CN1147317C - 含酪氨酸激酶抑制剂和化学阉割剂的组合物及其用于制药的用途 - Google Patents
含酪氨酸激酶抑制剂和化学阉割剂的组合物及其用于制药的用途Info
- Publication number
- CN1147317C CN1147317C CNB988081741A CN98808174A CN1147317C CN 1147317 C CN1147317 C CN 1147317C CN B988081741 A CNB988081741 A CN B988081741A CN 98808174 A CN98808174 A CN 98808174A CN 1147317 C CN1147317 C CN 1147317C
- Authority
- CN
- China
- Prior art keywords
- compound
- tyrosine kinase
- administration
- tumor
- kinase inhibitor
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
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Abstract
本发明公开了一种通过将酪氨酸激酶抑制剂如吲哚并咔唑类化合物和化学阉割剂同时给药来治疗前列腺癌的方法。本发明还公开了一种含有酪氨酸激酶抑制剂和化学阉割剂的组合物。
Description
技术领域
本发明涉及肿瘤学、内分泌学、男科学和药理学,具体而言,本发明涉及酪氨酸激酶抑制剂和化学阉割剂的联合使用以及含有酪氨酸激酶抑制剂和化学阉割剂的组合物。
背景技术
前列腺癌是男性中最常被确诊的癌症,在美国每年有近41000人因此而死亡(Parker,S.L.等人,(1996),临床癌症杂志(CA Cancer J.Clin.),65:5-27)。在早期,常常通过手术或放疗来控制局限在脏器内的前列腺癌,直至患者死于与此无关的原因。
癌症如乳腺癌、结肠癌和腺癌的特征在于细胞快速分裂。通常,用可以抑制细胞快速分裂的化疗药物进行治疗从而修正这些癌变。相反,前列腺癌的特征不在于细胞快速分裂。所以,常规的化疗药物一般对前列腺癌仅具有很低的功效。
前列腺癌常常对激素处理敏感。目前被普遍接受的前列腺癌治疗方法包括手术阉割、化学阉割或手术阉割与化学阉割联用。在切除生产初级睾酮的器官-睾丸后,循环雄激素的水平降低至正常水平的5%以下。雄激素水平的这种降低抑制了前列腺瘤生长。虽然手术阉割的抗肿瘤作用是直接的,但这种抗肿瘤作用却是暂时性的。手术阉割常会导致非雄激素依赖型前列腺瘤细胞的克隆选择。这使前列腺瘤以增生形式在无睾酮或DHT刺激的条件下再生(Isaacs等人(1981),癌症研究(Cancer Res.)41:5070-5075;Crawford等人(1989)新英格兰医学杂志(N.Eng.J.Med.)321:419-424)。
化学阉割(也称作药物阉割)经常取代初期治疗时所用的手术阉割。化学阉割的实施可以通过施用:雌激素类药物,如己烯雌酚(DES);LHRH(促黄体素释放激素)类似物,如醋酸亮丙瑞林(LUPRON)或醋酸戈舍瑞林(ZOLADEX);甾类抗雄激素类药物,例如醋酸环丙孕酮(CPA);非甾类抗雄激素类药物,例如氟他胺、尼鲁米特或卡索他(CASODEX);或联用上述药物来实现。
受体结合性酪氨酸激素是跨膜蛋白质,它含有胞外配体结合结构域、跨膜序列和胞质酪氨酸激酶结构域。酪氨酸激酶的功能是传递细胞信号。细胞的增生、分化、迁移、代谢和编程性死亡都是酪氨酸激酶介导的细胞反应的例子。
酪氨酸激酶涉及前列腺上皮细胞变形和肿瘤恶化。参与所述变形和恶化的酪氨酸激酶包括成纤维细胞生长因子(FGF)受体、上皮生长因子(EGF)受体和血小板衍生的生长因子(PDGF)受体。还有神经生长因子(NGF)受体、脑衍生神经营养因子(BDNF)受体、神经营养蛋白-3(NT-3)受体和神经营养蛋白-4(NT-4)受体。
美国专利5516771、5654427和5650407探讨了吲哚并咔唑型酪氨酸激酶抑制剂和前列腺癌。美国专利5475110、5591855和5594009以及WO 96/11933探讨了稠合的吡咯并咔唑型酪氨酸激酶抑制剂和前列腺癌。
发明内容
迄今已意外的发现,酪氨酸激酶抑制剂是通过非激素依赖性机制而发挥其对哺乳动物前列腺癌的抗肿瘤作用的。还进一步发现,酪氨酸激酶抑制剂疗法和抗激素疗法的联用具有协同作用。
基于上述发现,本发明提供一种治疗哺乳动物如人体中前列腺癌的方法,该方法包括给哺乳动物施用治疗有效量的酪氨酸激酶抑制剂,并且同时给哺乳动物施用化学阉割剂。酪氨酸激酶抑制剂和化学阉割剂可以协同地抑制前列腺瘤的发展。优选的酪氨酸激酶抑制剂包括吲哚并咔唑类化合物。优选的吲哚并咔唑类化合物包括下列化合物:
(化合物II-4),和
化合物II-4-LAE是化合物II-4的赖氨酰基-β-丙氨酸酯,或该酯的可药用盐,如二盐酸盐。化合物II-12公开在美国专利4923986中(“化合物20”)。化合物II-4公开在美国专利5461146中。化合物II-4-LAE公开在美国专利5650407(实施例14)中。酪氨酸激酶抑制剂也可以是稠合的吡咯并咔唑类化合物。酪氨酸激酶抑制剂可以通过任何适当的途径例如口服或非肠道途径给药。
适用于本发明的化学阉割剂包括:雌激素类药物;LHRH激动剂,如醋酸亮丙瑞林(LUPRON)或醋酸戈舍瑞林(ZOLADEX);LHRH拮抗剂类药物,例如ANTIDE(Ares-Serono)和GANIRELIX(AkzoNobel);抗雄激素类药物,例如氟他胺和尼鲁米特。
酪氨酸激酶抑制剂和化学阉割剂可以以独立剂型给药。另外,也可将它们配制在一起并以单一组合物给药。
本发明还提供一种作为酪氨酸激酶抑制剂的吲哚并咔唑类化合物与化学阉割剂用于制备抑制哺乳动物中前列腺瘤恶化的药物的用途,所述化学阉割剂选自雌激素、LHRH激动剂、LHRH拮抗剂和抗雄激素物质。
优选所述哺乳动物是人。
优选所述吲哚并咔唑类化合物具有如下结构:
(化合物II-12)
所述吲哚并咔唑类化合物具有如下结构:
所述吲哚并咔唑类化合物具有如下结构:
(化合物II-4-LAE)
优选所述的药物是经口服制剂。
优选所述的药物是经非肠道给药的制剂。
优选所述LHRH激动剂是醋酸亮丙瑞林。
优选所述抗雄激素物质是氟他胺。
优选所述化学阉割剂是LHRH激动剂和抗雄激素的混合物。
优选所述LHRH激动剂是醋酸亮丙瑞林,所述的抗雄激素是氟他胺。
本发明还提供一种含有酪氨酸激酶抑制剂和化学阉割剂的组合物。组合物中的酪氨酸激酶抑制剂适宜是酪氨酸激酶A(trkA)抑制剂、酪氨酸激酶B(trkB)抑制剂或酪氨酸激酶C(trkC)抑制剂。组合物中优选的酪氨酸激酶抑制剂是吲哚并咔唑。优选的吲哚并咔唑是:
(化合物II-4-LAE)
另外,组合物中的酪氨酸激酶抑制剂也可以是稠合的吡咯并咔唑类化合物。可以将该组合物配制为口服给药或非肠道给药的制剂。化学阉割剂可以是雌激素、LHRH类似物或抗雄激素,或是这些化合物中两种或多种的混合物。组合物中优选采用的LHRH类似物是醋酸亮丙瑞林。组合物中优选采用的抗雄激素是氟他胺。组合物中的化学阉割剂可以是LHRH类似物和抗雄激素类药物的混合物,例如醋酸亮丙瑞林和氟他胺的混合物。
在此所用的“化学阉割剂”是指:(1)抑制血清雄激素生成的化合物,(2)阻断血清雄激素与雄激素受体结合的化合物,或(3)抑制睾酮转化为DHT的化合物,或两种或多种此类化合物的混合物。
除非另有规定,在此所用的所有技术和科学术语具有本发明所属技术领域普通技术人员所熟知的含意。在有矛盾的情况中,将以本申请(包括定义)为准。在此提及的全部文献、专利申请、专利和其它参考文献均引入本文作为参考。
尽管类似于或等同于在此所述的所有方法和材料可以用于本发明的实践或实验中,但优选的方法和材料将如下所述。下列材料、方法和实施例仅作说明,它们对本发明不构成限定。本发明的其它特征和优越性将由于说明书的详细说明和权利要求书而显而易见。
附图说明
图1是大鼠活体内前列腺瘤模型体系中的相对肿瘤体积(倍数变化)随时间(天数)变化的曲线图。圆圈代表赋形剂对照组;向上的三角形代表单独用化合物II-4治疗的对照组;方形代表阉割对照组;向下的三角形代表化合物II-4/阉割联合治疗组。化合物II-4的剂量是10mg/kg,皮下注射。X轴上含有+号的矩形代表给药化合物II-4的时间。
图2是阉割大鼠中的相对肿瘤体积(Dunning H肿瘤中的倍数变化)随时间(天)变化的曲线图。圆圈代表赋形剂对照;方形代表化合物II-4。化合物II-4的给药时间由X轴上的矩形表示。
图3是已用化合物II-4预处理过的大鼠中的相对肿瘤体积(倍数变化)随时间(天)变化的曲线图。圆圈代表化合物II-4;方形代表化合物II-4/阉割治疗。化合物II-4的给药时间由X轴上的矩形表示。
图4是大鼠活体内前列腺瘤模型体系中的相对肿瘤体积(倍数变化)随时间(天数)变化的曲线图。圆圈代表赋形剂对照组;向上的三角形代表单独使用化合物II-12治疗的对照组;方形代表接受醋酸亮丙瑞林(LUPRON)化学阉割的对照组;向下的三角形代表化合物II-12/醋酸亮丙瑞林的联合治疗。化合物II-4的剂量是10mg/kg,每天2次,口服。X轴上的矩形代表化合物II-12的给药时间。
具体实施方式
酪氨酸激酶抑制剂和化学阉割剂的联合给药可以采用将各自独立的制剂,即酪氨酸激酶制剂和化学阉割剂制剂并行给药。如果给药时间能够使酪氨酸激酶抑制剂和化学阉割剂的药理学活性在接受治疗的哺乳动物中同时出现,那么这种给药时间就是独立制剂“并行”给药。
在本发明的某些实施方案中,酪氨酸激酶抑制剂和化学阉割剂的联合给药是通过将它们配制在单一组合物中来实现的。
酪氨酸激酶抑制剂的优选剂量是1μg/kg-1g/kg体重/天。更优选的酪氨酸激酶抑制剂的剂量是0.01mg/kg-100mg/kg体重/天。酪氨酸激酶抑制剂的最佳剂量将取决于多种因素,例如前列腺癌的类型和恶化程度,患者的全身健康状态,酪氨酸激酶抑制剂的效能和给药途径。对酪氨酸激酶抑制剂剂量进行最佳选择是所属领域普通技术人员的常识。
适用于本发明的酪氨酸激酶抑制剂有多种,它们是本领域中已知的。本发明优选的酪氨酸激酶抑制剂是酪氨酸激酶A抑制剂、酪氨酸激酶B抑制剂或酪氨酸激酶C抑制剂。适当的吲哚并咔唑类酪氨酸激酶抑制剂可以根据文献所公开的信息获得,所述文献例如是Dionne等人的美国专利5516771、Dionne等人的美国专利5654427、Lewis等人的美国专利5461146以及Mallamo等人的美国专利5650407。
在本发明的某些实施方案中,按照下列方法配制化合物II-4-LAE并对病人给药。将化合物II-4-LAE(二盐酸盐)和适当量的等渗甘露糖醇溶解在蒸馏水中,将pH调至约3.5。将该溶液冷冻干燥成粉末。为了储存且便于使用,制成含有27.5mg化合物II-4-LAE和55mg甘露糖醇的等份冻干粉。在使用时,将等份冻干粉重新溶解在注射用灭菌水(USP)中,得到1.1ml含有50mg/ml甘露醇和25mg/ml化合物II-4-LAE(二盐酸盐)的溶液。随后用适当体积的5%葡萄糖注射液(USP)稀释该溶液,以便使预定剂量的化合物II-4-LAE通过静脉内输注在约1小时内给药。此过程中化合物II-4-LAE的剂量一般以1mg/m2/天开始并且逐渐增加至例如64mg/m2/天或501mg/m2/天,同时监测患者的病情状况。
已知有多种化学阉割剂。适用于本发明的已知化学阉割剂有时被分成如下几类:雌激素,促黄体素释放激素(LHRH)激动剂、LHRH拮抗剂和抗雄激素。抗雄激素还可以进一步分为甾类和非甾类化合物。
雌激素如己烯雌酚(DES)能够使性激素-结合球蛋白的含量和血浆催乳激素的含量升高。由此通过负反馈反应而减少LH分泌和睾丸睾酮合成。DES的剂量通常为1mg/天-5mg/天。应当避免使用较高剂量的DES,因为有可能发生危及心血管的并发症。
适用于本发明的LHRH激动剂是醋酸亮丙瑞林,市售产品为LUPRON(Takeda Abbott Pharmaceuticals,Inc.)。醋酸亮丙瑞林的化学名称为5-氧代-L-脯氨酰基-L-组氨酰基-L-色氨酰基-L-丝氨酰基-L-酪氨酰基-D-亮氨酰基-L-亮氨酰基-L-精氨酰基-N-乙基-脯氨酰胺醋酸(盐)。作为LHRH激动剂,当连续且以治疗剂量给药时,醋酸亮丙瑞林是一种有效的抑制促性腺素分泌的抑制剂。这种作用会因中止给药醋酸亮丙瑞林而得以逆转。
醋酸亮丙瑞林,例如LUPRON DEPOT一定是通过负反馈机制起作用的。在人体中,每天皮下给药单剂量醋酸亮丙瑞林可引起血清促黄体素(LH)水平开始增高。在男性中,在开始给药醋酸亮丙瑞林后的2-4周内,血清睾酮下降至阉割水平。
当在本发明中使用时,醋酸亮丙瑞林是经皮下、肌肉内或静脉内给药。例如,可以每天皮下注射醋酸亮丙瑞林1mg。在本发明的某些实施方案中,醋酸亮丙瑞林是以延效型制剂给药的。延效型制剂一般在较长的时间如1-4个月内提供缓释的药物。延效型制剂的实例包括含有醋酸亮丙瑞林、纯化明胶、DL-乳酸和乙醇酸共聚物以及D-甘露糖醇的微球混悬剂。所述微球可以悬浮在含有羧甲基纤维素钠、D-甘露糖醇和水的载体中。市售的这种延效型制剂称作LUPRONDEPOTTM(Takeda Abbott Pharmaceuticals)并且适合肌肉内注射。
另一种适用于本发明的LHRH激动剂是醋酸戈舍瑞林,市售产品称作ZOLADEX(Zeneca)。醋酸戈舍瑞林的化学结构是焦-Glu-His-Trp-Ser-Tyr-D-Ser-(But)-Leu-Arg-Pro-Azgly-NH2醋酸盐。ZOLADEX是一种可在28天内连续释放的皮下注射用制剂。
适用于本发明的LHRH拮抗剂的例子是ANTIDE(Ares-Serono),其化学名称是D-丙氨酰胺N-乙酰基-3-(2-萘基)-D-丙氨酰基-4-氯-D-苯基丙氨酰基-3-(3-吡啶基)-D-丙氨酰基-L-丝氨酰基-N6-(3-吡啶基羰基)-L-赖氨酰基-N6-(3-吡啶基羰基)-D-赖氨酰基-L-亮氨酰基-N6-(1-甲基乙基)-L-赖氨酰基-L-脯氨酰。另一个适当的LHRH拮抗剂的例子是GANIRELIX(Roche/Akzo Nobel),其化学名称为N-Ac-D-Nal,D-pCl-Phe,D-Pal,D-hArg(Et)2,hArg(Et)2,D-Ala。
甾类抗雄激素的例子是醋酸环丙孕酮(CPA)和醋酸甲地孕酮,市售产品称作MEGACE(Bristol-Myers Oncology)。甾类抗雄激素可以封闭前列腺雄激素受体。它们也能够抑制LH的释放。对病人给药CPA的适当给药剂量是100mg/天-250mg/7天。
非甾类抗雄激素可封闭雄激素受体。它们还能够引起血清LH水平和血清睾酮水平升高。优选的非甾类抗雄激素药物是氟他胺(2-甲基-N-[4-硝基-3-(三氟甲基)苯基]丙酰胺),市售产品称作EULEXIN(Sehering Corp.)。氟他胺通过抑制雄激素摄取,通过抑制靶组织中核结合雄激素,或通过这两种方式来发挥其抗雄激素的作用。氟他胺通常以例如胶囊剂型经口服给药。氟他胺的剂量例如是250mg,每天3次,即每天共750mg。
另一种非甾类抗雄激素是尼鲁米特,其化学名称为5,5-二甲基-3-[4-硝基-3-(三氟甲基-4’-硝基苯基)-4,4-二甲基咪唑啉二酮。当本发明使用尼鲁米特时,尼鲁米特的剂量可例如是每天300mg,随后减少到150mg/天的剂量。
在本发明的某些实施方案中,化学阉割剂是LHRH激动剂如醋酸亮丙瑞林和抗雄激素如氟他胺或尼鲁米特的混合物。例如,醋酸亮丙瑞林可以经皮下、肌肉内或静脉内注射给药,而同时经口服给药氟他胺。酪氨酸激酶抑制剂可以作为第三制剂单独给药,或者将酪氨酸激酶抑制剂与LHRH激动剂或抗雄激素配制在一起。
另一种适用于本发明的非甾类抗雄激素是CASODEX。CASODEX的给药剂量例如是5mg-500mg/天,优选约50mg/天。
本发明所述的组合制剂的例子是在一个用于口服给药的胶囊中含有1-20mg化合物II-12和100-1000mg氟他胺,每天给患者服用1次、2次或3次。在一个优选实施方案中,为了提高化合物II-12的生物利用度,该制剂包括含有配比为1∶1(v/v)的吐温80和聚乙二醇的赋形剂。在一些实施方案中,通过肌肉内注射醋酸亮丙瑞林延效注射剂如LUPRON DEPOT来对上述化合物II-12/氟他胺的口服制剂进行补充。另一种酪氨酸激酶抑制剂例如化合物II-4或化合物II-4-LAE可以用于取代该制剂中的化合物II-12。本发明所述组合制剂的其它例子是在适合静脉内输注的单剂量溶液中含有化合物II-12、化合物II-4或化合物II-4-LAE以及化学阉割剂。
可以将酪氨酸激酶抑制剂和化学阉割剂各自或一起与可药用无毒赋形剂和载体混合而制成药物组合物。如此制得的组合物适用于:非肠道给药,优选以液体溶液或混悬剂形式;口服给药,优选以液体、片剂或胶囊形式;或经鼻给药,优选以粉末、滴鼻剂或气溶胶形式。
上述组合物通常以单位剂型给药并且可以通过任何本领域已知方法制备。这些方法公开在例如《Remington氏药物科学》(Mack Pub.Co.,Easton,Pa.,1980)中。
口服给药的液体剂型包括可药用乳液、微乳液、溶液、混悬剂、糖浆剂和酏剂。除了含有活性化合物以外,液体剂型可以含有所属领域常用的惰性稀释剂,例如水或其它溶剂,增溶剂和乳化剂如乙醇、异丙醇、碳酸乙酯、醋酸乙酯、苄醇、苯甲酸苄酯、丙二醇、1,3-丁二醇、二甲基甲酰胺、油(具体如棉籽油、花生油、玉米油、胚油、橄榄油、蓖麻油和芝麻油)、甘油、四氢呋喃、聚乙二醇和脱水山梨糖醇脂肪酸酯及其混合物。除了惰性稀释剂以外,口服组合物还可以含有辅料如湿润剂、乳化剂或悬浮剂、增甜剂、矫味剂和芳香剂。
通过在生物可降解聚合物如聚丙交酯-聚乙交酯中形成药物微囊基质可以制得可注射延效剂型。根据药物与聚合物的比例和所用具体聚合物的性质,可以调控药物的释放速率。其它生物可降解聚合物的例子包括聚原酸酯类化合物和聚酐类化合物。也可以通过将药物包入与机体组织相容的脂质体或微乳液中来制得延效型可注射制剂。
口服给药用固体制剂包括胶囊、片剂、丸剂、粉剂和颗粒剂。在这些固体剂型中,活性化合物与至少一种惰性可药用赋形剂或载体如柠檬酸钠或磷酸二钙和/或a)填充剂或增量剂如淀粉、乳糖、蔗糖、葡萄糖、甘露糖醇和硅酸,b)粘合剂如羧甲基纤维素、藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖和阿拉伯胶,c)湿润剂如甘油,d)崩解剂如琼脂、碳酸钙、土豆或木薯淀粉、藻酸、某些硅酸盐和碳酸钠,e)溶液阻滞剂如石蜡,f)吸收促进剂如季铵化合物,g)保湿剂如鲸蜡醇和甘油单硬脂酸酯,h)吸收剂如高岭土和膨润土,和i)润滑剂如滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠及其混合物,混合在一起。在胶囊、片剂和丸剂的剂型中还可包含缓冲剂。相似类型的固体组合物还可以作为填充剂与上述赋形剂如乳糖或奶糖以及高分子量聚乙二醇等一起填充在软胶囊和硬胶囊中。
固体剂型片剂、锭剂、胶囊、丸剂和颗粒剂还可以带有包衣和壳层,例如肠溶包衣和制药领域中已知的其它涂层。它们可以任选地含有不透明剂,并且也可以是仅在或优先在肠道某部分任选地以延迟方式释放活性组分的组合物。适用的包埋用组合物的例子中含有高分子物质和蜡。
相似类型的固体组合物还可以作为填充剂与上述赋形剂如乳糖或奶糖以及高分子量聚乙二醇等一起填充在软明胶和硬明胶胶囊中。
活性化合物还可以与上述一种或多种赋形剂一起形成微囊剂型。在固体剂型中,活性化合物可与至少一种惰性稀释剂如蔗糖、乳糖或淀粉混合在一起。在常规生产中,这种剂型除了含有惰性稀释剂以外也可含有附加物质,例如压片润滑剂和其它压片助剂如硬脂酸镁和微晶纤维素。在胶囊、片剂和丸剂的情况中,这些剂型中还可以含有缓冲剂。它们任选地含有不透明剂,并且也可以是仅在或优先在肠道某部分任选地以延迟方式释放活性组分的组合物。适用的包埋用组合物的例子中含有高分子物质和蜡。
本发明将通过下列实施例进一步说明。这些实施例只起说明目的,它们不以任何方式对本发明的范围和内容构成限定。
实施例
实施例1:化合物II-4结合手术阉割
从联合采用酪氨酸激酶抑制剂给药与手术阉割的动物实验获得的数据被认为与酪氨酸激酶抑制剂给药与化学阉割的联合治疗有关。
在这些实验中,选用Dunning R-3327H肿瘤(衍生自成年哥本哈根大鼠的特发型前列腺瘤),因为它们对雄激素具有敏感性且生长速率缓慢(Isaacs,1989,癌症研究(Cancer Res.)49:6290-6294)。实验设计中认为,对大鼠的Dunning H肿瘤进行手术阉割几乎可以立刻使肿瘤生长停止,随后在阉割后约5-6周时对雄激素不敏感的肿瘤发生消退(Isaacs等人,(1981),癌症研究,41:5070-5075)。
化合物II-4所诱发的Dunning H肿瘤的消退并不归因于该化合物对雄激素水平的作用,因为该实验是在体内植入了睾酮释放硅橡胶胶囊的大鼠上进行的。设计植入该胶囊的目的是为了使循环睾酮维持在生理水平。在实验末期测得的血清睾酮水平证实睾酮≥1-2ng/ml。
下列实验有三个目的:1)为了测定化合物II-4给药与手术阉割的联合是否能够产生比单独采用化合物II-4或手术阉割更高的抗肿瘤效能;2)为了确定化合物II-4是否能够引起经过预先阉割宿主动物而已有选择地对激素不敏感的Dunning H肿瘤发生消退;和3)测试肿瘤在用化合物II-4处理若干个给药周期后是否仍然对手术阉割敏感。
化合物II-4由Cephalon,Inc.合成且将其配制(10mg/ml)于赋形剂中,所述赋形剂是在水(48%)中含有40%聚乙二醇(PEG 1000,Spectrum,Los Angeles,CA)、10%聚乙烯吡咯烷酮(C30,ISP Boundbrook,NJ)、2%苄醇(Spectrum,Los Angeles,CA)。
成年雄性近交哥本哈根大鼠(200-240g)得于Harlan SpragueDawley(Indianapolis,IN)且以每笼3只进行饲养,让这些大鼠可以随意地获得市售饲料(Purina Formulab 5001)和水。室内的动物处于受控湿度和温度的条件下,并且接受12小时交替的光照/黑暗周期。在实验操作前1周对大鼠进行检疫。用套管针将大鼠前列腺癌Dunning R-3327 H瘤植入。处死长有Dunning H肿瘤的成年雄性哥本哈根大鼠并分离出肿瘤。将肿瘤切片并将小片的肿瘤皮下接种在成年雄性哥本哈根大鼠体内。
实验是按照Johns Hopkins大学动物保护和使用协会协议No.RA91M517和Cephalon学院动物保护和使用协会协议No.03-008的指导进行的。
为了进行手术阉割,给大鼠肌肉内注射氯胺酮(KETAMINETM)(4.1mg/100g体重)和塞拉嗪(XYLAZINETM)(0.85mg/100g体重)将带有移植Dunning H肿瘤的大鼠麻醉。将各大鼠背部向下放置。在阴囊后端的皮肤上划出一个小切口(0.5-1cm)。另一个切口是将睾丸周围的连接膜割开。拉出附睾、睾丸、输精管、精囊血管以及脂肪并把它们割下来。将其它组织放回囊内,用自动缝合夹封闭切口。术后5-7天除去自动缝合夹。
将36只带有Dunning H瘤(0.9-18cm3)的大鼠分成4组,每组9个动物。第1组作为赋形剂对照组。第2组在第1天阉割。第3组按下列方法接受化合物II-4(10mg/kg,皮下)的注射。第4组在第1天阉割且按下列方法接受化合物II-4注射。给第1组和第3组在第1天时(在胁腹中)植入2厘米长的填充有睾酮的密封硅橡胶管。这种尺寸的硅橡胶植入物适合在6个月的时间内将血清睾酮长期维持在1-3ng/ml的生理范围内。用化合物II-4经皮下周期性对第3和第4组给药(10mg/kg/天),给药周期为5天并且两周期之间间隔约10天。即,在第1-5、14-18、29-33和42-46天给药。以与化合物II-4治疗组相同的给药方案给第1组和第2组施用药物赋形剂。
在第60天,从第2组中取8只动物分为两组,每组4只动物。一组用化合物II-4以10mg/kg处理(皮下)5天,随后停药9天,再接受第二次为期5天的给药(10mg/kg/天(皮下))。第2组以相同的给药方案接受赋形剂。
在第60天从上述试验的第3组中取7只大鼠分为2组。一组(N=3)大鼠接受阉割。两组动物均用化合物II-4以10mg/kg处理(皮下)5天,随后停药9天,再接受第二次为期5天的给药。
用游标卡尺在指定时间间隔测定麻醉(用异氟烷气体麻醉约1-2分钟)动物的肿瘤的大小。用下列公式计算肿瘤体积:V(cm3)=0.5236×长度(cm)×宽度(cm)[(长度(cm)+宽度(cm))/2]。
利用Sigmastat程序,根据Dunnett氏试验、Mann-Witney秩和检验法、配对t试验或有正负号的排列试验对显著性进行统计学分析。
观察到Dunning H肿瘤在未接受手术而只用赋形剂处理的大鼠中的生长呈线性,并且在60天内肿瘤体积增加了约3.5倍(图1)。手术阉割引起肿瘤快速消退,即5天消退了25%。到第12天时在阉割大鼠中观察到肿瘤再生,并且在第38天时曾消退的肿瘤体积已经完全恢复了。
化合物II-4单独给药(10mg/kg,皮下,4个独立的化合物II-4治疗周期:用药物治疗5天,随后停药约10天)引起肿瘤生长完全被抑制或诱发肿瘤消退。在化合物II-4的各给药周期(第5、19、34和47天;未给出数据)后,接受药物处理的动物的平均肿瘤体积比接受赋形剂处理的对照动物的明显减小(p<0.01)。此外,与各给药周期开始时相比,化合物II-4的各给药周期均使肿瘤体积减小(未给出数据)。
化合物II-4给药和手术阉割的结合彻底抑制了肿瘤的生长或诱发肿瘤消退(图1)。总之,化合物II-4给药和手术阉割的结合比单独手术阉割更加有效。在活体内观察到在受阉割和未阉割动物中停用化合物II-4后肿瘤均发生再生,然而,在受阉割动物中的肿瘤再生得到了最大程度的减小(p<0.01,图1)。
上述结果证明,化合物II-4给药可以与手术阉割联合采用,从而最大程度和/最长期地使活体内接受的前列腺癌模型中的肿瘤发生消退。
进行其它实验的目的是为了测定化合物II-4是否可以使因事先的雄激素去除而选择出的对激素不敏感的肿瘤发生消退。在第60天时从上述实验(预先未用化合物II-4处理)的阉割组中取8只大鼠分为2组,每组4只。第1组用化合物II-4以10mg/kg处理(皮下)5天,随后停药9天,然后再接受第二次为期5天的皮下给药10mg/kg/天。第2组以相同的给药方案接受赋形剂。
用化合物II-4处理3天后阉割大鼠中的雄激素不敏感性DunningH肿瘤的生长明显降低(P<0.05;图2)。在第6天观察到消退达到最大值(p<0.05)。停药使肿瘤再生。然而,即使在化合物II-4的第1个给药周期结束后的10天内,用化合物II-4处理的大鼠中的肿瘤体积也明显小于用赋形剂处理的动物中的肿瘤体积。经事先的雄激素去除而选择出的对激素不敏感的Dunning H肿瘤仍然对化合物II-4的抗肿瘤作用敏感。
实验还测定了对带有Dunning H肿瘤的大鼠用化合物II-4进行预处理是否能够引起对随后经手术阉割的雄激素去除不敏感型肿瘤的选择。在第60天从上述实验中的化合物II-4处理组中取7只大鼠,分成两组。1组(N=3)按照上述方式阉割。两组均接受化合物II-4的处理,按10mg/kg,皮下处理5天,随后停药9天,再接受第二次为期5天的相同给药方案。在接受了四个化合物II-4的预给药周期和两个并行处理周期后,手术阉割引起不具统计学意义的肿瘤消退(图3)。总之,数据表明,反复暴露在化合物II-4下并不能选择出Dunning H肿瘤的雄激素不敏感种群。
阉割、化合物II-4处理以及化合物II-4处理和手术阉割的结合均可被很好的耐受。在用赋形剂或化合物II-4处理的对照和阉割组中均观察到有限的死亡率。在各组中,在测定肿瘤时均有死亡出现,这被假设为麻醉过度。
实施例2:化合物II-12与化学阉割的结合
化合物II-12是由Cephalon,Inc.合成的,化合物II-12二盐酸盐被配制在含有3∶2(v/v)Gelucire(Gattefosse,Saint-Priest,France)和丙二醇(Spectrum,Gardena,CA)的赋形剂中。
本试验采用得自Harlan Sprague Dawley(Indianapolis,IN)的成年雄性近交哥本哈根大鼠(200-240g)。按照上述实施例1所述的方法进行大鼠饲养和操作以及Dunning R-3327 H肿瘤的移植。
将46只带有Dunning H瘤(肿瘤大小为1/6-33.2cm3)的大鼠(体重:380±8g)分成4组。第1组(N=12)作为赋形剂对照组(1ml/kg,口服,每天2次,第0-20天和31-45天)。第2组(N=10)用醋酸亮丙瑞林(LUPRONDEPOT)处理(5.2mg/kg,第0天和第21天,皮下给药)。第3组(N=12)接受化合物II-12(10mg/kg,口服,每天2次,第0-20和31-45天)。第4组(N=12)接受醋酸亮丙瑞林(5.2mg/kg,第0天和第21天,皮下给药)和化合物II-12(10mg/kg,口服,每天2次,第0-20和31-45天)的联合给药。给第1组和第3组的大鼠在第1天时皮下植入2厘米长的填充有睾酮的密封硅橡胶管。
按照实施例1所述的方法测量肿瘤并进行统计学分析。
在用赋形剂处理的动物中Dunning H肿瘤在体内持续生长。经过53天后观察到肿瘤体积增加了约2.5倍。化合物II-12的各处理周期(10mg/kg,每天2次,口服21天,且停药期为10天)均使Dunning H肿瘤的生长得到抑制且引起肿瘤明显消退。与赋形剂对照组相比,由化合物II-12处理组观察到的对肿瘤生长的抑制作用具有统计学意义。从对肿瘤的初次测量(即第4天的测量)直至试验结束的测量均存在上述显著性差异。单独用醋酸亮丙瑞林处理也可以使肿瘤消退。在亮丙瑞林处理开始后约32天时观察到肿瘤的缓慢再生(图4)。
与单独使用亮丙瑞林或单独使用化合物II-12相比,化合物II-12/亮丙瑞林的组合在维持肿瘤低速生长方面比单独使用上述两种药物中的任何一种具有更明显的效果(p<0.05)(图4)。在化合物II-12处理组和亮丙瑞林处理组中观察到在处理开始后约30天时肿瘤开始再生。相反,联合给药处理组在较长时间内表现出肿瘤生长减弱,并且分别从第35和39天开始直至该试验在第54天结束时,对肿瘤生长的抑制作用,联合给药组与化合物II-12处理组和亮丙瑞林处理组具有显著性差异,(p<0.05;图4)。
这些试验结果证实,化合物II-12给药和化学阉割的组合具有协同的抗肿瘤功效(图1和4)。
Claims (19)
1.作为酪氨酸激酶抑制剂的吲哚并咔唑类化合物与化学阉割剂用于制备抑制哺乳动物中前列腺瘤恶化的药物的用途,所述化学阉割剂选自雌激素、促黄体素释放激素激动剂、促黄体素释放激素拮抗剂和抗雄激素物质。
2.权利要求1所述的用途,其中所述哺乳动物是人。
3.权利要求2所述的用途,其中所述吲哚并咔唑类化合物具有如下结构:
(化合物II-12)
6.权利要求1所述的用途,其中所述的药物是经口服制剂。
7.权利要求1所述的用途,其中所述的药物是经非肠道给药的制剂。
8.权利要求1所述的用途,其中所述促黄体素释放激素激动剂是醋酸亮丙瑞林。
9.权利要求1所述的用途,其中所述抗雄激素物质是氟他胺。
10.权利要求1所述的用途,其中所述化学阉割剂是促黄体素释放激素激动剂和抗雄激素的混合物。
11.权利要求10所述的用途,其中所述促黄体素释放激素激动剂是醋酸亮丙瑞林,所述的抗雄激素是氟他胺。
12.一种含有酪氨酸激酶抑制剂和化学阉割剂的组合物,所述的酪氨酸激酶抑制剂是吲哚并咔唑类化合物,所述化学阉割剂选自雌激素、促黄体素释放激素激动剂、促黄体素释放激素拮抗剂和抗雄激素物质。
14.权利要求12所述的组合物,其中该组合物被配制成经口服给药的制剂。
15.权利要求12所述的组合物,其中该组合物被配制成经非肠道给药的制剂。
16.权利要求15所述的组合物,其中所述促黄体素释放激素激动剂是醋酸亮丙瑞林。
17.权利要求15所述的组合物,其中所述抗雄激素物质是氟他胺。
18.权利要求12所述的组合物,其中所述化学阉割剂是促黄体素释放激素激动剂和抗雄激素物质的混合物。
19.权利要求18所述的组合物,其中所述促黄体素释放激素激动剂是醋酸亮丙瑞林,所述抗雄激素是氟他胺。
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DE (1) | DE69802422T3 (zh) |
DK (1) | DK1011648T4 (zh) |
EA (1) | EA002525B1 (zh) |
ES (1) | ES2163293T5 (zh) |
HK (1) | HK1028565A1 (zh) |
HU (1) | HUP0003194A3 (zh) |
NO (1) | NO325526B1 (zh) |
NZ (2) | NZ517497A (zh) |
PL (1) | PL193375B1 (zh) |
PT (1) | PT1011648E (zh) |
TR (1) | TR200000415T2 (zh) |
UA (1) | UA61970C2 (zh) |
WO (1) | WO1999008668A2 (zh) |
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JP7256796B2 (ja) | 2017-10-13 | 2023-04-12 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Thomsen-nouvelle(tn)抗原に対するヒト抗体 |
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