CN1188137C - 红细胞生成素、具有激活epo受体能力或模拟epo活性的分子在制药中的用途 - Google Patents
红细胞生成素、具有激活epo受体能力或模拟epo活性的分子在制药中的用途 Download PDFInfo
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Abstract
提供了一种提高抗肿瘤制剂对实体瘤疗效的方法。该方法包括给予个体抗肿瘤制剂和血细胞比容提升剂。该血细胞比容提升剂可在抗肿瘤制剂给药之前给药或同时给药。
Description
发明领域
本发明涉及癌症治疗领域。更具体地说,本发明涉及通过促进化疗期间血细胞比容来提高化疗制剂治疗实体瘤的效果。
发明背景
抗肿瘤制剂
虽然癌症治疗获得了许多进展,但实体瘤仍然难于治疗。结果,许多患者发展至癌症晚期,常规治疗一般无效。因此,正在研究新颖类型癌症药物的抗癌症活性。近年来,人们对铂配位化合物产生了浓厚的兴趣(Rosenberg等人,1969,Nature,222:385-386)。在结构上,该化合物是一种复合体,中心为铂原子,周围围绕着顺式或反式不同排列的氯原子和氨基。以铂为基础的多种制剂化疗法已成为晚期卵巢癌患者首选的手术后治疗法(American Cancer Society,1995,Facts andFigures)。顺氯氨铂(顺式二胺二氯铂)和碳铂〔1,1-环丁烷基二羧基二胺铂(II)〕是细胞毒性铂配位化合物的例子,它们可用于治疗各种恶性肿瘤。已知对癌症细胞具有细胞毒素作用的其他铂化合物包括1,4-和1,2-二氨基环己烷铂(iV)复合物(美国专利5434256号)。
虽然铂化合物可用来抗恶性肿瘤,但是在治疗过程中肿瘤产生的抗药性限制了该化合物的应用。铂抗肿瘤的许多具体机制还没有完全了解。由于没有详细的铂细胞毒性机制的资料,难于克服肿瘤对顺氯氨铂的抗性问题,也因此难于提高铂及其他抗肿瘤制剂的疗效。
实体瘤含有充分氧合细胞和含氧量低细胞两种细胞群。缺氧通常发生在离血液供应最远的细胞中,这些细胞繁殖缓慢,但是也对抗癌药物较有抗性。例如,数据表明,含氧量低细胞对顺氯氨铂的细胞毒作用的抗性比氧合细胞更大(Herman等人,1988,Cancer Research,48:2342-2347;Melvic等人,1988,Radiat.Res.,114:489-499;Grau等人,1988,Radiother.Oncol.,13:301-309)。因而,肿瘤对抗癌制剂具有抗性的一个机制可能归因于这些肿瘤细胞的缺氧状态。
常观察到的一些副作用如肾毒性、耳毒性和肾中毒限制了铂化合物的疗效。贫血也是铂治疗的一种常见副作用。顺氯氨铂治疗后特别常见贫血,患者常常需要输血。虽然顺氯氨铂治疗后出现贫血的原因可能是多方面的,但是发现红细胞生成素水平降低,因此红细胞生成素不足看起来是重要的。已报道顺氯氨铂治疗或其他化疗之后给予重组人红细胞生成素对逆转与这些治疗有关的贫血有效(Abels 1992,Seminars in Oncilogy,19:29-35)。
红细胞生成调节剂
本世纪之初便第一次提出了存在着调节红细胞生成即产生红血球的激素。从那以后,有利于红细胞生成的体液调节的资料继续增加。这导致了红细胞生成素(EPO)的纯化和其氨基酸序列的测定以及最终导致了人类EPO基因的克隆(Jacobs等人,1985,Nature,313:806-810;Lin,1985,Proc.Natl.Acad.Sci.,82:7580-7584;Lin,美国专利4403008号)。重组EPO的纯化在Lai等人的美国专利4667016号中有描述。
EPO是调节红血球循环水平的主要激素。天然EPO在胎儿时期由肝产生,成人主要由肾产生。通过基因工程技术产生重组EPO涉及用EPO编码基因转化的宿主细胞蛋白质产物的表达。与许多细胞表面和分泌性蛋白质相似,EPO也是糖基化的。糖基化通常有两种类型:O连接的寡糖结合于丝氨酸或苏氨酸残基,而N连接的寡糖结合于天冬酰胺残基。从人尿得到的EPO含有三个N连接寡糖链和一个O连接寡糖链,它们占了糖蛋白总分子量的40%。对应于不同糖基化水平的不同同工型EPO已有所描述(Elliott等人,1995,EP 0640619A1)。
EPO通过与EPO受体结合而发挥其作用。EPO受体的激活产生了几种生物学效应,包括刺激增殖、刺激分化和抑制凋亡(Liboi等人,1993,Proc.Natl.Acad.Sci.,USA,1990,11351)。EPO受体还能被激动剂如EPO突变体和类似物、肽和抗体激活。除了EPO外,也已鉴定以其他具有EPO类似活性的化合物。例如,已报道从肾细胞癌中鉴定到一种分子对红血球生成具有EPO类似作用,但是其免疫学性质与EPO不同(Sytkowski等人,1979)。其他的红血球生成刺激物包括过渡金属的水溶性盐(Brugnara等人,美国专利第5369014号)。
虽然更多接受采用铂治疗晚期实体瘤,但没有评估过血细胞比容或血红蛋白与化疗制剂抗肿瘤效果之间的临床关系,以确定提高血细胞比容的制剂是否能增加肿瘤对抗肿瘤制剂的敏感性。鉴于非常规抗肿瘤制剂的应用增加,仍存在提高对这些制剂的抗肿瘤应答的需要。
发明概述
本发明公开了一种提高抗肿瘤制剂疗效的方法。该方法包括在提高血细胞比容的条件下给予需要这种治疗的个人一种抗肿瘤制剂。
因此,本发明的一个目的是提供一种治疗实体瘤的方法,即联合给予抗肿瘤制剂和血细胞比容提升剂(elevator)。在一个较佳实施例中,血细胞比容提升剂在抗肿瘤制剂之前给药。
本发明的另一目的是提供一种治疗实体瘤的方法,即给予抗肿瘤铂化合物和EPO或EPO类似化合物。
本发明的又一目的是提供一种治疗卵巢肿瘤的方法,即联合给予患者顺氯氨铂和EPO。
附图的简短说明
图1表示以时间为函数给予顺氯氨铂、EPO或两者对卵巢肿瘤生长的效果图。
图2表示以时间为函数给予顺氯氨铂、EPO或两者对血细胞比容百分比变化的效果图。
发明详细描述
本说明书和权利要求书中所用的术语“丙二酸铂配位化合物”指铂(II)和铂(IV)的顺式和反式同分异构体,它们含有可取代或不取代的二齿丙二酸双配位体。铂II型配位化合物具有空间平面排列,而铂IV型配位化合物具有空间八面排列。这些化合物公开在Clesry等人的美国专利4140707号和4657927号中,本文引用这些文献作为参考。
术语“抗肿瘤制剂”和“抗癌制剂”可互换使用,在本说明书和权利要求书中指有效抑制、减缓或阻止癌细胞生长的化合物或组合物,或者是对癌细胞具有细胞毒作用的化合物或组合物。本说明书和权利要求书中的抗肿瘤制剂“化疗有效量”指给予个体的药物的量足以抑制、减缓或阻止癌细胞的生长,或者足以对癌细胞产生细胞毒作用。
本说明书和权利要求书的“抗肿瘤作用”或“抗肿瘤活性”指对癌细胞生长的抑制、减缓或阻止,或者产生细胞毒作用。可测定的抗肿瘤作用的一个例子是肿瘤体积减少。
本说明书和权利要求书的“红细胞生成素”或“EPO”指通过化学分离和纯化技术获得或分离得到的全部或部分的红细胞生成素;任何类型的红细胞生成素包括用重组DNA技术制得的人红细胞生成素。这个“术语”还包括转染了含有编码EPO基因的外源遗传物质个体的细胞产生的EPO,或者由于移植了转染的原代或次代细胞(含有编码EPO基因的外源遗传物质)到这些个体中而产生的EPO。在美国专利5733761号中公开了制备和传送这些产物或感染细胞的技术,在本说明书中引用作为参考。
本说明书和权利要求书中的术语“EPO类似”的分子或物质指通过化学分离或纯化技术或者通过重组技术获得的、具有激活EPO受体能力或者模拟EPO活性(如刺激红细胞生成)的任何分子。因此,这个定义包括:天然或重组EPO的片段,它们可能比完整的EPO分子短并能激活EPO受体;融合分子,通常包括完整EPO分子中存在的部分氨基酸序列;类似物,如Okasinski的美国专利5888772号(本文引用作为参考)所公开的,其氨基酸序列与天然EPO相似但不相同,具有刺激红细胞生成的生物学活性;EPO衍生物,其中EPO结构已被加入(或删除)的一个或多个取代基或化学分子所修饰;EPO的同工型,包括EPO的各种糖基化状态,如Strickland在美国专利5856298号(本文引入作为参考)中的描述;含有额外的糖基化位点或重排糖基化位点的重组产生的EPO同工型,如Eliott等人在欧洲专利(EP 0640619B1,纳入本文作为参考)中所描述的;能结合于EPO受体并将其激活、或者具有EPO激动剂作用的肽,如Wrighton等人的美国专利5772569号和Wilson等人的美国专利5835382号(本文引入作为参考)所公开的;具有改变的生物学活性的突变分泌性EPO蛋白,如Sytkowski等人的美国专利5614184号(本文引入作为参考)中所公开的。在此定义中还包括竞争性的抗体或其片段,如Elliott等人的美国专利5885574号(本文引入作为参考)所公开的,它能激活EPO受体或模拟EPO的活性。所有与EPO类似的物质的共有特征是模拟一种或多种EPO活性的能力。
血细胞比容提升剂的“治疗有效”量指足以增进红细胞的产生、从而使血细胞比容增至正常范围之上的天然或重组产生的EPO或EPO类似物质的量。例如,美国专利5013718号(本文引入作为参考)公开的15-1500单位/千克体重、较佳50-300单位/千克体重的量是治疗有效量。
本发明涉及一种通过增进血细胞比容提高某些抗肿瘤制剂效果的方法。本发明方法包括给予需要这种治疗的患者联用抗肿瘤制剂和增加血细胞比容的制剂。
本发明方法可用于对铂化合物治疗敏感的哺乳动物癌瘤的治疗,包括人癌瘤,特别是实体瘤。这些肿瘤的例子包括但不限于腺癌、黑色素瘤、淋巴瘤、肉瘤、和肺、乳腺、卵巢、头和/或颈、前列腺、子宫颈、子宫内膜、结肠直肠、胃、肝、输卵管、食道、小肠、胰腺、肾、肾上腺、阴道、外阴、脑和睾丸的肿瘤。
对于本发明方法,将一种或多种抗肿瘤制剂与增加血细胞比容的制剂联合给药。抗肿瘤制剂和血细胞比容提升剂可以同时或按顺序给药。较佳的是,在抗肿瘤制剂给药之前给予血细胞比容提升剂。抗肿瘤制剂的一个例子是含铂化合物,如任何一种铂配位化合物。本发明的铂配位化合物包括但不限于铂(II)和铂(IV)化合物。
已知对癌细胞有细胞毒作用的两个铂化合物的例子是顺氯氨铂和碳铂。由于它们的结构中存在(OOC)2-C连接,这两种化合物属于称为“丙二酸的”化合物组。顺氯氨铂是一种淡黄白色粉末,在同一水平面上含有氯和氨基。碳铂是一种白色晶状粉末。与顺氯氨铂类似,碳铂已被用来治疗各种人类癌症,包括小细胞肺癌、鳞状细胞癌和睾丸癌(见U.S.Pharmacists,1989年9月,第62-63页)。虽然不受任何理论所束缚,但铂配位化合物被认为是通过引起DNA互补链的交联干扰了DNA合成而发挥了抗肿瘤活性。在一个较佳的实施例中,铂化合物是顺氯氨铂。
抗肿瘤制剂可通过常规适当的具体化疗途径以药学上可接受的载体形式给予患者。例如,抗肿瘤制剂可以通过静脉、腹膜腔内、皮下、肌肉途径传送,或者通过输液以确保其以有效形式传送到血流中。另外,抗肿瘤制剂可以如美国专利5620703号(本文引入作为参考)公开的以脂质体包囊形式给药。本发明抗肿瘤制剂的有效剂量是那些已知具有抗肿瘤作用的制剂的剂量。这些剂量本领域技术人员是熟知的,或者可凭经验确定。例如,许多化疗药物的剂量指导原则一般在Physician′s desk Reference中列出。通常,铂化合物的剂量范围是大约1-200mg/kg/剂。这些化合物可以在一定天数内(如3-5天)以单次输液或多次输液方式给药。如需要可以重复进行。较佳的是,在治疗的第一天以单次静脉输液方式给药。顺氯氨铂的剂量一般是25-300mg/m2。更佳的范围是50-100mg/m2。为了维持足量的水合作用,先给予生理盐水,再进行顺氯氨铂输液。
本发明的血细胞比容提升剂包括能使采用该制剂治疗的个体的红细胞数增加的任何制剂。例如,用于本发明的血细胞提升剂包括但不限于EPO和EPO类似物质。血细胞比容提升剂可以以常规的方式给药,包括但不限于静脉、腹膜腔内或皮下途径,给药的剂量是本领域技术人员所熟知的对增加血细胞比容有用的剂量。基于EPO在血浆中的半衰期为大约5小时,EPO可以多剂量给药。或者,还可以使用转染技术将EPO递送到个体的细胞中。可监测血细胞比容数值作为EPO作用效果的指示物。相似的给药途径可用于EPO类似物质。在一个较佳的实施例中,通过静脉或皮下途径以每周三次每次50-100单位/千克体重的量给药。
可通过评估肿瘤确定治疗的效果。可触诊的肿瘤可通过常规的方法测量。成像技术如CT扫描、MRI扫描、超声波扫描等也可用来测量和评估肿瘤的大小。或者,也可定量测定特殊的肿瘤标记物,比如但不限于用于前列腺癌的PSA、用于卵巢癌的CA-125、用于乳腺癌的CA-15-3以提供肿瘤的评估。可用标准的准则来评估治疗反应。例如,可以按世界卫生组织(WHO)的Reporting Results of CancerTreatment手册(WHO Offset Publication,1979)提出的准则评估。因此,肿瘤可分为完全反应、部分反应或无反应。顺氯氨铂和EPO轮流治疗可以不断进行,直到获得可接受的反应或观察到不可接受的毒性作用为止。
实施例1
这个实施例证明使用EPO预处理、提高和维持血细胞比容引致顺氯氨铂对移植在SCID小鼠中的人细胞敏感效果。为阐明这个实施例,在携带有人卵巢癌的免疫缺陷SCID小鼠身上进行了试验。本领域熟练技术人员都知道这种小鼠是证明潜在化疗剂抗肿瘤活性的合适动物模型。
使用了80只CB 17-SCID/SCID小鼠(Taconic Labs)。这些动物饲养在无菌的和控制光亮的条件中。通过本领域技术人员熟知的方法将患有复发性IIIC期、3级卵巢乳头状浆液性腺癌患者的一部分肿瘤移植到SCID小鼠身上并增殖。简而言之,在将肿瘤移植到实验动物身上之前,异种移植物至少生长和传代5次。根据Sakakibara等人(1996,Can.J.Sci.Amer.,2:291-300)描述的方法(本文引入该方法作为参考),通过缝合连接将2-3mm的人异种移植肿瘤种植到40例6周龄实验小鼠的生殖腺脂肪垫(GFP)中。通过腹部检查可触及GFP肿瘤异种移植物长成大的腹膜腔内块状物。接着将各只小鼠从胸骨延伸到髂骨骨嵴的中线切口作剖腹术。溶解肿瘤粘着物,并在不扰乱GFP蒂带的情况下将该肿瘤从腹膜腔中取出,在三维方向上用游标卡尺测量该肿瘤。然后将该肿瘤放回它在腹膜腔内的原始位置,接着将腹部单层缝合。手术后三天开始进行治疗方案。将小鼠随机分为4组。第零天是指腹膜腔内(ip)注射顺氯氨铂或腹膜腔内注射磷酸缓冲盐溶液(PBS)的第一天。I组动物(对照组)从第-15天到第+6天每周皮下接受100μl的PBS三次,第零天ip注射300微升PBS。II组(EPO组)小鼠从第-15天到第+6天皮下注射一剂20单位EPO的100微升PBS每周三次,第零天ip注射300微升PBS。III组(顺氯氨铂组)小鼠从第-15天到第+6天每周皮下注射100微升PBS三次,在第零天ip注射一剂5mg/kg顺氯氨铂的300微升PBS。IV组小鼠(EPO+顺氯氨铂组)小鼠如第II组一样,从第-15天到第+6天皮下注射EPO,并如第III组在第零天ip注射顺氯氨铂。观察小鼠至第8天。
在第-15、-7、0和+7天从各组随机选出的3只小鼠的尾血获得自动测定的血细胞比容。所有的小鼠都没有放血两次。在第7天,处死小鼠并进行尸体解剖。切下肿瘤并在三个方向上用游标卡尺测量。肿瘤体积的计算如下:
(宽)×(长)×(高)=肿瘤体积
肿瘤生长比例用下式计算:
〔(解剖得到的肿瘤体积/起初肿瘤的体积)-1〕×100=肿瘤生长百分比
在各个治疗组中,起初剖腹所测肿瘤三维大小相同,约为2cm×1.5cm×1cm。在用和不用顺氯氨铂治疗的组中,观察到肿瘤生长有显著的差异。观察了只接受顺氯氨铂的小鼠和接受顺氯氨铂加EPO的小鼠之间的肿瘤大小,其差异(p=0.07)表明顺氯氨铂的效果通过EPO得到了提高。对照组和EPO组之间没有观察到有什么差异。
在本实施例另一例示中,治疗期间给予顺氯氨铂两次。在另外40只6周龄实验小鼠中种植了2mm的人卵巢癌异种移植物。种植后三天,随机安排治疗组动物。I组动物(对照组)从第-15天到第+13天每周皮下注射100微升PBS三次,第0天和第7天ip注射300微升PBS。II组小鼠(EPO组)从第-15天到第+13天皮下注射一剂20单位EPO的100微升PBS每周三次,在第0天和第7天ip注射300微升PBS。III组小鼠(顺氯氨铂组)从第-15天到第+13天每周皮下注射100微升PBS三次,第0天和第7天ip各注射一剂5mg/kg顺氯氨铂的300微升PBS。IV组小鼠(EPO+顺氯氨铂组)从第-15天到第+13天接受如第II组的皮下EPO注射,每周三次,在第0天和第7天接受如第III组的ip顺氯氨铂注射。观察小鼠直到+15天。
如上所述,在第-15、-7、0、+7和+14天获得自动测定的血细胞比容。将血细胞比容相对于其起初的血细胞比容的变化对时间作图。从第0天开始用游标卡尺作肿瘤结节(nodule)两维大小的一系列测定。在第0天,各组小鼠的肿瘤长到大约4mm×5mm的大小。用下式计算第0、+2、+3、+5、+7、+9、+11、+13和15天的肿瘤体积:
(长)×(宽)2/2=肿瘤体积
用各指定天与第0天相比计算肿瘤生长百分比,并对时间作图。统计学分析包括用于大GFP肿瘤实验中的全部肿瘤生长的Student T检验。产生了生长较小皮下肿瘤组的曲线,并通过方差分析分析了代表血细胞比容对时间变化的曲线。P值小于0.05定义为显著性。
当每周给予顺氯氨铂两次时,在EPO+顺氯氨铂组和顺氯氨铂组之间观察到了显著差异(图1)。患有皮下肿瘤结节的小鼠的肿瘤生长曲线显示了EPO+顺氯氨铂组比顺氯氨铂组具有更显著的肿瘤衰退。另外,在对照组和EPO组之间没有观察到差异。
患有小皮下肿瘤小鼠的每周血细胞比容和血细胞比容对时间的变化分别表示在表1和图2中。患有大GFP肿瘤小鼠的血细胞比容相似(未给出数据)。EPO的给药使血细胞比容比初始值(-2周)增加25-35%,与对照组相比(P<0.01)有显著差异。没有EPO的顺氯氨铂的给药使血细胞比容降低20%。对照组是肿瘤小鼠的血细胞比容在此时间内降低2%(图2)。
表1
时间 | 血细胞比容 | |||
对照 | EPO | 顺氯氨铂 | EPO+顺氯氨铂 | |
-2周 | 39.5±0.1 | 39.5±0.2 | 39.8±0.2 | 39.6±0.2 |
-1周 | 39.7±0.3 | 44.9±0.2 | 39.8±0.2 | 45.1±0.3 |
0周 | 39.8±0.3 | 48.9±0.3 | 39.8±0.2 | 48.9±0.2 |
+1周 | 40.8±0.2 | 49.3±0.3 | 40.7±0.1 | 52.7±0.3 |
+2周 | 38.6±0.3 | 53.6±0.4 | 33.1±0.3 | 50.9±0.3 |
这些数据证明,使用EPO+顺氯氨铂比单用顺氯氨铂治疗的小鼠肿瘤衰退显著得多。EPO+顺氯氨铂组的小鼠的血细胞比容比顺氯氨铂组小鼠提高25-35%。
实施例2
本实施例证明增加血细胞比容减少了与抗肿瘤制剂毒性相关的死亡率。为阐明本实施例,评估了实施例1中接受不同治疗的小鼠的行为表现(performance)状况。在第0、+7和+14天用与发病率和死亡率相关的5个客观准则评估了实验小鼠的行为表现。5个准则是(1)竖毛;(2)虚弱/冷漠;(3)与对照组动物平均体重相比的20%体重损失;(4)脊柱隆起的状况;(5)死亡。0级表示正常健康,+5级表示死亡。
第0天所有小鼠的行为表现分值表明各治疗组的小鼠正常健康(所有的分值=0)。如表2所示,顺氯氨铂组的发病率信号出现在第+7天(表2)。对照组和EPO组所有小鼠保持0分值的行为表现。顺氯氨铂组的10只小鼠中,所有小鼠都有竖毛并出现虚弱/冷漠,与对照组相比,有6只在第+7天体重损失20%。EPO+顺氯氨铂组中所有小鼠都有竖毛,7只出现虚弱型/冷漠。第+14天,顺氯氨铂组小鼠行为表现恶化,有4只死亡,3只脊柱隆起。EPO+顺氯氨铂组中只有1只死亡,另外一只脊柱隆起。
表2
小鼠编号 | 对照组 | EPO组 | 顺氯氨铂组 | EPO+顺氯氨铂组 |
1 | 0 | 0 | +++++ | ++ |
2 | 0 | 0 | +++ | +++ |
3 | 0 | 0 | ++++ | +++ |
4 | 0 | 0 | +++++ | ++ |
5 | 0 | 0 | +++++ | +++ |
6 | 0 | 0 | +++ | ++++ |
7 | 0 | 0 | ++++ | ++ |
8 | 0 | 0 | +++ | ++ |
9 | 0 | 0 | ++++ | +++++ |
10 | 0 | 0 | +++++ | +++ |
总计 | 0 | 0 | 43+ | 29+ |
因而,在顺氯氨铂治疗动物中观察到比EPO+顺氯氨铂治疗小鼠更多的死亡率。而且,EPO治疗保持了更好的行为表现并具有较少的与顺氯氨铂有关的死亡。虽然不想受任何理论所束缚,可以假定EPO+顺氯氨铂组获得的抗肿瘤效应提高是由于血细胞比容增加的缘故,而不是因为保持了可接受的行为表现。
应能理解当对本发明作详细描述时,这些实施例仅仅是说明性的。对本发明实施例所作的本领域技术人员能明白的其他修改都在随后的权利要求书的范围中。
Claims (4)
1.红细胞生成素、或具有激活EPO受体能力或模拟EPO活性的分子在制备用于提高顺氯氨铂或碳铂抗肿瘤活性的药剂中的用途。
2.如权利要求1所述的用途,其特征在于,所述顺氯氨铂给药剂量在25mg/m2到300mg/m2之间。
3.如权利要求2所述的用途,其特征在于,所述顺氯氨铂给药剂量在50mg/m2到100mg/m2之间。
4.如权利要求1所述的用途,其特征在于,在所述抗肿瘤制剂给药之前给予所述红细胞生成素或所述具有激活EPO受体能力或模拟EPO活性的分子。
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