决在放射线治疗后可能发生的敏感性问题。就这点而言在另一优选的实施方案中，给予异黄酮类化合物发生在放射线治疗后。
化疗剂通常分组为DNA相互作用剂、抗代谢药、微管蛋白相互作用剂、激素类药、其它诸如天冬酰胺酶或羟基脲等药剂。每一组化疗剂可进一步根据活性或化合物类型再分。与本发明式(I)异黄酮类化合物或其盐联合使用的化疗剂可选自这些组别的任一组，但不限于此。为详细讨论这些化疗剂及其给药方法，参见Dorr等人，癌症化学疗法手册(Cancer Chemotherapy Handbook)，第二版，第15-34页，Appleton和Lang(Connecticut，1994)出版，其在此引作参考。
举例而言，DNA相互作用剂包括：烷化剂，例如顺铂、环磷酰胺、六甲蜜胺；DNA链断裂剂，例如博莱霉素；嵌入型拓扑异构酶II抑制剂，例如放线菌素D和多柔比星；非嵌入型拓扑异构酶II抑制剂，例如依托泊苷和替尼泊苷；DNA小沟结合物普卡霉素。
烷化剂与细胞DNA、RNA或蛋白质分子或与较小的氨基酸谷胱甘肽或类相似的化学药品形成共价化学加合物。一般而言，烷化剂与细胞成分中的亲核原子(例如核酸、蛋白质、氨基酸或谷胱甘肽中的氨基、羧基、磷酸根或巯基)反应。这些烷化剂在癌症治疗中的机理和作用不很明确。
典型的烷化剂包括但不限于：氮芥类，例如瘤可宁、环磷酰胺、异环磷酰胺、氮芥、美法仑、乌拉莫司汀；氮丙啶，例如塞替派；甲磺酸酯，例如白消安；亚硝基脲，例如卡莫司汀、洛莫司汀、链佐星；铂络合物，例如顺铂、卡铂；生物还原性烷化剂，例如丝裂霉素和丙卡巴肼、达卡巴嗪和六甲蜜胺。
举例而言，DNA链断裂剂包括博莱霉素。
举例而言，DNA拓扑异构酶II抑制剂包括下列：嵌入剂，例如安吖啶、放线菌素D、柔红霉素、多柔比星(阿霉素)、伊达比星和米托蒽醌；非嵌入剂，例如依托泊苷和替尼泊苷。
DNA小沟结合物例如为普卡霉素。
抗代谢药通过两种主要机理之一干扰核酸形成。某些药物抑制DNA合成的直接前体--三磷酸脱氧核糖核苷形成，因此抑制DNA复制。某些化合物为嘌呤或嘧啶类似物，且可掺入核苷酸合成代谢途径中。于是这些类似物代替其正常对应物取代进入DNA或RNA中。
本文中有用的抗代谢药包括但不限于：叶酸拮抗剂，例如氨甲喋呤和曲美沙特；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，包括巯基嘌呤、6-硫代鸟嘌呤、氟达拉滨、喷司他丁；而核糖核苷酸还原酶抑制剂包括羟基脲。
微管蛋白相互作用剂通过结合到微管蛋白特定位点上起作用，微管蛋白为一种聚合形成细胞微管的蛋白质。微管是关键的细胞结构单位。当这些药剂与该蛋白质结合时，细胞不能形成微管。举例而言，微管蛋白作用剂包括长春新碱和长春碱这两种生物碱和紫杉醇(泰素)。
激素类药同样可用于治疗癌症和肿瘤。其用于易受激素影响的肿瘤，通常为天然来源。激素类药包括但不限于：雌激素类、结合雌激素和乙炔雌二醇和己烯雌酚、氯烯雌醚和idenestrol；孕激素类，例如己酸羟孕酮、甲羟孕酮和甲地孕酮；雄激素类，例如睾酮、丙酸睾酮、氟甲睾酮和甲睾酮。
肾上腺皮质激素类源自天然肾上腺皮质醇或氢化可的松。因其抗炎益处以及某些抑制有丝分裂和中断DNA合成的能力而得到使用。这些化合物包括但不限于泼尼松、地塞米松、甲泼尼龙和泼尼松龙。
促黄体激素释放激素类药或促性腺激素释放激素拮抗剂主要用于治疗前列腺癌症。这些包括醋酸亮丙瑞林和醋酸戈舍瑞林。其在试验中可防止类固醇生物合成。
举例而言，抗激素抗原包括：抗雌激素剂，例如他莫昔芬；抗雄激素剂，例如氟他胺；抗肾上腺药，例如米托坦和氨鲁米特。
其它药剂包括下列：羟基脲似乎主要是通过抑制核糖核苷酸还原酶这种酶起作用，而天冬酰胺酶为一种将天冬酰胺转化为非功能性的天冬氨酸的酶，由此阻断肿瘤中蛋白质合成。
优选的化疗剂为顺铂、卡铂、泰素(紫杉醇)、氟尿嘧啶、氟尿苷、环磷酰胺、异环磷酰胺、六甲密胺、雌莫司汀、丝裂霉素和多西他塞。
式(I)化合物同样表现出化疗活性，在这方面尤其可提及脱氢雌马酚、化合物12和化合物32与39。
本发明优选的双齿和三齿铂配位体包括那些在本领域众所周知的配位体。举例而言，合适的双芽配位体可选自-1，2-乙二胺与1，10-菲咯啉(phenathraline)和其它为本领域所熟知的配位体。
本发明化合物在治疗与下列作用相关疾病或起因于下列作用的疾病方面具有特殊应用：雌激素作用、雄激素作用、血管舒张和痉挛作用、炎症作用和氧化作用。这些作用进一步阐述于国际专利申请WO 98/08503和WO 03/086386中。
在本发明治疗性治疗中所需式(I)化合物量视许多因素而定，这些因素包括特定应用、所用特定化合物的性质、拟治疗的病症、给药方式和患者状况。式I化合物可按常规使用的方式和量来给药。举例而言，参见Goodman和Gilman，The Pharmacological Basis ofTherapeutics，1299(第7版，1985)。如上所述，所用具体剂量应视拟治疗病症、受试者状态、给药途径和其它众所周知的因素而定。一般而言，每一患者的日剂量可在0.1毫克到10克之间，通常从0.5毫克到1克，最好从50毫克到200毫克。重要的是通式(I)异黄烷类化合物与抗癌剂之间的协同关系使得在(举例而言)诸如顺铂、紫杉醇和卡铂等相对有毒的药物的用量方案中可显著减少用量。
用于治疗本文所述治疗适应症的药物组合物(为了方便下文称作“活性化合物”)的生产通常如本领域所熟知是与一种或多种药学上或兽药学上可接受的载体和/或赋形剂混合。
当然，该载体必须是在与该制剂中任何其它组分相容的情况下可接受，且必须对受试者无害。该载体或赋形剂可为固体或液体或两样都可以，最好是与所述化合物调配为单位剂量，如片剂，其可含有0.5％到59％(重量)的活性化合物或直到100％(重量)的活性化合物。一种或多种活性化合物可包括在本发明制剂中，其可以制药业任何熟知技术来制备，大体上包括混合各组分，任选包括一种或多种辅助组分。
尽管在任一特定病例中最合适的途径应视拟治疗病症的性质和严重程度和所用特定活性化合物的性质而定，但本发明制剂包括那些适于口服给药、直肠给药、眼睛给药、口腔含化给药(举例而言舌下给药)、胃肠外给药(举例而言，皮下给药、肌肉内给药、皮内给药或静脉内给药)和经皮给药的制剂。
适于口服给药的制剂可在以分离的单位(例如胶囊、袋装、锭剂或片剂，每一种皆含有预定量的活性化合物)存在，以粉剂或颗粒剂存在；其在水性或非水性液体中的溶液剂或混悬剂存在；或其以水包油或油包水乳剂存在。此等制剂可以制药业中任何合适方法来制备，其包括使该活性化合物与合适载体(其可如上所述含有一种或多种辅助成分)相结合这一步骤。一般而言，本发明制剂通过将该活性化合物与液体或精细固体载体或二者均一且密切混合，然后若需要，将得到的混合物成形以形成一单位剂量来制备。举例而言，片剂可通过将含有该活性化合物、任选的一种或多种辅助组分的粉末或颗粒压片或模制来制备。压制片可通过在一合适机器中将任选与粘合剂、润滑剂、惰性稀释剂和/或表面活性剂/分散剂混合的自由流动的化合物(例如粉末或颗粒)压制来制备。模制片可通过在合适机器中将用惰性液体粘合剂润湿的粉状化合物制模来制备。
适于口腔含化(舌下)给药的制剂包括在矫味基质(通常为蔗糖和阿拉伯胶或西黄蓍胶)中包含该活性化合物的糖锭剂和在一惰性基质(例如明胶和甘油或蔗糖和阿拉伯胶)中包含该活性化合物的软锭剂。
本发明适于胃肠外给药的组合物方便地包含该活性化合物的无菌水性制剂，这些制剂最好与计划中的接受者的血液等渗。尽管也可借助皮下注射、肌肉内注射或皮内注射进行给药，但这些制剂最好通过静脉内给药。此等制剂可方便地通过将该化合物与水或甘氨酸缓冲液混合并使得到的溶液无菌和与血液等渗来制备。本发明注射用制剂通常含有0.1％到60％(w/v)的活性化合物，其以0.1毫升/分钟/公斤或适当速率给药。胃肠外给药为本发明化合物优选的给药途径。
适于直肠给药的制剂最好以栓剂这种单位剂量存在。其可通过将该活性化合物与一种或多种常规固体载体(举例而言，可可脂)混合然后将得到的混合物成形来制备。
适于局部给予皮肤的制剂或组合物最好采用膏剂、霜剂、洗剂、糊剂、凝胶剂、喷雾剂、气雾剂或油剂形式。可用载体包括凡士林、羊毛脂、聚乙二醇、醇类及其中两种或多种的组合。该活性化合物通常以0.1％到0.5％(w/w)的浓度存在，举例而言，以0.5％到2％(w/w)的浓度存在。这些组合物的实例包括化妆用皮肤霜剂。
适于经皮给药的制剂可以分离的贴剂存在，其适合保持与接受者表皮较长时间紧密接触。举例而言，就所述活性化合物而言，此等贴剂适宜地含有呈任选缓冲过的0.1M到0.2M浓度的水性溶液的活性化合物。
适于经皮给药的制剂同样可通过离子电渗疗法来递送(举例而言，参见Pharmaceutical Research 3(6)，318(1986))，且通常采用该活性化合物的任选缓冲过的水性溶液形式。合适的制剂包含柠檬酸盐或bis/tris缓冲液(pH6)或乙醇/水及含有0.1M到0.2M的活性组分。
该活性化合物可以食品形式提供，例如加入到食品中，混合于食品中，在食品中涂覆，组合到食品中或用其它方式加入到食品中。术语食品以其最广泛的含义来使用，包括液体制剂(例如包括乳制品在内的饮料)和其它食物(例如健康棒状食品、甜食)等等。含有本发明化合物的食物制剂可按照标准操作容易地制备。
治疗方法、用途和组合物可用于给予人类或动物，包括诸如宠物和家养动物(例如狗和猫)与家畜动物(例如牛、绵羊、猪和山羊)等哺乳动物、鸟类(例如鸡、火鸡、鸭)等等。
该活性化合物或其药学上可接受衍生物、前药或盐同样可与不削弱所期需作用的其它活性物质或与补充所期需作用的物质(例如抗生素、抗真菌剂、抗炎药或抗病毒化合物)共同给药。该活性剂可包含两种或多种异黄酮或其衍生物组合或协同混合物。这些活性化合物同样可与降脂药(例如普罗布考和烟酸)、血小板凝聚抑制剂(例如阿斯匹林)、抗血栓形成剂(例如可迈丁(coumadin))、钙通道阻滞药(例如维拉帕米、地尔硫卓和硝苯地平)、血管紧张素转换酶(ACE)抑制剂(例如卡托普利和依那普利)及β-阻断剂(例如普萘洛尔、特布洛尔(terbutalol)和拉贝洛尔)一同给药。这些化合物同样可与诸如布洛芬、消炎痛、阿斯匹林、非诺洛芬、甲芬那酸、氟芬那酸和舒林酸等非类固醇抗炎药联合给药。这些化合物同样可与皮质类固醇一同给药。
共同给药可为同时或依次。同时给药可通过化合物在同一单位剂量或在单独和分离的单位剂量于相同或相似时间给予来实现。次序给药可为所需要的任何次序，通常当给予第二种或随后的活性剂(尤其是在期望累积性或协同性结果)时，需要当时第一种或初始活性剂的即时(ongoing)生理效应发生。
用于本发明的式(I)异黄酮可来源于多种易于为本领域技术人员确认的来源中的任何一种。其最好通过人工合成获得。举例而言，参见Chang等人，(1994)，其揭示了合成各种异黄酮的合适方法。式(I)异黄酮同样可从植物中通过化学提取获得，所需化合物在植物中或者天然存在或者可通过提取和半合成程序来获得。
国际专利申请WO 98/08503和WO 00/49009(其全部内容在此引作参考)和其中引用的参考文献同样提供用于制备本发明所用的异黄烷类化合物的通用合成方法。
按照已知方法制备3，4二芳基苯并二氢呋喃，举例而言，例如那些公开于美国专利第3,340,276号和第3,822,287号中的方法。在美国专利第3,822,287号和第4,447,622中可发现特定异构体合成和互换的方法。
本发明人发现在式(I)化合物(特别是式(VI)异黄酮-3-烯化合物)与已知放射线治疗方法之间令人惊讶的协同作用。本发明人同样发现在式(I)化合物(特别是式(VI)异黄酮-3-烯化合物)与化疗剂之间令人惊讶的协同作用。发现本发明异黄烷类化合物可恢复或至少改进先前有抗性的癌细胞系的化学敏感性。另外，它们能通过区分细胞特征保护非癌细胞或正常细胞或组织块不受放射疗法或化学疗法的影响。
特别是，发现脱氢雌马酚(12)和化合物32及化合物39与干扰素-γ、Fas配体、TRAIL配体、生长受体抑制剂(例如表皮生长因子受体抑制剂、血小板衍生生长因子受体抑制剂、成纤维细胞生长因子受体抑制剂、肿瘤坏死因子受体抑制剂、胰岛素样生长因子受体抑制剂)表现出协同作用。认为这些化合物由于对XIAP具抑制作用得以通过上调细胞凋亡和下调细胞生存来提高癌细胞的放射线敏感性(或化学敏感性)而具有活性。
这些结果进一步阐明于下列实施例中。这些结果显示放射疗法和/或化学疗法与异黄酮类化合物联合可用于通过降低标准化学疗法的IC50来治疗癌细胞和瘤性肿瘤增殖。给予(或者同时、顺序给药或者作为标准治疗方案的预治疗给药)本文所述异黄烷类化合物增加了癌细胞和肿瘤对化学毒性剂和对放射疗法的敏感性。
本发明参考下列非限制性实施例得到进一步阐述。
实施例1
在培养板上评估异黄酮类化合物的选择对各种受放射疗法影响的癌细胞系的效果。用CellTitert来测定细胞的生存能力。用Hoechst33342染料来评估细胞凋亡。
结果显示通过用脱氢雌马酚(化合物12)和化合物32及化合物39(以2和10μM)既实施预治疗(1天和8小时)方案又实施顺序/后治疗(-30分钟/+4小时)方案，可增加人乳房癌细胞系、人前列腺癌细胞系、人卵巢癌细胞系、人胰腺癌细胞系和人宫颈癌细胞系的放射线敏感性。
同样地，某些其它异黄酮类化合物(化合物7和化合物8)表现出相似的结果，但在人类癌细胞系之间表现出不同的程度。
令人惊讶地发现对于癌细胞系用异黄酮处理细胞可作为放射线增敏剂起作用。
结果提示，在所研究的模型中，异黄酮类化合物在一主要机制途径中抑制XIAP，从而大大地降低了辐射后的细胞生存，提供了更好的肿瘤控制。另外，发现这些异黄酮化合物类对标准抗放射线细胞的作用使得其与对照组相比放射疗法更为敏感。
这些实施例突出了式(I)异黄酮类化合物作为治疗剂与放射疗法联合用于增加或恢复抗性癌细胞和肿瘤的敏感性及诱导放射线抗性癌细胞的敏感性的效用。
式(I)化合物同样可用于普遍性下调细胞增殖和治疗、改善、防卫、预防和/或防止治疗适应症。
本领域技术人员应认识到，此处所述本发明容许有不同于那些具体阐述的方案的变化和改良。应该理解本发明包括所有此等变化和改良。
本发明同样包括所有在本说明书中单独地或共同地提及或指出的步骤、特征、组合物和化合物及所述步骤或特征中任一种以及和所有任意两种或多种的组合。
本说明书中提及任何现有技术并不且不应解释为承认或以任何方式提示该现有技术构成所属领域的常识的一部分。
Claims (12)
1.一种通过用如本文所定义的式(I)异黄酮类化合物或其药学上可接受盐接触癌细胞或肿瘤来增加或恢复所述细胞或肿瘤对放射疗法的敏感性的方法。
2.一种通过用式(I)异黄酮类化合物或其药学上可接受盐接触癌细胞或肿瘤来增加或恢复细胞或肿瘤对化学疗法的敏感性的方法。
3.一种通过用式(I)异黄酮类化合物或其药学上可接受盐接触正常细胞或组织块来保护所述细胞或组织块不受放射疗法和/或化学疗法影响的方法。
4.一种联合疗法，其包括将有效治疗量的式(I)化合物或其药学上可接受盐给予正经历放射疗法或将要经历放射疗法的受试者。
5.权利要求4所述联合疗法，其中该给予发生在放射疗法之前。
6.权利要求5所述联合疗法，其中该给予发生在来自先前的放射线治疗的受试者出现放射线抗性之后。
7.一种联合疗法，其包括将有效治疗量的式(I)化合物或其药学上可接受盐及化疗剂给予受试者。
8.权利要求6所述联合疗法，其中该给予发生在化学疗法之前。
9.权利要求8所述联合疗法，其中该给予发生在来自先前的化学疗法治疗的受试者出现化学抗性之后。
10.权利要求4到9项任一项所述联合疗法，其中该拟治疗的病症为显示恶性特征的癌症、诸如恶变前损害(例如非典型、发育异常、上皮内瘤形成)等癌症的早期阶段和良性癌症。
11.式(I)化合物或其药学上可接受盐用于制造供增加或恢复癌细胞或肿瘤对放射疗法的敏感性用的药物的用途。
12.式(I)化合物或其药学上可接受盐用于制造供增加或恢复癌细胞或肿瘤对化学疗法的敏感性用的药物的用途。
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|---|---|---|---|---|
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| CA3058503A1 (en) | 2016-04-06 | 2017-10-12 | Noxopharm Limited | Isoflavonoid composition with improved pharmacokinetics |
| AU2017254774B2 (en) * | 2016-04-22 | 2021-10-21 | Noxopharm Limited | Chemotherapy improvements |
| KR102005237B1 (ko) * | 2017-02-28 | 2019-07-30 | 서울대학교산학협력단 | 에쿠올 유도체를 생산하는 재조합 대장균 및 이를 이용한 에쿠올 유도체 합성 방법 |
| PT3781561T (pt) | 2018-04-18 | 2024-06-18 | Constellation Pharmaceuticals Inc | Moduladores de enzimas modificadoras de metilo, composições e usos dos mesmos |
| US11919912B2 (en) | 2018-05-21 | 2024-03-05 | Constellation Pharmaceuticals, Inc. | Modulators of methyl modifying enzymes, compositions and uses thereof |
| AU2020313090A1 (en) * | 2019-07-17 | 2021-12-23 | Noxopharm Limited | Immuno-oncology therapy using isoflavone compounds |
| JP2023519990A (ja) | 2020-03-30 | 2023-05-15 | ノクソファーム リミティド | 感染に関連する炎症の治療のための方法 |
| CN113209076A (zh) * | 2021-04-25 | 2021-08-06 | 上海市第六人民医院 | 大豆苷元在制备减轻铂类药物毒性的药物中的应用 |
Family Cites Families (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0617304B2 (ja) * | 1982-09-09 | 1994-03-09 | 理化学研究所 | 制癌剤 |
| JPS60178815A (ja) * | 1984-02-24 | 1985-09-12 | Rikagaku Kenkyusho | 制癌剤 |
| US5005588A (en) * | 1989-10-13 | 1991-04-09 | David Rubin | Method for increasing tumor sensitivity to chemotherapy |
| JP2514500B2 (ja) * | 1991-09-14 | 1996-07-10 | 呉羽化学工業株式会社 | 多剤耐性抑制剤及び発現阻害剤 |
| AUPO203996A0 (en) * | 1996-08-30 | 1996-09-26 | Novogen Research Pty Ltd | Therapeutic uses |
| US6004558A (en) * | 1998-02-25 | 1999-12-21 | Novogen, Inc. | Methods for treating cancer with legume plant extracts |
| AUPQ266199A0 (en) * | 1999-09-06 | 1999-09-30 | Novogen Research Pty Ltd | Compositions and therapeutic methods involving isoflavones and analogues thereof |
| US6380405B1 (en) * | 1999-09-13 | 2002-04-30 | Nobex Corporation | Taxane prodrugs |
| JP2001114687A (ja) * | 1999-10-13 | 2001-04-24 | Mitsui Norin Co Ltd | 抗癌剤 |
| WO2001095937A2 (en) * | 2000-08-08 | 2001-12-20 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Phytoestrogenic isoflavone compositions |
| AU2001271296A1 (en) * | 2000-06-14 | 2001-12-24 | Alla Shapiro | Radioprotective agents |
| WO2003039537A1 (en) * | 2001-11-05 | 2003-05-15 | Alla Shapiro | Chemoprotectant compositions |
| IL163876A0 (en) * | 2002-04-09 | 2005-12-18 | Novogen Res Pty Ltd | Therapeutic methods and compositions involving isovlav-3-ene and isoflavan structures |
| AU2002951833A0 (en) * | 2002-10-02 | 2002-10-24 | Novogen Research Pty Ltd | Compositions and therapeutic methods invloving platinum complexes |
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- 2004-11-19 MX MXPA06005697A patent/MXPA06005697A/es active IP Right Grant
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- 2004-11-19 JP JP2006540083A patent/JP2007525485A/ja active Pending
- 2004-11-19 EP EP04797067A patent/EP1686981A4/en not_active Withdrawn
- 2004-11-19 US US10/547,077 patent/US20060167037A1/en not_active Abandoned
- 2004-11-19 CA CA002542351A patent/CA2542351A1/en not_active Abandoned
- 2004-11-19 NZ NZ546150A patent/NZ546150A/en unknown
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Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103183598A (zh) * | 2011-12-28 | 2013-07-03 | 沈阳药科大学 | 1,2-二取代芳基-2-丙烯-1-酮类化合物及其用途 |
| CN103183598B (zh) * | 2011-12-28 | 2015-12-09 | 沈阳药科大学 | 1,2-二取代芳基-2-丙烯-1-酮类化合物及其用途 |
| CN103349661A (zh) * | 2013-07-12 | 2013-10-16 | 浙江省中医院 | 一种刺氟合剂的制备方法及应用 |
| CN105980372A (zh) * | 2014-02-07 | 2016-09-28 | 诺沃根有限公司 | 官能化的苯并吡喃化合物及其用途 |
| CN105980372B (zh) * | 2014-02-07 | 2018-05-08 | 凯捷治疗有限公司 | 官能化的苯并吡喃化合物及其用途 |
| CN107667100A (zh) * | 2015-05-11 | 2018-02-06 | 肯塔基大学研究基金会 | 用于治疗癌症的抗肿瘤剂3‑芳基‑4h‑色烯‑4‑酮 |
| CN113185486A (zh) * | 2015-05-11 | 2021-07-30 | 肯塔基大学研究基金会 | 用于治疗癌症的抗肿瘤剂3-芳基-4h-色烯-4-酮 |
| CN113185486B (zh) * | 2015-05-11 | 2024-05-10 | 肯塔基大学研究基金会 | 用于治疗癌症的抗肿瘤剂3-芳基-4h-色烯-4-酮 |
| CN117599041A (zh) * | 2024-01-22 | 2024-02-27 | 中国人民解放军军事科学院军事医学研究院 | 去氢雌马酚及其衍生物作为新型辐射防护剂和细胞保护剂的医药用途 |
| CN117599041B (zh) * | 2024-01-22 | 2024-05-03 | 中国人民解放军军事科学院军事医学研究院 | 去氢雌马酚及其衍生物作为新型辐射防护剂和细胞保护剂的医药用途 |
Also Published As
| Publication number | Publication date |
|---|---|
| NZ546150A (en) | 2010-04-30 |
| WO2005049008A1 (en) | 2005-06-02 |
| JP2007525485A (ja) | 2007-09-06 |
| IL174741A0 (en) | 2008-04-13 |
| NO20062876L (no) | 2006-08-08 |
| CA2542351A1 (en) | 2005-06-02 |
| EP1686981A1 (en) | 2006-08-09 |
| EP1686981A4 (en) | 2011-02-23 |
| US20060167037A1 (en) | 2006-07-27 |
| MXPA06005697A (es) | 2006-08-17 |
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