CN102917701A - 利鲁唑在治疗或预防抗癌药的副作用中的用途 - Google Patents
利鲁唑在治疗或预防抗癌药的副作用中的用途 Download PDFInfo
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- CN102917701A CN102917701A CN2011800121161A CN201180012116A CN102917701A CN 102917701 A CN102917701 A CN 102917701A CN 2011800121161 A CN2011800121161 A CN 2011800121161A CN 201180012116 A CN201180012116 A CN 201180012116A CN 102917701 A CN102917701 A CN 102917701A
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- chemical compound
- anticarcinogen
- side effect
- riluzole
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Abstract
本发明涉及用于治疗或预防与给予具有神经毒性作用的抗癌药相关的副作用的利鲁唑,所述抗癌药例如铂盐、紫杉烷和长春花生物碱。
Description
本发明涉及用于治疗或预防与给予具有神经毒性作用的抗癌药相关的副作用的利鲁唑,所述抗癌药例如铂盐、紫杉烷和长春花生物碱。
利鲁唑
奥沙利铂
奥沙利铂是抗肿瘤的细胞毒性化合物,其由与1,2-二氨基己烷(DACH)和草酸基络合的铂原子组成。除了其他方面,其还用于治疗结直肠癌。其最近还被用于治疗晚期转移性结直肠癌(Baker,RevGastroenterol Disord.2003 3:31-8;Screnci等人,Br J Cancer 2000 82:966-72)并且还已经显示出在其他癌症中的活性:卵巢癌、乳腺癌、肺癌(Muggia,Semin Oncol.2004 31:17-24;Petit等人,Anticancer Drugs.2006 17:337-43)。神经毒性是这种分子的常见副作用并且这种作用通常以两种形式发生:急性和慢性。
急性神经毒性的特征为由具有或没有感觉异常的寒冷诱导的末梢感觉迟钝的快速发作(Gamelin等人,Semin Oncol.2002 29:21-33;Lehky等人,Muscle Nerve.2004 29:387-92),和肌肉病症:肌强直、痉挛、影响腿、手和颌并抑制移动的持久的肌颤(Grolleau等人,JNeurophysiol.2001 85:2293-7)。约85%至95%的治疗的患者发展这些症状,其在输液期间开始并且持续第一个24至48小时。
这种急性神经毒性的强度依赖于奥沙利铂的血浆浓度,并且因此预防浓度峰值是适当的(Grothey,Clin Colorectal Cancer.2005 5:S38-S46)。在约一周内发生症状的分解,但在下一次输液中症状再次出现。与其他铂源药物相比,由于这种急性神经毒性,奥沙利铂的神经毒性曲线是特别的。在具有这样的急性症状的患者中,研究已经表明很少有轴索变性,这表示奥沙利铂对感觉神经元和运动神经元的特定作用。在首次治疗后观察到的问题的强度并且特别是对寒冷的超敏性是神经毒性的标志。
慢性和累积性外周神经毒性被认为是奥沙利铂的剂量限制性副作用并且可以导致治疗中断。神经毒性的症状能够包括外周感觉神经病、感官缺损、感觉性共济失调和/或良好感觉运动协调缺陷(déficit decoordination fine sensori-motrice)。在780mg/m2至850mg/m2的累积剂量后,神经病在约10%至15%的患者中渐进地发展,相当于在85mg/m2的剂量下的约六个循环(Gamelin等人,Semin Oncol.2002 29:21-33)。外周感觉神经病以失去感觉的末梢感觉迟钝和感觉异常(手、足、脚趾)的形式出现。感觉神经病、感觉性共济失调和/或良好感觉运动协调缺陷导致书写、持物等方面出现问题。感觉神经病的发展与累积的奥沙利铂剂量有关(Wilson等人,J Clin Oncol.2002 20:1767-74)。
动物研究使得能够开发由单次灌注奥沙利铂诱导的神经毒性模型,其具有在人类中观察到的主要症状,特别是对寒冷的超敏性(Ling等人,Toxicology.2007 234:176-84;Ling等人,Pain.2007 128:225-34)。
更通常地,神经毒性是许多抗癌药共同的副作用。因此,紫杉烷和长春新碱诱导人的神经病(Quastoff和Hartung,J Neurol.2002 249:9-17;Stillman和Cata,Curr Pain Headache Rep.2006 18:321-324;Park等人,Curr Med Chem.2008 15:3081-3094)。
因此亟需能够治疗或预防由抗癌药,特别是诱导神经毒性的抗癌药导致的副作用的化合物。
发明描述
已经发现利鲁唑能够预防与给予奥沙利铂相关的副作用的出现。
更具体地,本发明人评价了利鲁唑降低寒冷超敏性现象的能力。在动物模型中,发现利鲁唑能够纠正由奥沙利铂诱导的寒冷超敏性。这种重要作用导致我们预期利鲁唑对所有感觉症状,特别是在给予人奥沙利铂期间观察到的神经毒性的有益作用。
因此,本发明的第一方面涉及用于治疗或预防由抗癌药诱导的副作用,特别是神经毒性的通式(I)化合物,以及所述化合物的药物可接受的盐:
其中:
—R1选自氢原子、C1-C6烷基和C1-C6卤代烷基;
—R2、R3相同或不同,选自氢原子或C1-C6烷基C1-C6。
本发明还涉及这样的通式(I)化合物在制备用于治疗或预防由抗癌药诱导的副作用,特别是神经毒性的药物中的用途。
例如,R1可以为卤代烷基,优选为全卤代烷基。优选地,R1为全氟代烷基,例如三氟甲基。
例如,R2和/或R3能够为氢原子。
在具体的实施方案中,通式(I)化合物的特征为其为式(II)化合物,或所述式(II)化合物的药物可接受的盐:
根据本发明,烷基表示具有直链或支链的1至6个碳原子、优选1至4个碳原子的饱和烃基。当它们为直链时,其能够特别引用甲基、乙基、丙基、丁基、戊基和己基。当它们为支链或被一个或多个烷基取代时,其能够特别引用异丙基、叔丁基、2-甲基丁基、2-甲基戊基和1-甲基戊基。
本发明的卤代烷基包括上面定义的烷基,其中一个或多个氢原子被卤素原子(氟、氯、溴、碘)取代,特别是被氯原子或氟原子取代。卤代烷基能够为全卤代烷基,即其中全部氢原子都被卤素原子取代的卤代烷基,特别是通式CnF2n+1的全氟代烷基,其中n表示1至6的全部数字。作为全氟代烷基的实例,能够特别引用三氟甲基。
能够在任意阶段治疗副作用,特别是神经毒性。“治疗”是指治愈性治疗(意图缓解、减缓或停止副作用)。“预防”是指预防性治疗(意图降低副作用出现的风险)。
术语“药物可接受的盐”是指本发明的化合物的相对无毒的无机和有机酸加成盐。能够在化合物的最终分离和纯化期间原位制备这些盐。特别地,能够通过分别使纯化形式的纯化合物与有机或无机酸反应并分离由此形成的盐来制备酸加成盐。酸加成盐的实例为氢溴酸盐、氢氯酸盐、硫酸盐、硫酸氢盐、磷酸盐、硝酸盐、醋酸盐、草酸盐、戊酸盐、油酸盐、棕榈酸盐、硬脂酸盐、月桂酸盐、硼酸盐、苯甲酸盐、乳酸盐、磷酸盐、甲苯磺酸盐、柠檬酸盐、马来酸盐、延胡索酸盐、琥珀酸盐、酒石酸盐、萘酸盐(naphthylate)、甲磺酸盐、葡庚糖酸盐(glucoheptanate)、乳糖酸盐(lactobionate)、氨基磺酸盐、丙二酸盐、水杨酸盐、丙酸盐、亚甲基双-b-羟基萘甲酸盐、龙胆酸、羟乙基磺酸盐、二-对甲苯酰基酒石酸盐、甲烷磺酸盐、乙烷磺酸盐、苯磺酸盐、对甲苯磺酸盐、环己基氨基磺酸盐和奎尼酸月桂醇磺酸盐(quinateslaurylsulfonate)等(参见例如,S.M.Berge等人“PharmaceuticalSalts(药物盐)”J.Pharm.Sci,66:p.1-19(1977),其以引用形式并入本文)。
在优选的实施方案中,所述通式(I)化合物是利鲁唑(其以上述式(II)化合物表示)。“利鲁唑”是指2-氨基-6-三氟-甲氧基-苯并噻唑及其药物可接受的盐。能够根据例如专利EP 0 050 551中描述的方法制备利鲁唑。利鲁唑在治疗神经变性病理中的用途描述在例如专利US6,872,739和专利申请EP 0 558 861中。
在本发明的优选实施方案中,抗癌药是铂盐。铂盐通常用于治疗癌症。然而,铂盐诱导许多副作用,包括神经毒性、骨髓抑制、肾毒性、耳毒性、恶心和呕吐。
在本发明的背景下,优选地,副作用相当于神经毒性,其具体地表现为对寒冷和/或肌肉干扰(troubles musculaires)的超敏性。然而,副作用可以相当于其他副作用,例如骨髓抑制、肾毒性、耳毒性、恶心或呕吐。本领域技术人员可以参考Wolf等人,European Journal ofCancer 2008,44:1507-1515。
在一实施方案中,副作用为对寒冷的超敏性。
用于治疗癌症的铂盐具体地包括奥沙利铂(以商品名销售)、顺铂(CDDP,以商品名销售)和卡铂(CDCP,以商品名销售)。因此,奥沙利铂、顺铂和卡铂是本发明的优选铂盐。在特别优选的方式下,铂盐是奥沙利铂。
奥沙利铂具体地用于治疗结肠癌、结直肠癌、卵巢癌和胃癌。其与5-氟-尿嘧啶和亚叶酸的结合被称为FOLFOX方案。相对于其他铂盐,这种药物具有低血液毒性并且没有肾毒性。然而,其具有高神经毒性。其对特定感觉神经病负责,被寒冷增强,并且其严重性随剂量的累积而增加。
顺铂是许多化疗方案的基础,并且特别用于治疗睾丸癌、前列腺癌、子宫颈癌、卵巢癌、子宫内膜癌、肺癌、膀胱癌、呼吸消化道癌、肉瘤和成神经细胞瘤。其主要毒性是肾(肾小管肾毒性)和神经病学(神经毒性)的。
在1975年发现,卡铂具有替代顺铂的两个氯原子的两个羧酸酯基团。其用于治疗睾丸癌、卵巢癌、呼吸消化道癌和肺癌。与顺铂相比,其具有较低的肾毒性和神经毒性。然而,存在较高的出血风险。
本发明还涉及通式(I)化合物,特别是利鲁唑,其用于治疗或预防由除了铂盐以外的抗癌药诱导的副作用,特别是神经毒性。确实,大部分抗癌药具有副作用,并且特别是神经毒性。由于本发明人已经证明了通式(I)化合物适于治疗和/或预防奥沙利铂诱导的神经毒性,可以推论通式(I)化合物也适于治疗和/或预防由其他抗癌药诱导的神经毒性。
在一实施方案中,副作用为对寒冷的超敏性。
“抗癌药”是指用于治疗癌症的任何活性成分。抗癌药具体地包括烷化剂、抗代谢药、插入剂、有丝分裂纺锤体毒素、抗肿瘤抗生素和DNA三级结构的修饰物,例如拓扑异构酶抑制剂。
优选地,本发明的抗癌药是诱导作为副作用的神经毒性的抗癌药。有丝分裂纺锤体毒素尤其如此,例如长春花生物碱和紫杉烷。
“长春花生物碱(vinca-)”或“长春花生物碱(de lapervenche)”在这里是指能够从长春花(例如,长春花(Vinca rosea)和长春花(Catharanthus roseus))提取的生物碱,或源自这些物质的生物碱。长春花生物碱包括长春新碱、长春碱、长春地辛和长春瑞滨。
这还适用于上述铂盐。
在本发明的背景下,通式(I)化合物,更具体地为利鲁唑,优选与预防某抗癌药副作用的抗癌药组合使用。能够同时或相继给予通式(I)化合物和抗癌药。
抗癌药可以存在于与通式(I)化合物相同的药物组合物中。因此,本发明涉及药物组合物,其包含药物可接受的载体和作为活性成分的通式(I)化合物,更具体地为利鲁唑,以及抗癌药,更具体地为铂盐。根据一实施方案,药物组合物包括利鲁唑和铂盐。根据另一实施方案,药物组合物包括利鲁唑和奥沙利铂。
或者,抗癌药可以存在于与包含通式(I)化合物的药物组合物分开的药物组合物中。因此,本发明涉及组合(试剂盒),其包含(i)含药物可接受的介质和通式(I)化合物的第一药物组合物;以及(ii)含药物可接受的载体和抗癌药的第二药物组合物。本发明的试剂盒可以任选地包括关于用于治疗和预防癌症的第一和第二药物组合物的给药方式的说明。可以同时或相继使用(给予)这样的组合(试剂盒)的第一和第二药物组合物。根据一实施方案,第一药物组合物包含利鲁唑并且第二药物组合物包含铂盐。根据另一实施方案,第一药物组合物包含利鲁唑并且第二药物组合物包含奥沙利铂。
“药物可接受的载体”是指在人或动物中不产生诸如过敏反应的副反应的任意溶剂、分散介质、吸收延缓剂等。药物可接受的载体是本领域技术人员熟知的,并且包括描述在“Remington's PharmaceuticalSciences(雷明顿制药学)”(Mack Publishing Company,Easton,USA,1985)中的那些。特别根据给药途径选择药物可接受的载体,所述给药途径可以为例如口服、舌下、鼻、颊、直肠、肠胃外(即静脉内、皮下、皮内或肌内)。给药途径优选为口服或肠胃外。剂量依赖于诸如考虑的活性成分、给药途径、治疗的适应症和患者的年龄、体重和状态的因素。
有利地,本发明的药物组合物和本发明的组合(试剂盒)用于治疗或预防癌症。癌症可以选自睾丸癌、甲状腺癌、卵巢癌、子宫颈癌和/或子宫内膜癌、乳腺癌、食管癌、膀胱癌、耳鼻喉癌(ORL)、肺癌、胃癌、前列腺癌、肉瘤、成神经细胞瘤、结直肠癌、直肠癌和结肠癌。
在优选的实施方案中,本发明的药物组合物和本发明的组合(试剂盒)包含作为铂盐的奥沙利铂,作为通式(I)化合物的利鲁唑,并且用于治疗或预防结直肠癌。在本发明的这样的药物组合物和组合(试剂盒)中,利鲁唑使得能够治疗或预防副作用,特别是由抗肿瘤药奥沙利铂诱导的神经毒性。
本发明还涉及治疗或预防由抗癌药诱导的副作用的方法,所述方法包括给予个体有效量的通式(I)化合物,更具体地为利鲁唑。该个体能够为已经被抗癌药治疗的个体,正在被抗癌药治疗的个体,或者将要被抗癌药治疗的个体。上面描述的不同特征适用于该方法。因此,抗癌药能够为铂盐,特别是奥沙利铂。因此,副作用同样能够为神经毒性,例如对寒冷的超敏性。个体优选为哺乳动物,并且更具体地是人。本领域技术人员能够容易确定有效治疗剂量。
本发明还涉及治疗或预防癌症的方法,包括给予有需要的个体治疗有效量的通式(I)化合物,更具体地为利鲁唑,以及抗癌剂,更具体地为铂盐,特别是奥沙利铂。根据本发明的特征,该方法为治疗或预防癌症的方法,以及治疗或预防与所用抗癌剂相关的副作用的方法。应当理解,通过与抗癌药组合,个体可以为已经被抗癌药治疗的个体,正在被抗癌药治疗的个体,或者将要被抗癌药治疗的个体。个体优选为哺乳动物,并且更具体地为人类。本领域技术人员可以容易地确定有效治疗剂量。上述不同特征适用于该方法。因此,抗癌药能够为铂盐,特别是奥沙利铂。因此,副作用同样能够为神经毒性,例如对寒冷的超敏性。
最后,本发明的另一方面涉及用于鉴定适于治疗或预防由抗癌药诱导的副作用的化合物的筛选方法,其中所述方法包括下列步骤:
a)给予非人动物模型抗癌药;
b)给予非人动物模型抗癌药和合成利鲁唑类似物;
c)检测由步骤(a)和(b)中的铂盐诱导的副作用;
d)比较有和无所述合成利鲁唑类似物的情况下检测的副作用;以及,任选地
e)处死已经用于步骤(a)和(b)的动物
其中与无所述合成利鲁唑类似物的情况下检测的副作用相比,在有所述合成利鲁唑类似物的情况下,检测到的副作用显著较低,表明所述合成利鲁唑类似物适于治疗或预防由抗癌药诱导的副作用。
“合成利鲁唑类似物”是指源自利鲁唑的化学化合物。利鲁唑衍生物特别是指包括或多或少被取代的苯并噻唑骨架的化合物。这样的类似物包括但不限于通式(I)化合物。
因此,在EP 0 282 971中限定的化合物在这里被认为是合成类似物,因此合成类似物为满足下列通式(III)的化合物:
其中:
R1和R2能够彼此相同或不同,表示氢原子、包括1至6个碳原子的直链或支链烷基、C1-C6-烷基-C6-C10-芳基、C1-C6-烯基或苯基、CF3或羟基、C1-C6-烷氧基、C1-C6-硫代烷基或C1-C6-烷基磺酰基、在6位的CF3O、卤素原子、硝基或羧基、C1-C6-烷氧基-羰基、NR5R6CO、NR5R6、R5CONR5、CN或CR5R6SO2基团;
其中:
R5和R6可以彼此相同或不同,表示氢原子、C1-C6-烷基或C6-C10-芳基;
R1和R2可以一起形成碳环或亚甲二氧基环;
R3表示氢原子;
R4表示氢原子、C1-C6-烷基、被杂环基取代的C1-C6-烷基或取代的杂环基、其中环烷基包含高至6个碳原子的甲基环烷基、苄基、苯乙基、苯基或取代的苯基、C1-C6-烷基、炔丙基;
条件是当R4不是氢原子时,R1、R2和R3表示氢原子。
化合物III是衍生物,其选自:
2-氨基-6-甲基苯并噻唑、
2-氨基-6-三氟甲氧基苯并噻唑、
2-氨基-6-三氟甲基苯并噻唑、
2-氨基苯并噻唑、
2-氨基-4-甲基苯并噻唑、
2-氨基-6-乙氧基苯并噻唑、
2-氨基-6-硝基苯并噻唑、
2-氨基-5-甲氧基苯并噻唑、
2-氨基-6-甲基磺酰基苯并噻唑、
2-氨基-4,6-二甲基苯并噻唑、
乙基氨基苯并噻唑、
2-苄基氨基苯并噻唑、
2-氨基-4-三氟甲基苯并噻唑、
2-氨基-5-三氟甲基苯并噻唑、
2-氨基-6-溴苯并噻唑、
2-氨基-6-氯苯并噻唑、
2-氨基-4-氯苯并噻唑、
2-氨基-6-氟苯并噻唑、
2-氨基-5-甲氧基苯并噻唑、
2-氨基-4,6-二氟苯并噻唑、
2-氨基-6-甲基硫代苯并噻唑、
2-氨基-萘并[1,2-d]噻唑,以及
2-[[2-(1-甲基-2-吡咯烷基)乙基]氨基]-苯并噻唑。
在本发明的筛选方法的背景下检测的副作用能够相当于例如由铂盐诱导的神经毒性、骨髓抑制、肾毒性、耳毒性、恶性或呕吐。在本发明的优选实施方案中,副作用为神经毒性。在本发明的优选实施方案中,副作用为对寒冷的超敏性。
例如,可以如实施例2所述,通过检测通式(I)化合物在作为动物模型的大鼠中对铂盐诱导的对寒冷的超敏性的作用来检测由铂盐诱导的神经毒性。由紫杉烷或长春新碱诱导的神经毒性的动物模型是本领域已知的,并且也能够使用(Authier等人,Brain Res.2000 291:73-76;Authier等人,Neurotherapeutics.2009 6:620-629;Authier等人,Neurotoxicology.2003 24:797-805)。
下列实施例和附图显示本发明而不限制其范围。
附图简述
图1和2显示利鲁唑能够纠正由奥沙利铂注射诱导的对寒冷的超敏性。
实施例
实施例1:方案
1.1.动物
在22°C、温度控制环境中,在12h/12h日/夜的循环下,将重量为175至200克的雄性Sprague-Dawley大鼠(Charles River Lab,法国)放置在具有自由采食的食物和水的笼子内。在遮蔽条件下在安静的房间中由相同试验员进行试验,同时仔细遵守动物试验的规定。
1.2.分子
使用了下列分子:利鲁唑(Sigma Chemical Co.,St Louis,MO)和奥沙利铂(Debiopharm,洛桑,瑞士)。将利鲁唑制备在NaCl(0.9%)中。将奥沙利铂稀释在葡萄糖溶液(5%)中。
1.3.用奥沙利铂在大鼠中化学诱导神经毒性的模型
每只大鼠腹膜内(IP)接受一定剂量的奥沙利铂或葡萄糖5%对照注射。在注射奥沙利铂或载体之前和之后72小时进行行为测试,将大鼠的尾部浸入10°C的水中。然后,皮下给予剂量为2.5mg/kg、5mg/kg或7.5mg/kg的利鲁唑或其载体,并且根据下列动力学再次检测动物:在注射利鲁唑或载体之后15、30、45、60、90和120分钟。
1.4.将大鼠尾部浸入10°C水中的试验
这种低温浸入试验使得能够检测动物对寒冷的超敏性。将大鼠尾部的底部三分之一浸入10°C温控浴直至其移走或直至30秒的“结束”设定(Necker and Hellon.1978 Pain.4:231-242)。
1.5.统计学分析
使用软件程序Sigma STAT,Windows 3.0版本(STAT32 SoftwareInc.,圣地亚哥,CA)分析了试验数据。使用双因素方差分析和多重比较检定分析了对基于温度的刺激的反应时间的动力学以研究随时间的变化。用学生t检验比较了用利鲁唑治疗的组和对照组的分数。显著阈值为P<0.05。
实施例2.利鲁唑对患有奥沙利铂诱导的神经毒性的大鼠的寒冷敏感性的影响
在注射奥沙利铂之前和72小时后,使用将尾部浸入10°C水中的基于温度的实验检测了腹膜内注射的三种剂量的利鲁唑(2.5mg/kg、5mg/kg和7.5mg/kg)的作用。奥沙利铂减少了寒冷敏感性阈值(10°C)(图1)。在大约12秒后未处理的大鼠移走了其尾部,而用奥沙利铂处理的大鼠在7秒后移走了其尾部,并且这种作用在整个实验中持续。
图1清楚地表明,在注射剂量为5mg/kg的利鲁唑后用奥沙利铂处理的大鼠的反应时间非常高。用利鲁唑处理的奥沙利铂动物对寒冷的反应时间甚至高于注射奥沙利铂之前观察的反应时间(较少的敏感性)。统计数据分析显示出在5mg/kg(p<0.05)和7.5mg/kg(p<0.001)的剂量下的显著区别(图1、图2)。
实施例3:结论
评价了利鲁唑对降低寒冷超敏性现象的能力。在大鼠动物模型中,利鲁唑纠正了奥沙利铂诱导的寒冷超敏性。这种重要的作用表明,利鲁唑可能对在与使用奥沙利铂治疗人体病理相关的神经毒性中观察到的所有感觉症状具有有益作用。
Claims (16)
2.如权利要求1所述的化合物,其中所述由抗癌药诱导的副作用是神经毒性。
3.如权利要求2所述的化合物,其中所述由抗癌药诱导的副作用是对寒冷的超敏性。
4.如权利要求1、2或3所述的化合物,其中所述抗癌药为铂盐、紫杉烷或长春花生物碱。
5.如权利要求4所述的化合物,其中所述抗癌药为奥沙利铂、顺铂或卡铂。
6.如权利要求5所述的化合物,其中所述抗癌药为奥沙利铂。
7.如权利要求4所述的化合物,其中所述抗癌药为长春新碱、长春地辛或长春瑞滨。
8.如权利要求4所述的化合物,其中所述抗癌药为紫杉醇或多烯紫杉醇。
9.如权利要求1-8中任一权利要求所述的化合物,其中所述通式(I)化合物为利鲁唑。
10.药物组合物,其包含药物可接受的载体、奥沙利铂和权利要求1所述的通式(I)化合物。
11.如权利要求10所述的组合物,其中所述通式(I)化合物包括利鲁唑。
12.试剂盒,其包含:
-药物组合物,其包含药物可接受的载体和权利要求1所述的通式(I)化合物;以及
-第二药物组合物,其包含药物可接受的载体和奥沙利铂,
所述试剂盒用于在癌症的治疗或预防中同时或相继使用所述第一和第二药物组合物。
13.如权利要求12所述的试剂盒,其中所述通式(I)化合物包括利鲁唑。
14.治疗或预防由抗癌药诱导的副作用的方法,其包括给予个体治疗有效量的权利要求1所述的通式(I)化合物,其中所述个体为已经被抗癌药治疗的个体,正在被抗癌药治疗的个体,或者将要被抗癌药治疗的个体。
15.治疗或预防癌症的方法,所述方法包括给予治疗有效量的权利要求1所述的通式(I)化合物以及抗癌药。
16.鉴定适于治疗或预防由铂盐诱导的副作用的化合物的筛选方法,其中所述方法包括下列步骤:
a)给予非人动物模型抗癌药;
b)给予非人动物模型抗癌药和包括苯并噻唑骨架的合成利鲁唑类似物;
c)检测由步骤(a)和(b)中动物模型中的抗癌药诱导的副作用;
d)比较在步骤(a)的动物模型中检测的副作用和在步骤(b)的动物模型中检测的副作用;以及,
e)处死已经用于步骤(a)和(b)的动物
其中与无所述合成利鲁唑类似物的情况下检测的副作用相比,在有所述合成利鲁唑类似物的情况下,检测到的副作用显著较低,表明所述合成利鲁唑类似物适于治疗或预防由所述抗癌药诱导的副作用。
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