CN101590057A - 含有紫杉烷衍生物的抗肿瘤组合物 - Google Patents
含有紫杉烷衍生物的抗肿瘤组合物 Download PDFInfo
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Abstract
本发明涉及含有紫杉烷衍生物的抗肿瘤组合物,它含有乙酰环丙泰索帝或其衍生物,和烷化剂、抗代谢物、纺锤体毒物、表鬼臼毒素、抗生素酶、拓扑异构酶抑制剂、铂配位复合物、生物反应修饰剂或生长因子抑制剂中的至少一种。
Description
本申请为2002年3月21日提交的申请号为PCT/IB2002/000853、发明名称为“含有紫杉烷衍生物的抗肿瘤组合物”的国际申请的分案申请,该国际申请是提交于2000年11月6日的美国专利申请09/705,739号的后续部分,739号申请是提交于1999年8月10日的09/371,520号申请的分案申请,520号申请是提交于1998年10月30日的现已放弃的09/182,900号申请的后续申请,900号申请是提交于1997年11月10日的08/967,036号申请的分案申请,其现在的美国专利号为5,908,835,036号申请是提交于1995年5月9日的08/424,470号申请的分案申请,其现在的美国专利号为5,728,687。PCT/IB2002/000853号国际申请于2003年9月19日进入中国国家阶段,申请号为02806857.2。
技术领域
本发明涉及由紫杉酚、泰索帝(Taxotere)及其类似物和可有效治疗肿瘤疾病的物质构成的组合物。
背景技术
紫杉酚,泰索帝及其类似物具有令人瞩目的抗肿瘤和抗白血病特性,在治疗结肠、卵巢、乳腺或肺部的肿瘤时尤其有效。
例如,紫杉酚、泰索帝及其衍生物的制备形成了欧洲专利EP 0,253,738和EP 0,253,739以及国际申请PCT WO 92/09,589的主题。
根据待治疗的受试者的不同,所用剂量通常为,腹膜内施用为1-10mg/kg或静脉内施用为1-3mg/kg。
发明内容
现已发现,这也是本发明的主题,当将紫杉酚,泰索帝及其类似物与至少一种在抗癌治疗中有治疗效果且与这种紫杉烷衍生物有相同或不同机理的物质联合施用时其效果可大大改善。
可与紫杉酚,泰索帝或其类似物联合使用或合并使用的物质有,烷化剂如环磷酰胺、异环磷酰胺、美法仑、六甲基蜜胺、硫替派或达卡巴嗪,抗代谢物如嘧啶类似物、例如5-氟尿嘧啶和阿糖胞苷,或其类似物如2-氟脱氧胞嘧啶,或叶酸类似物如氨甲喋呤、依达曲沙(idatrexate)或三甲曲沙,纺锤体毒物包括长春花生物碱如长春花碱或长春新碱及其合成性类似物如诺维本(navelbine)或雌莫司汀或紫杉烷二萜(taxoids),表鬼臼毒素(epidophylloptoxin)如依托泊甙或替尼泊甙,抗生素如柔红霉素、阿霉素、博来霉素或丝裂霉素,酶如L-天冬酰胺酶、拓扑异构酶抑制剂如选自CPT-11和托泊替康的喜树碱衍生物或吡啶并苯并吲哚衍生物,和各种制剂如甲基苄肼、米托蒽醌、铂配位复合物如顺氯氨铂或卡铂,以及生物反应修饰剂或生长因子抑制剂如干扰素或白细胞介素。
此外,由于所述产品的活性取决于所用剂量,可以使用较高的剂量并增加活性,同时可与造血类型的生长因子如G-CSF或GM-CSF或某些白细胞介素和紫杉酚,泰索帝、它们的类似物联用或将它们与其它治疗活性物质联用,以减小毒性现象或延迟毒性发作。
本发明的这种组合或联合可延缓待避免的多效耐药性或“多种药物抗性”现象。
更具体地,本发明涉及紫杉酚,泰索帝及其类似物和长春花生物碱、环磷酰胺、5-氟尿嘧啶、阿霉素、顺氯氨铂、诺维本、喜树碱和依托泊甙的联用。
通过测定其治疗增效作用可证明本发明组合的改进效果。如果某组合在治疗上的作用优于以最佳剂量应用的某一种或其它组分,则该组合具有治疗增效作用(T.H.Corbett等,Cancer Treatment Reports,66:1187(1982))。
为证明某组合的效果,可能需要在研究时将该组合的最大耐受剂量与每种组分的最大耐受剂量进行比较。这种效果可被量化,例如,以log10杀伤细胞值表示,其用以下公式计算:
log10杀伤细胞数=T-C(天数)/3.32×Td
其中,T-C表示细胞生长所用的时间,它是治疗组(T)的肿瘤和治疗组(C)肿瘤达到预定值(例如1g)的平均天数,Td表示对照动物中肿瘤体积加倍所需的天数[T.H.Corbett等,Cancer,40,2660-2680(1977);F.M.Schabel等,Cancer Drug Development,B部分,Methods in Cancer Research,17,3-51,纽约,Academic Press公司(1979)]。如果log1杀伤死细胞值大于或等于0.7则认为该产品是有活性的。如果log10杀伤细胞值大于2.8则认为该产品活性非常强。
当log10杀伤细胞值大于最佳组分单独给药的log10杀伤细胞值时,则认为以其最大耐受剂量使用的该组合,当联用时每种组分通常以不超过其最大耐受剂量,具有治疗增效作用。
联用对实体瘤的效果可按以下方法通过实验来测定:
在第0天对用来进行此项实验的动物,通常是小鼠,皮下两侧移植30-60mg某肿瘤片段。在进行各种治疗和作为对照之前将负载肿瘤的动物混合。在治疗晚期肿瘤时,让肿瘤长到所需的大小,去除肿瘤生长不充分的动物。将所出的动物随机分成治疗组和对照组。对不负载肿瘤的动物也进行与肿瘤负载动物相同的处理,以便能将毒性作用与对肿瘤的特定作用区分开。根据肿瘤的类型通常在移植后3-22天内开始化学治疗,每天观察动物。对不同的动物组每周称重3或4次,直到获得最大体重下降,然后各组至少每周称重一次直到试验结束。
每周测量肿瘤2或3次直到肿瘤达到约2g,或直到动物死亡,如果这发生在肿瘤达到2g之前。处死动物时作尸体解剖。
根据所记录的不同参数确定抗肿瘤活性。
为研究所述组合对白血病的作用,将特定数量的细胞移植给动物,然后以治疗小鼠相对于对照小鼠存活时间的增加来测定抗肿瘤活性。就P388白血病而言,如果存活时间的增加超过27%则认为该产品有活性,如果该值大于75%则认为该产品活性很强。
用泰索帝和各种化学治疗剂,如环磷酰胺(烷化剂)、5-氟尿嘧啶(抗代谢物)、依托泊甙(半合成的鬼臼毒素制剂)和长春新碱(长春花生物碱)的组合,所述组合物以其最佳剂量使用,得到的结果作为例子给在下表中。
表1
表2
表3
表4
还用泰索帝的类似物N-脱苄基-N-t-丁氧基-羰基-7-脱氧-8-去甲基-7,8-环丙泰索帝(以后称为乙酰环丙泰索帝)和几种化学治疗剂进行了实验。乙酰环丙泰索帝的结构如下:
在负载皮下植入肿瘤的小鼠中评价了乙酰环丙泰索帝和各种化学治疗剂,如阿霉素(抗生素)、顺氯氨铂(铂配位复合物)、诺维本(纺锤体毒物)和CPT-11(拓扑异构酶抑制剂)的组合。用来评价各种药物组合物的肿瘤模型的选择,通常是根据它对单独使用的各试剂的反应性。用静脉内间歇注射的方法,对每一制剂和各种组合进行了全部剂量反应的测试。
除了上述参数,还测定了组合的毒性指数(CTI)。参见Corbett,T.H.等,Response of transplantable tumors of mice to anthracenedione derivativesalone and in combination with clinically useful agents,Cancer Treat,Rep.66:1187-1200(1982)。CTI表示最佳组合中所用的各个制剂的10%致死剂量(LD10)的分数之和。它表明了对宿主毒性的重叠程度。例如,CTI为1表明组合中只可使用各个制剂的50% LD10(或任何比例,70∶30、40∶60等)不造成额外的毒性,而CTI为2表明组合中可采用各个制剂的100% LD10。
下表总结了各种组合的治疗反应和各项研究、单一试剂和组合的最高无毒性剂量。
表:最佳剂量的环丙toxol组合物实验
所用缩写:Td=肿瘤倍增天数;bwl=体重损失;TFS=肿瘤消除的幸存者;CTI=组合毒性;IV=静脉内;PO=通过口;CR=完全反应
与阿霉素联合时,最佳组合在负载MA 13/C的小鼠中产生的log杀伤细胞值为5.3,并导致了100%的完全消退(未治愈),而单一制剂产生较低的细胞杀伤Iog,即乙酰环丙泰索帝的log杀伤细胞值为2.9,阿霉素为3.0。该组合的毒性指数为1.42,这表明可联用各个制剂的HNTD的大约70%而没有额外毒性。
联用顺氯氨铂,第122天时,最佳组合在负载结肠51的小鼠中产生的log杀伤细胞值为3.6,并有2/7的幸存者肿瘤消除,而单用一种剂剂,乙酰环丙泰索帝产生的log杀伤细胞值为1.4,顺氯氨铂的log杀伤细胞值为2.7,没有幸存者肿瘤消除。治愈的宿主中有CTI为0.68的重要重叠,这表明不到35%的各个单一制剂可联合使用。然而,当接受顺氯氨铂时小鼠没有发生水份过多,这可以解释毒性的程度。
发现乙酰环丙泰索帝和CPT-11联用至少与该组合中最好的单一制剂一样有效(此组合的log杀伤细胞wfhg为1.7,乙酰环丙泰索帝为1.5,CPT-11为1.1)。然而,CTI为0.6表明对宿主的毒性有重要重叠。
最后,在负载MA 17/A的小鼠中乙酰环丙泰索帝和诺维本之间有非常好的协同效应,该组合的log杀伤细胞值为8.1(第123天有2只幸存者肿瘤消除),乙酰环丙泰索帝为4.8,诺维本为5.5。该组合对宿主的毒性产生的重叠最小,CTI为1.42。
总之,发现所测试的四种乙酰环丙泰索帝组合都有协同作用,即该组合的抗肿瘤活性在最高无毒性剂量时大于单一制剂。
就耐受性而言,乙酰环丙泰索帝与阿霉素或诺维本的组合可较好的被耐受,其CTI约为1.4,而当环丙紫杉酚与顺氯氨铂或CPT-11联合时需要减少剂量(CTI<1)。
因此,本发明还涉及含有本发明诸种组合的药物组合物。
所述组合的诸组分可同时、半同时、分别,或隔开一段时间施用,以使该组合发挥最大效果;各种给药方式在持续时间上可以不同,以快速给药至连续输注。
结果,出于本发明的目的,所述组合并不限于诸组分的物理合而获得的组合,还包括同时或隔开一段时间分别给药的那些联合。
本发明的组合物最好是肠胃道外给药用的组合物。然而局部治疗时,这些组合物可口服或腹膜内给药。
供肠胃道外给药的组合物通常是药学上可接受的无菌溶液或悬液,它可在使用时按需要制备。为制备无水溶液或悬液,可以使用天然植物油如橄榄油、芝麻油或液态石油或可注射的有机酯类如油酸乙酯。无菌水溶液可由该产品的水溶液组成。只要大致调节pH并使溶液等渗,例如用足量的氯化钠或葡萄糖,就可使这些水溶液适合静脉内给药。可通过加热或其它不会对该组合物造成不利影响的方法进行灭菌。所述组合物还可采用脂质体形式或与环糊精或聚乙二醇等运载体结合的形式。
供口服或腹膜内施用的组合物优选为水悬液或溶液。
在本发明的组合物中,诸组分的施用可以是同时、分别或隔开一段时间进行,特别有利的是,紫杉烷衍生物的量占所述组合重量的10-90%,这一含量可根据相关底物的性质、希望达到的效果和待治疗癌症的性质而不同。
本发明的组合对于治疗结肠、乳房、卵巢或肺部癌症以及黑色素瘤和白血病特别有效。特别是,其可提供的优点是可以远低于各组分单独用量的量使用。
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FR2697752B1 (fr) * | 1992-11-10 | 1995-04-14 | Rhone Poulenc Rorer Sa | Compositions antitumorales contenant des dérivés du taxane. |
FR2698871B1 (fr) | 1992-12-09 | 1995-02-24 | Rhone Poulenc Rorer Sa | Nouveau taxoïdes, leur préparation et les compositions pharmaceutiques qui les contiennent. |
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FR2601676B1 (fr) | 1986-07-17 | 1988-09-23 | Rhone Poulenc Sante | Procede de preparation du taxol et du desacetyl-10 taxol |
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- 2002-03-21 HU HU0500478A patent/HUP0500478A2/hu unknown
- 2002-03-21 AT AT02713093T patent/ATE355837T1/de active
- 2002-03-21 JP JP2002572997A patent/JP4467885B2/ja not_active Expired - Lifetime
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- 2002-03-21 PT PT02713093T patent/PT1478355E/pt unknown
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DE60218751T2 (de) | 2007-11-22 |
EP1478355B1 (en) | 2007-03-07 |
JP4467885B2 (ja) | 2010-05-26 |
ATE355837T1 (de) | 2007-03-15 |
CN1536995A (zh) | 2004-10-13 |
DE60218751D1 (de) | 2007-04-19 |
SI1478355T1 (sl) | 2007-08-31 |
HUP0500478A2 (hu) | 2005-08-29 |
CA2440160C (en) | 2011-07-05 |
US20020031505A1 (en) | 2002-03-14 |
WO2002074289A3 (en) | 2004-09-02 |
PT1478355E (pt) | 2007-05-31 |
EA006878B1 (ru) | 2006-04-28 |
BR0208274A (pt) | 2004-07-13 |
IL157992A (en) | 2008-08-07 |
JP2004536790A (ja) | 2004-12-09 |
CY1106582T1 (el) | 2012-01-25 |
CA2440160A1 (en) | 2002-09-26 |
WO2002074289A2 (en) | 2002-09-26 |
EP1478355A2 (en) | 2004-11-24 |
EA200301047A1 (ru) | 2004-06-24 |
ES2282400T3 (es) | 2007-10-16 |
US6441026B1 (en) | 2002-08-27 |
AU2002244877B2 (en) | 2006-07-20 |
DK1478355T3 (da) | 2007-07-02 |
MXPA03008539A (es) | 2004-08-11 |
WO2002074232A2 (en) | 2002-09-26 |
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