CN101068564B - 含有vegf抑制剂与5fu或其中一种衍生物的抗肿瘤组合物 - Google Patents
含有vegf抑制剂与5fu或其中一种衍生物的抗肿瘤组合物 Download PDFInfo
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Abstract
本发明涉及由VEGF抑制剂与5-氟尿嘧啶或5-氟嘧啶并用组成的抗肿瘤组合物，它们在治疗上用于治疗肿瘤疾病。
Description
本发明涉及VEGF抑制剂和5氟尿嘧啶或5氟嘧啶类化学毒性(chimiotoxique)试剂的组合物，它们用于治疗瘤(néoplastiques)疾病。
VEGF抑制剂是内皮血管生长因子抑制剂，它们在大多数情况下是选自可溶受体、反义、RNA核酸适体(aptameère)和抗体的生物产品。5氟嘧啶衍生物选自5-氟尿嘧啶、希罗达(capecitabine)或健择(gemcitabine)，它们具有明显的抗肿瘤和抗白血病性质，它们特别用于治疗卵巢、乳房、肺或结肠癌。本发明组合物的目的具体地是治疗结肠或胃癌。
专利申请WOOO/75319描述了本发明优选使用的VEGF抑制剂的制备方法，该抑制剂是嵌合体蛋白质。这种嵌合体蛋白质有多种实施方式。相应于VEGF-Trap的实施方式是图24(序列)描述的方式。本发明使用的VEGF Trap是融合蛋白质，它包括与VEGFRl受体域Ig D2融合的VEGFRl信号序列，它本身与VEGFR2受体域Ig D3融合，而域IgD3依次与IgGl的域融合，也称之VEGFRl R2-FcΔCI或Flt1D2.Flk1D3.FcΔCl。
一般而言，使用的剂量取决于待治疗病人的固有因素，这些剂量是皮下给药为每千克20-800微克，静脉内为每千克2-20微克或任选地鼻内给药为每千克约0.01皮克以下至1mg。
5氟尿嘧啶一般通过静脉途径给药，其剂量是每星期500mg/m2至5000mg/m2，涉及5-氟嘧啶衍生物，例如希罗达时，它们通常通过口服途径给药，其剂量是500-3000mg/m2，一般是每天分两个剂量给药。健择一般通过静脉内途径给药，其剂量是每星期500-2000mg/m2。
H Hurwitz，L Fehrenbacher，W Novotny，T Cartwright，JHainsworth，W Heim，J Berlin，A Baron，S Griffmg，E Holmgren，N Ferrara，G Fyfe，B Rogers，R Ross，F Kabbinavar发表在《新英格兰医学杂志》(The New England Journal of Médecine)的文章中已描述临床试验，该试验证明了使用阿瓦斯丁(bevacizumab)与伊立替康，5FU和亚叶酸组合物与不含有阿瓦斯丁的同样组合物相比存活率更好。在这个临床试验中没有任何东西证明存活率的提高源于5FU与阿瓦斯丁的组合，这种组合还可能令人满意地源于伊立替康或亚叶酸与阿瓦斯丁的组合或可能源于四重组合。然而如人们所知，每种抗癌剂连同其治疗效果一起带来毒副作用，最大限度地限制它们的存在似乎合适，没有它们中的至少一种也可以达到同样效果时尤其如此。在现在的情况下，人们知道伊立替康引起严重的腹泻，其腹泻有时会导致停止治疗。另一方面，这篇文章没有证明在Corbett意义上的任何协同作用，即该组合物的每个元素单独以最大容许剂量都不可能达到的效果。
现在已发现，正是构成本发明的主题，与至少一种在这些抗癌治疗中治疗使用的、与VEGF抑制剂不同作用机制的物质并用时，可以显著地提高VEGF抑制剂的功效。
另外，由于这些产品活性取决于使用剂量，可能的是使用更高的剂量，而通过与VEGF抑制剂并用，或与生血类生长因子的其它治疗活性物质的类似物，例如G-CSF或GM-CSF或某些白细胞介素并用，降低这些毒性现象或延迟这些现象出现，也可能提高其活性。
更特别地，本发明涉及VEGF Trap与5氟尿嘧啶或其衍生物，例如希罗达或健择并用。本发明还涉及这些组合物，其中还包含一般与5-FU并用的亚叶酸。
通过确定治疗的协同作用可以证明本发明组合物改进的功效。
如果在治疗上优于以其最佳剂量使用的一种或另一种组分，则该组合物表明有治疗协同作用[T.H.CORBETT等人，《癌治疗报告》(Cancer Treatment Reports)，66，1187(1982)]。
为了证明一种组合物的功效，可能需要将该组合物的最大耐受剂量与在涉及的研究中所分离每种组分的最大耐受剂量进行比较。例如利用根据下式确定的log10杀死细胞可以对这种功效进行定量：
Log10杀死细胞＝T-C(天)/3.32×Td
式中T-C表示治疗组肿瘤(T)和对照组肿瘤(C)达到预定值(例如1g)时细胞生长延缓时间，它是以天表示的平均时间，而Td表示在这些对照动物体内这种肿瘤体积加倍所需要的以天表示的时间[T.H.CORBETT及其同事，《癌》(Cancer)，40，2660-2680(1977)；F.M.SCHABEL及其同事，《癌药物进展》(Cancer Drug Development)，B部，癌研究方法，17，3-51，New-York，Académie Press Inc.(1979)]。如果log10杀死细胞大于或等于0.7，则可以认为该产品是活性的。如果log10杀死细胞大于2.8，则可以认为该产品是非常活性的。
log10杀死细胞值高于最佳组分单独给药时的log10杀死细胞值的情况下，以固有的最大耐受剂量使用的组合物，其中每种组分的剂量一般低于或等于其最大耐受剂量，显示出其治疗的协同作用。
可以下述方式由实验可以确定这些组合物对固体肿瘤的功效。
在第0天，让这些受试动物(一般是老鼠)在两侧皮下移植30-60mgMC13/C哺乳动物肿瘤片段。在进行各种治疗与对照处理之前，这些有肿瘤的动物随机抽样。在处理早熟肿瘤的情况下，让这些肿瘤发展直到所希望的大小，除去肿瘤还未充分发展的动物。这些选择动物随机分配进行治疗和对照处理。没有肿瘤的动物也可以进行与有肿瘤的动物同样的处理，以便能够将对肿瘤的毒性作用与固有作用分开。化学疗法一般根据肿瘤类型在移植肿瘤后第3-22天开始，每天都要观察这些动物。这些不同组动物每个星期称量三次或四次，直至达到它们的体重下降最大，然后这些组动物每个星期称量至少一次，直至试验结束。
这些肿瘤每个星期测量二次或三次直至达到约2g，或如果它的肿瘤达到2g前还存活直到动物死亡。这些动物死亡时进行尸体解剖。
测量抗肿瘤活性随记录不同参数的变化。
为了研究这些组合物对白血病的作用，往这些动物移植一定数量的细胞，并且与对照相比由治疗老鼠存活时间的增加测定抗肿瘤活性。在白血病P388的情况下，如果存活时间增加超过27％，则认为该产品是活性的，如果存活时间增加超过75％，则认为该产品是非常活性的。
作为实例，在下面这些表中给出了以其最佳剂量使用的VEGFTrap与5-氟尿嘧啶组合物所得到的结果。
本发明还涉及含有本发明组合物的药物组合物。
组成这种组合物的产品可以同时、分开或随着时间推移散开给药，以便达到该组合物的最大功效；每次给药可以有不同的时间，从完全快速给药到连续输药。
由此得出，在本发明的意义上，这些组合物不仅限于通过这些组分物理混合得到的这些组合物，而且还限于有可能分开给药的这些组合物，这种分开给药可以是同时或随着时间推移散开给药的这些组合物。
本发明的这些组合物优选地是通过胃肠外途径可给药的组合物。但是，这些组合物可以通过口服给药。
胃肠外给药的组合物一般是在药学上可接受的无菌溶液或悬液，它们可以任选地在使用时临时制备得到。为了制备非水溶液或悬液，可以使用天然植物油，例如橄榄油或芝麻油，或可注射石蜡油或有机酯，例如油酸乙酯。含水无菌溶液可以由该产品在水中的溶液组成。这些含水溶液只要适当调节pH与例如使用足够量的氯化钠或葡萄糖实现等渗性就适合于静脉内给药。可以采用加热或采用任何不改变该组合物的其它办法进行灭菌。这些组合物可以呈脂质体形式或呈与例如环式糊精或聚乙二醇的载体并用形式。
在本发明的组合物中，其组分可以是同时、分开或随着时间推移散开给药的，特别有利的是VEGF Trap衍生物的量为该组合物的2-80体积％，这个含量可以随着并用物质的性质、所追求的功效以及待治疗癌的性质而改变。
本发明的组合物特别用于治疗结肠癌和/或胃癌。特别地，它们的优点是可以使用这些组分的剂量比它们单独使用时的剂量低得多。
下面实施例说明本发明的组合物。
实施例
根据一般技术制备皮下给药的1cm3安瓿，它装有25mg稀释在磷酸盐缓冲液中的VEGF Trap。
根据一般技术，使用5cm3含有250mg用5％葡萄糖水溶液稀释的5FU商品溶液制备每只老鼠静脉内给药的0.2ml。
这些溶液在适当稀释后采用输液方式同时给药。
每天或每星期重复治疗多次，直到部分或完全好转或恢复。
BCM-1428(05/28/04-07/30/2004)：肿瘤成倍的时间＝2.8天。对照750mg的平均时间＝22.2天。治疗时间＝18天。
VEGF-trap和组合物，5-FU为15天。
采用的缩写：T/C＝在第24天肿瘤生长的抑制，(T-C)肿瘤生长延缓，lck＝log杀死细胞。
Claims (5)
1.可治疗性使用于治疗瘤疾病的含有VEGF-Trap与5-氟尿嘧啶的组合物。
2.根据权利要求1所述的组合物，其特征在于它们还含有亚叶酸。
3.根据权利要求1或2中所述的组合物，其特征在于它们含有2-80重量％的VEGF-Trap。
4.含有VEGF-Trap和5-氟尿嘧啶的产品，它作为在抗癌治疗中同时使用、分开使用或随着时间推移散开使用的联合使用制剂。
5.组合物，其含有VEGF-Trap与5-氟尿嘧啶和亚叶酸，但在治疗瘤疾病中具有治疗协同作用的任何其它化学毒性衍生物除外。
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| FR0412870 | 2004-12-03 | ||
| PCT/FR2005/003005 WO2006059012A1 (fr) | 2004-12-03 | 2005-12-02 | Combinaisons antitumorales contenant un agent inhibiteur de vegf et du 5fu ou un de ses derives |
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| JO3283B1 (ar) * | 2011-04-26 | 2018-09-16 | Sanofi Sa | تركيب يتضمن أفليبيرسيبت, حمض فولينيك, 5- فلورويوراسيل (5- Fu) وإرينوسيتان (FOLFIRI) |
| US9840553B2 (en) | 2014-06-28 | 2017-12-12 | Kodiak Sciences Inc. | Dual PDGF/VEGF antagonists |
| TR201909951T4 (tr) | 2014-07-18 | 2019-07-22 | Sanofi Sa | Kanser olduğundan şüphelenilen bir hastanın aflibersept ile tedavisinin sonucunun öngörülmesine yönelik yöntem. |
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| CN114786731A (zh) | 2019-10-10 | 2022-07-22 | 科达制药股份有限公司 | 治疗眼部病症的方法 |
| CN115197948A (zh) * | 2021-04-13 | 2022-10-18 | 江苏康缘瑞翱生物医药科技有限公司 | 一种重组新城疫病毒rNDV-VEGF-Trap、其基因组、制备方法及其用途 |
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