CN1946421A - 使用病毒和喜树碱进行的癌症治疗 - Google Patents
使用病毒和喜树碱进行的癌症治疗 Download PDFInfo
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- CN1946421A CN1946421A CNA2005800130396A CN200580013039A CN1946421A CN 1946421 A CN1946421 A CN 1946421A CN A2005800130396 A CNA2005800130396 A CN A2005800130396A CN 200580013039 A CN200580013039 A CN 200580013039A CN 1946421 A CN1946421 A CN 1946421A
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Abstract
本发明涉及使用病毒和喜树碱进行的癌症治疗。具体地，本发明涉及对患有肿瘤的哺乳动物受试对象施用病毒和诸如伊立替康或托泊替康等喜树碱化合物所进行的治疗。所述病毒选自新城疫病毒、麻疹病毒、水泡性口炎病毒、流感病毒、辛德毕斯病毒、小核糖核酸病毒和粘液瘤病毒。所述治疗还可包括施用诸如西妥昔单抗等抗表皮生长因子受体的单克隆抗体。
Description
背景技术
在WO 00/62735(第35～36页)中公开有溶瘤病毒和其他化学治疗剂的共施用。对于近期有关抗癌病毒疗法的综述，参见Kirn D(Cancer GeneTher 2002；9：959-960；Virotherapy for cancer：current status，hurdles andfuture directions)和Bell JC等(Cur Gene Ther 2002，2：243-254；OncolyticViruses：programmable tumour hunters)。对于本领域来说，提高所述病毒疗法的功效是非常重要的，而且所述方法正得到认可和广泛应用。具体地，与病毒显示出上述额外功效的药物将是最为有利的。
在Garcia-Carbonero等(Clin.Cancer Res.，2002年3月，8：641-661)；和Pizzolato JF与Saltz LB(The camptothecins，Lancet 2003 361：2235-2242)的文章中有喜树碱作为抗癌剂的用途的综述。喜树碱具有抗肿瘤活性，这是根据喜树碱能结合并抑制拓扑异构酶I，所述拓扑异构酶I是在DNA复制时减小扭转应力并在DNA复制中起重要作用的核酸酶。托泊替康和伊立替康是美国食品药物管理局(FDA)已批准在临床中应用的两种喜树碱。其他用于癌症治疗的喜树碱仍在开发中(Ulukan和Swaan，(Campothecins：a review of their chemotherapeutic potential.Drugs，2002，62：2039-2057)；以及Garcia-Carbonero和Supko，2002)。
在美国专利公开号2002/0071832(Fong等)第7段和第40段中公开有联合使用特定突变疱疹病毒和包括伊立替康和托泊替康在内的众多抗癌剂中的任意抗癌剂所进行的癌症治疗。在美国专利公开号2003/0068307(Yu等)第13页中公开有联合使用靶细胞特异性腺病毒载体和抗肿瘤剂(包括伊立替康或托泊替康)来治疗肿瘤的方法。另外参见Nemunaitis等(Cancer Gene Ther.(2003)10(5)：341-352；和Meck等(CancerRes.(2001)61(13)：5083-5089)的文章。美国FDA在2004年2月已经批准联合使用伊立替康和西妥昔单抗来治疗结肠直肠癌。
发明内容
本发明提供了一种治疗患有肿瘤的哺乳动物受试对象的方法，该方法包括对所述受试对象联合施用有效治疗该受试对象的量的病毒和喜树碱化合物；其中所述病毒选自新城疫病毒、麻疹病毒、水泡性口炎病毒、流感病毒、辛德毕斯病毒(Sindbis virus)、小核糖核酸病毒和粘液瘤病毒。在本发明的一个实施方式中，所述治疗进一步包括对所述受试对象联合施用有效治疗该受试对象的量的抗表皮生长因子受体的单克隆抗体以及所述病毒和喜树碱化合物。
本发明提供了病毒和/或喜树碱化合物在制造用于与所提及的其它成分联合治疗患有肿瘤的受试对象的药物中的用途；其中所述病毒选自新城疫病毒、麻疹病毒、水泡性口炎病毒、流感病毒、辛德毕斯病毒、小核糖核酸病毒和粘液瘤病毒。本发明还提供抗表皮生长因子受体的单克隆抗体在制造用于与如上所述病毒和/或喜树碱化合物联合治疗患有肿瘤的受试对象的药物中的用途。
本发明基于如下发现，即联合使用抗癌病毒和喜树碱可有效地抵抗肿瘤细胞。为了说明，如实施例所示，新城疫病毒的中等毒力株和伊立替康(喜树碱化合物)表现出了比加和水平更高的体内抗肿瘤活性。
具体实施方式
本文使用的过渡性术语(transitional term)“包含”是开放式的术语。使用该术语的权利要求除了在该权利要求中所列举的要素外还可以包含更多的要素。因此，例如，权利要求只要存在所列举的要素或与该要素相当的要素，则可以理解为该权利要求还包括其中未具体提出的其他治疗剂或治疗性病毒的治疗方案。
本文使用的“NDV”是新城疫病毒的缩写。本文使用的“DLT”是剂量限制性毒性的缩写。本文使用的术语“蚀斑形成单位”(PFU)意指一个传染性病毒颗粒。本文使用的“BPFU”意指十亿PFU。本文使用的“PP”意指“噬斑纯化的”。因此，例如PPMK107意指噬斑纯化的新城疫病毒株MK107。本文使用的“PFU/m2”是表示剂量的标准单位，意指每平方米患者表面积的PFU。本文使用的术语“具有复制能力的”病毒是指在癌细胞中能产生传染性子代的病毒。
在本发明的一个实施方式中，病毒具有复制能力。
根据本发明，当病毒是新城疫病毒时，它可以具有低毒性(弱毒力)、中等毒性(中等毒力)、高毒性(强毒力)。毒性水平依照鸡胚平均死亡时间(MDT)试验来测定(Alexander，“第27章：Newcastle Disease”，LaboratoryManual for the Isolation and Identification of Avian Pathogens，第3版，Purchase等编(Kendall/Hunt，Iowa)，第117页)。病毒根据MDT试验分为弱毒力(MDT＞90小时)；中等毒力(MDT在60～90小时)；和强毒力(MDT＜60小时)。目前优选中等毒力的NDV。
根据本发明，可以采用对受试对象施用病毒的任意常规途径或技术。例如，WO 00/62735中所提及的施用途径。在本发明的一个实施方式中，病毒通过全身性施用，例如通过静脉内施用。根据本发明，在通过静脉内施用治疗性病毒时，所述病毒优选为新城疫病毒的中等毒力株。在本发明的一个优选实施方式中，通过静脉内对人类受试对象施用12×109PFU/m2～120×109PFU/m2每剂量，更优选12×109PFU/m2～48×109PFU每剂量的新城疫病毒的中等毒力株。本文使用的“mg/m2”意指每平方米患者表面积的毫克数。
在本发明的一个实施方式中，小核糖核酸病毒是脊髓灰质炎病毒、埃可病毒或柯萨奇病毒。根据本发明，适宜的柯萨奇病毒的例子包括如下类型：A21、A13、A15和A18。适宜的埃可病毒包括1型埃可病毒。
本文使用的术语“喜树碱化合物”意指被认为是喜树碱、喜树碱类似物、喜树碱衍生物或喜树碱轭合物的一类化合物。这些化合物基于喜树碱的特征性五环骨架：
根据本发明，可以使用任意的喜树碱化合物。喜树碱化合物的例子包括伊立替康(CAMPTOSAR，7-乙基-10-[4-(1-哌啶子基)-1-哌啶子基]-羰基氧喜树碱)、托泊替康(HYCAMPTIN，(S)-9-N，N-二甲基氨乙基-10-羟基喜树碱)、9-氨基喜树碱(9-氨基-20(s)-喜树碱)、9-硝基喜树碱(又称为卢比替康)、勒托替康(7-(4-甲基哌嗪基亚甲基)-10，11-亚乙二氧基-20(S)-喜树碱)、依沙替康、卡仑尼替星(karenitecin)和高喜树碱。一些喜树碱化合物的结构和临床信息可在Garcia-Carbonero等(Clin.Cancer Res.，2002年3月，8：641-661)的文章中找到。喜树碱化合物的例子也可在美国专利4,604,463、6,403,569和5,004,758，以及WO 2004/012661、WO2003/101998、WO 2003/101996、WO 2003/101406、WO 2003/093274、WO 2003/086471、WO 01/76597、WO 01/64194、WO 00/70275、WO00/53607、WO 99/17805、WO 99/17804、WO 99/05103、WO 98/35969、WO 97/28164、WO 97/25332、WO 97/16454中找到，其所有内容均在此处引入作为参考。
根据本发明的联合疗法，喜树碱化合物可在施用所述病毒前一个月直至施用所述病毒后一个月施用。在更为具体的实施方式中，所述喜树碱化合物和病毒可在单个24小时的时段施用于所述受试对象；或者所述喜树碱化合物在施用所述病毒前24小时至一个月，优选24小时至一周施用；或者所述喜树碱化合物在施用所述病毒后24小时至一个月，优选24小时至一周施用于所述受试对象。喜树碱和抗癌病毒的剂量、施用技术和方案在本领域内是已知的(参见例如Garcia-Carbonero等；WO00/62735；WO 2004/000209；Pecora等，J.Clin.Oncol.(2002)20(9)：2251-2266)，并且喜树碱和抗癌病毒对特定患者的优化处于有经验的临床医师的能力范围内。伊立替康通常施用于病人的剂量为62.5mg/m2至125mg/m2，每周4次，更优选为80mg/m2至125mg/m2，每周4次；或300mg/m2至350mg/m2，每3周一次，或更优选为300mg/m2至350mg/m2，每3周一次。
根据本发明，可以使用抗表皮生长因子受体的任何抗体。优选嵌合的和人源化的单克隆抗体。适宜的抗EGF抗体的例子包括西妥昔单抗(商品名：ERBITUX)、ABX-EGF、MDX-447、h-R3和EMD-7200(参见Mendelsohn J和Baselga J，“Status of epidermal growth factor receptorantagonists in the biology and treatment of cancer”，2004J Clin Oncol 21：2787-2799)。西妥昔单抗优选通过静脉内对病人施用，并通常以200mg/m2至400mg/m2进行初始静脉输注，之后大约每周以125mg/m2至250mg/m2进行随后的输注。
根据本发明进行治疗的受试对象可以是人类受试对象或非人类的哺乳动物受试对象。根据本发明，任何肿瘤均可治疗，所述肿瘤包括但不限于如下肿瘤：直肠癌、骨盆癌、结肠癌、肺癌、乳腺癌、前列腺癌、恶性胶质瘤、肾癌、胰腺癌、头颈癌、子宫内膜癌、成神经细胞瘤、类癌、黑素瘤、卵巢癌、肉瘤、食管胃连接癌、胃癌、食管癌、肝癌和子宫颈癌。
虽然对所述治疗的监测不是本发明的必需方面，但也有测定治疗的疗效的技术。这些技术包括：测量施用病毒后肿瘤的尺寸，并将肿瘤尺寸的减小作为阳性结果。
参考如下实施例将可以更好地理解本发明，所述实施例说明但不限制本文所描述的发明。在如下实施例1至6中，NDV是经三重噬斑纯化的MK107，该MK107是一种减毒(中等毒力)型的新城疫病毒，该病毒在2000年10月26日公开的国际专利公开号WO 00/62735(Pro-Virus，Inc.)中有更详细的描述。此处引入WO 00/62735的全部内容作为参考。
实施例
实施例1.NDV和伊立替康的联合
对无胸腺小鼠皮下注射一千万个人类HT1080纤维肉瘤细胞。5天后，当皮下肿瘤的大小约为100mm3时，通过腹膜内对动物组施用伊立替康(25mg/kg)或载体进行治疗。两天后，通过静脉内对动物施用NDV(6×106蚀斑形成单位，PFU)或载体进行治疗。接受伊立替康和NDV的组的肿瘤完全消退(CR，100％肿瘤减小)的发生率(60％)远比单独施用伊立替康(30％)或NDV(0％)的高；参见表1。
表1.在NDV治疗前两天使用伊立替康治疗荷肿瘤小鼠较单独使用任一种试剂产生更高的完全肿瘤反应。
| 治疗 | 小鼠数目 | CR，％ |
| 伊立替康 | 10 | 30％ |
| NDV | 10 | 0％ |
| 伊立替康和NDV | 10 | 60％ |
| 载体对照 | 10 | 0％ |
实施例2.NDV和伊立替康的联合
对无胸腺小鼠皮下注射一千万个人类HT1080纤维肉瘤细胞。7天后，当皮下肿瘤的大小约为125mm3时，通过腹膜内对动物组施用伊立替康(25mg/kg)或载体进行治疗，随后在约一小时后，通过静脉内对所述动物组施用NDV(6×106蚀斑形成单位，PFU)或载体进行治疗。接受伊立替康和NDV的组的肿瘤完全消退(CR，100％肿瘤减小)的发生率(90％)远比单独施用伊立替康(50％)或NDV(0％)的高；参见表2。
表2.在NDV治疗的同一天使用伊立替康治疗荷肿瘤小鼠较单独使用任一种试剂产生更高的完全肿瘤反应。
| 治疗 | 小鼠数目 | CR，％ |
| 伊立替康 | 10 | 50％ |
| NDV | 10 | 0％ |
| 伊立替康和NDV | 10 | 90％ |
| 载体对照 | 10 | 0％ |
实施例3.NDV和伊立替康的联合
对无胸腺小鼠皮下注射一千万个人类HT1080纤维肉瘤细胞。7天后，当皮下肿瘤的大小约为387mm3时，通过静脉内对动物组施用NDV(6×106蚀斑形成单位，PFU)或载体。两天后，接着通过腹膜内对所述小鼠施用伊立替康(25mg/kg)或载体进行治疗。接受伊立替康和NDV的组的肿瘤完全退化(CR，100％肿瘤减小)的发生率(70％)远比单独施用伊立替康(10％)或NDV(0％)的高；参见表3。
表3.在NDV治疗后两天使用伊立替康治疗荷肿瘤小鼠较单独使用任一种试剂产生更高的完全肿瘤反应
| 治疗 | 小鼠数目 | CR，％ |
| 伊立替康 | 10 | 10％ |
| NDV | 10 | 0％ |
| 伊立替康和NDV | 10 | 70％ |
| 载体对照 | 10 | 0％ |
实施例4.NDV和每周施用伊立替康的联合
癌症患者在使用NDV治疗后，使用伊立替康进行治疗。在6周周期的每个3周部分，NDV治疗包括共6次的静脉内治疗(2周，每周3次)，随后为一周的休息期(参见下表4)。每个周期的第一剂量包括120亿PFU/m2至240亿PFU/m2(对于第一过程，施用了3小时，对于所有其他过程，施用了1小时)，随后是240亿PFU/m2至480亿PFU/m2(每剂量施用了1小时)的另外剂量。在第1周期的第3周或第4周开始以周为基础连续施用4周的伊立替康，随后两周不进行伊立替康治疗(作为例子，参见下表4)。对患者施用另外6周过程(也称为周期)的NDV和伊立替康。
表4.NDV和采用4周每周施用伊立替康(80mg/m2至125mg/m2)的联合治疗。治疗周期按每6周进行重复。
| 周期 | 周 | NDV？ | 伊立替康？ |
| 1 | 1 | 两周，3剂量/周；随后停止一周 | 否 |
| 2 | 否 | ||
| 3 | 是，一剂量施用90分钟 | ||
| 4 | 两周，3剂量/周；随后停止一周 | 是，一剂量施用90分钟 | |
| 5 | 是，一剂量施用90分钟 | ||
| 6 | 是，一剂量施用90分钟 | ||
| 2 | 1 | 两周，3剂量/周；随后停止一周 | 否 |
| 2 | 否 | ||
| 3 | 是，一剂量施用90分钟 | ||
| 4 | 两周，3剂量/周；随后停止一周 | 是，一剂量施用90分钟 | |
| 5 | 是，一剂量施用90分钟 | ||
| 6 | 是，一剂量施用90分钟 |
实施例5.NDV和每3周施用一次伊立替康的联合
癌症患者在使用NDV治疗后使用伊立替康进行治疗。NDV治疗包括共6次的静脉内治疗(两周，每周3次)，随后为一周休息期(参见下表5)。6次静脉内治疗的第一剂量包括120亿PFU/m2至240亿PFU/m2(对于第一过程，施用了3小时，对于所有其他过程，施用了1小时)，随后是240亿PFU/m2至480亿PFU/m2的另外剂量(每剂量施用了1小时)。患者在第3周开始他们的伊立替康疗法，并每3周施用一个剂量(参见下表5)。在另外3周过程对所述患者施用NDV和伊立替康。
表5.NDV和采用每3周施用一次伊立替康的联合治疗。治疗周期按每3周进行重复。
| 周期 | 周 | NDV？ | 伊立替康？ |
| 1 | 1 | 两周，3剂量/周；随后停止一周 | 否 |
| 2 | 否 | ||
| 3 | 是，以300mg/m2至350mg/m2的一个剂量进行30分钟的静脉内输注 | ||
| 2 | 4 | 两周，3剂量/周；随后停止一周 | 否 |
| 5 | 否 | ||
| 6 | 是，以300mg/m2至350mg/m2的一个剂量进行30分钟的静脉内输注 |
实施例6.NDV与伊立替康和西妥昔单抗的联合
按实施例4和5中所述对癌症患者使用NDV和伊立替康进行治疗，不同之处在于他们另外还接受西妥昔单抗[ERBITUX，一种抗表皮生长因子受体(EGFR)的单克隆抗体(mAb)]治疗。西妥昔单抗的用药开始于第3周或第4周。对于首次静脉内(IV)输注，西妥昔单抗的剂量为200mg/m2至400mg/m2[以120分钟的静脉内输注施用(最大输注速率为5mL/min)]，随后每周以125mg/m2至250mg/m2施用[静脉内输注60分钟]。某些患者还可接受初始测试剂量为20mg的西妥昔单抗。施用通常有助于缓解西妥昔单抗引起的任何输注反应的苯海拉明(50mg IV)。
Claims (20)
1.一种治疗患有肿瘤的哺乳动物受试对象的方法，该方法包括对所述受试对象联合施用有效治疗该受试对象的量的病毒和喜树碱化合物；其中所述病毒选自新城疫病毒、麻疹病毒、水泡性口炎病毒、流感病毒、辛德毕斯病毒、小核糖核酸病毒和粘液瘤病毒。
2.如权利要求1所述的方法，该方法进一步包括对所述受试对象联合施用有效治疗该受试对象的量的抗表皮生长因子受体的单克隆抗体以及所述病毒和喜树碱化合物。
3.病毒在制造用于与喜树碱化合物联合治疗患有肿瘤的受试对象的药物中的用途；其中所述病毒选自新城疫病毒、麻疹病毒、水泡性口炎病毒、流感病毒、辛德毕斯病毒、小核糖核酸病毒和粘液瘤病毒。
4.喜树碱化合物在制造用于与病毒联合治疗患有肿瘤的受试对象的药物中的用途；其中所述病毒选自新城疫病毒、麻疹病毒、水泡性口炎病毒、流感病毒、辛德毕斯病毒、小核糖核酸病毒和粘液瘤病毒。
5.抗表皮生长因子受体的单克隆抗体在制造用于与病毒和喜树碱化合物联合治疗患有肿瘤的受试对象的药物中的用途；其中所述病毒选自新城疫病毒、麻疹病毒、水泡性口炎病毒、流感病毒、辛德毕斯病毒、小核糖核酸病毒和粘液瘤病毒。
6.如权利要求1～5中任一项所述的方法或用途，其中所述病毒具有复制能力。
7.如权利要求1～5中任一项所述的方法或用途，其中所述病毒是新城疫病毒。
8.如权利要求7所述的方法或用途，其中所述病毒是新城疫病毒的中等毒力株。
9.如权利要求1～5中任一项所述的方法或用途，其中所述病毒是选自脊髓灰质炎病毒、埃可病毒和柯萨奇病毒的小核糖核酸病毒。
10.如权利要求9所述的方法或用途，其中所述病毒是选自类型A21、A13、A15和A18的柯萨奇病毒。
11.如权利要求9所述的方法或用途，其中所述病毒是1型埃可病毒。
12.如权利要求1～5中任一项所述的方法或用途，其中所述病毒通过静脉内施用。
13.如权利要求1～5中任一项所述的方法或用途，其中所述喜树碱化合物选自伊立替康、托泊替康、9-氨基喜树碱、依沙替康、卡仑尼替星、卢比替康、勒托替康和高喜树碱。
14.如权利要求13所述的方法或用途，其中所述喜树碱化合物是伊立替康。
15.如权利要求1～5中任一项所述的方法或用途，其中所述喜树碱化合物和病毒在单个24小时的时段施用于所述受试对象。
16.如权利要求1～5中任一项所述的方法或用途，其中所述喜树碱化合物在施用所述病毒前24小时至一个月施用。
17.如权利要求16所述的方法或用途，其中所述喜树碱化合物在施用所述病毒前24小时至一周施用。
18.如权利要求1～5中任一项所述的方法或用途，其中所述喜树碱化合物在施用所述病毒后24小时至一个月施用于所述受试对象。
19.如权利要求18所述的方法或用途，其中所述喜树碱化合物在施用所述病毒后24小时至一周施用于所述受试对象。
20.如权利要求2或5所述的方法或用途，其中所述单克隆抗体是西妥昔单抗。
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| CN107669707A (zh) * | 2017-11-16 | 2018-02-09 | 邹罡 | 埃可病毒作为溶瘤病毒在抗肿瘤中的应用 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107669707A (zh) * | 2017-11-16 | 2018-02-09 | 邹罡 | 埃可病毒作为溶瘤病毒在抗肿瘤中的应用 |
Also Published As
| Publication number | Publication date |
|---|---|
| US20140065140A1 (en) | 2014-03-06 |
| CN1946421B (zh) | 2013-07-17 |
| IL178492A (en) | 2010-06-30 |
| CA2562904A1 (en) | 2005-12-01 |
| WO2005113018A3 (en) | 2006-03-02 |
| JP2007534761A (ja) | 2007-11-29 |
| EP1744780B1 (en) | 2013-08-07 |
| ZA200608119B (en) | 2008-05-28 |
| US20160303175A1 (en) | 2016-10-20 |
| JP5170741B2 (ja) | 2013-03-27 |
| RU2006141654A (ru) | 2008-06-27 |
| AU2005244768A1 (en) | 2005-12-01 |
| EP1744780A2 (en) | 2007-01-24 |
| RU2408387C2 (ru) | 2011-01-10 |
| NZ550430A (en) | 2009-06-26 |
| AU2005244768B2 (en) | 2011-06-09 |
| JP2013047276A (ja) | 2013-03-07 |
| HK1096583A1 (en) | 2007-06-08 |
| IL178492A0 (en) | 2007-02-11 |
| KR20070008710A (ko) | 2007-01-17 |
| EP1744780A4 (en) | 2009-08-05 |
| US9844574B2 (en) | 2017-12-19 |
| US20070207149A1 (en) | 2007-09-06 |
| WO2005113018A2 (en) | 2005-12-01 |
| RU2010138887A (ru) | 2012-03-27 |
| MXPA06012145A (es) | 2007-01-31 |
| CA2562904C (en) | 2013-07-02 |
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