CN100490820C - 单独包含去纤苷酸或与其它抗肿瘤剂联合的抗肿瘤制剂 - Google Patents

单独包含去纤苷酸或与其它抗肿瘤剂联合的抗肿瘤制剂 Download PDF

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CN100490820C
CN100490820C CNB2004800253315A CN200480025331A CN100490820C CN 100490820 C CN100490820 C CN 100490820C CN B2004800253315 A CNB2004800253315 A CN B2004800253315A CN 200480025331 A CN200480025331 A CN 200480025331A CN 100490820 C CN100490820 C CN 100490820C
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L·I·费罗
M·亚科贝利
P·里查森
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Abstract

本发明描述了去纤苷酸单独或与其它具有抗肿瘤作用的活性成分联合作为抗肿瘤剂的用途。

Description

单独包含去纤苷酸或与其它抗肿瘤剂联合的抗肿瘤制剂
技术领域
本发明的主题是通过向哺乳动物给药有效量的去纤苷酸来治疗受肿瘤侵袭的哺乳动物的方法。
发明背景
术语去纤苷酸(以下称为DF)通常是指通过从动物和/或植物组织提取获得的多聚脱氧核糖核苷酸(1，2)；所述多聚脱氧核糖核苷酸常用形式是一种碱金属盐、通常是钠盐，并且通常分子量是45-50kDa(CAS注册号：83712-60-1)。
使用DF主要是由于它的抗血栓形成活性(3)，尽管它可用于其它应用，例如，治疗急性肾功能不全(4)以及治疗急性心肌局部缺血(5)。DF还用于治疗临床紧急情况，例如，抑制与高剂量化学疗法有关的毒性，特别是肝静脉闭塞综合症(10，11)；已证明DF对氟达拉滨引起的细胞凋亡以及对内皮和上皮细胞的异常激活(alloactivation)具有保护作用，还不改变氟达拉滨的抗白血病效果(12)；也存在着关于DF保护效应的预临床数据，这是在由脂多糖介导的内皮损伤模型中获得的(13)。
在美国专利(6，7)中叙述了生产DF的方法，可以生产的产品具有均一的和明确的物理/化学特征并且还没有可能的不期望的副作用。
发明内容
在下面的研究中，在小鼠EMT-6乳腺癌细胞模型和牛内皮细胞中、在细胞培养物以及使用接受高剂量化疗携带肿瘤的大鼠的实验模型中，检测了DF与抑制生长的细胞毒剂的联合。
在鼠EMT-6乳腺癌细胞与4-氢过氧化环-磷酰胺(4HC)一起培养接触之前和期间、或在培养接触期间和之后，接触50μg/ml浓度的DF都相当地增大了4HC的细胞毒性，以致浓度在50和250μmol之间的4HC对肿瘤细胞的杀死提高2个对数单位的程度(见图1)。接触浓度50μg/ml的DF还导致增大三胺硫磷的细胞毒性，其中依据接触方法不同而存在明显差异。具体地，在与三胺硫磷接触之前和期间使EMT-6细胞接触DF，则浓度在100和250μmol之间的三胺硫磷对肿瘤细胞的细胞毒性增大2个对数单位。出现的一个有意义的数据是在与三胺硫磷接触期间和之后使EMT-6接触DF，导致细胞毒性增大，尽管程度较小，显示出增加的三胺硫磷细胞毒性在0.5和1对数单位之间。类似的结果在卡铂中观察到；然而，在与苯丙氨酸氮芥接触之前和期间、或接触期间和之后接触DF对于苯丙氨酸氮芥对培养的鼠EMT-6乳腺癌细胞的细胞毒性没有表现出任何明显的作用。
另一方面，尽管证明单独的这些抑制生长的烷化剂(AA)对培养的牛内皮细胞的细胞毒性与在EMT-6乳腺癌细胞中观察到的类似，但此类细胞培养模型在与AA和50μg/ml浓度的DF联合接触时显示细胞毒性没有增加。
在使用携带乳腺癌13762的大鼠的实验模型中，在体内测试了单独或与DF联合的肝毒素野百合碱和AA卡氮芥(BCNU)。在此实验模型中，当动物与这些试剂连同DF一起接触时，它们没有表现出附加的毒性，但是观察到显著的肿瘤生长延迟(TGD)(见表1以及图2a和2b)。
表1.在单独使用野百合碱或BCNU或与去纤苷酸(DF)联合治疗后，携带乳腺癌13762的大鼠中的肿瘤生长延迟。在第0天植入肿瘤，并在第8和18天进行化疗。
 
治疗组 达到500mm<sup>3</sup>的天数 TGD(天数) P值
对照 14.6+0.8 - -
野百合碱(350mg/kg)腹腔注射第8和18天                  15.6±1.0 1.0 0.435
DF(200mg/kg)静脉注射每天2次，第8-26天+野百合碱 16.1+0.6 1.5 0.134
DF(200mg/kg)静脉注射每天2次，第10-26天+野百合碱 18.2±1.5 3.6 0.034
BCNU(150mg/kg)腹腔注射第8和18天              18.0±2.5 3.4 0.195
DF(200mg/kg)静脉注射每天2次，第10-26天+BCNU 19.7±1.5 5.1 0.003
DF(200mg/kg)静脉注射每天2次，第10-26天+BCNU 21.3±1.6 6.7 0.0002
业已在同样的实验模型中单独使用野百合碱、BCNU以及环磷酰胺(CTX)或与DF联合重复了这些研究。与对照相比，单独使用DF观察到显著的肿瘤生长延迟(TGD) (p<0.05)；当DF与CTX和BCNU联合使用时，这种延迟特别显著(p<0.04)，并明显地大于分别使用每一试剂所获得的结果。出乎意外的是，当单独使用DF时，起初它延迟肿瘤的生长，但是随后肿瘤的生长又变为正常。而且，当DF与AA联合使用时，一终止DF的共同给药，肿瘤的继续生长就变快。这个数据不仅表明了DF的附加抗肿瘤作用而且表明了DF自身直接的抑制生长活性。
无论是否与卡铂联合，与单独的细胞毒疗法相比，当紫杉醇治疗加入DF时，在携带Lewis肺癌的小鼠中还观察到肿瘤生长(TGD)和肺转移量的下降，但是没有显示毒性明显增加(数据未列出)。这些作用潜在的机理有待于解释，但是考虑到细胞粘附在与药物抗性相关的机理中的作用，可能涉及DF的抗粘附特性(8，9)。
还测试了在人多发性骨髓瘤(MM)鼠模型中DF是否具有体内活性。对60只雄性SCID/NOD小鼠(6-8周龄)进行辐照(450拉德)并在24小时后皮下注射5×106MM-1S人MM细胞。一旦形成可触知的肿瘤，即随机地将小鼠分成6个群组(每群组10只小鼠)，每群组接受a)载体；b)DF(静脉注射450mg/kg，每天两次)；c)苯丙氨酸氮芥(MEL)2.5mg/kg，腹腔注射，每周一次；d)环磷酰胺(CTX)50mg/kg，腹腔注射，在第8、10、12、20、22和24天；e)和f)DF(300mg/kg，静脉注射)分别与MEL或CTX联合。q3天监测小鼠体重、潜在毒性、以及基于电子卡尺的肿瘤体积。
在所有组中，DF作为单剂或与MEL或CTX联合，都被很好地耐受而没有出血并发症或体重下降(P>0.05)。主要的终点效应是a)肿瘤体积的变化和b)总体存活(当肿瘤直径>2厘米予以处死时的时间)。DF治疗导致肿瘤体积与对照小鼠相比显著更低(通过方差分析和事后检验，所有比较P<0.05)；DF与MEL或CTX联合诱导的肿瘤体积与各相应的单剂细胞毒化疗相比显著更低(所有比较P<0.05)。
Kaplan-Meier存活分析显示DF作为单剂或与细胞毒化疗(MEL或CTX)联合给药，分别地与载体处理对照组或MEL或CTX处理组比较，与总体存活有统计学意义的延长相关(所有比较P<0.001，log-rank检验)。有趣地是，体外研究没有显示出DF针对MM细胞的显著直接的体外细胞毒效果，这提示所观察到的体内活性可能是由于它对MM细胞与其局部微环境相互作用的影响。
这些可喜的结果证明DF在这种MM化疗模型中并不赋予肿瘤保护作用，并构成了首要的证据材料，即DF不但具有针对MM的体内抗肿瘤活性，而且增强细胞毒治疗的应答。这个研究提示DF的抗-MM活性可能是由于它对MM细胞与其微环境之间相互作用的影响，并提供了未来DF与其它试剂联合治疗MM和其它瘤形成的临床试验的框架。
由此本发明的一个目标是一种通过给药有效量的DF治疗受肿瘤侵袭的哺乳动物优选人的方法。DF可以与至少另外一种具有抗肿瘤作用的活性成分联合给药。所述其它具有抗肿瘤作用的活性成分可以选自紫杉醇、野百合碱、BCNU、苯丙氨酸氮芥和/或环磷酰胺。
本发明另外的目标是表述为包含DF和至少一种其它具有抗肿瘤作用的活性成分的制剂；所述制剂优选是水溶液的形式，并且甚至更优选适合静脉给药，而且可以包含本领域公知的赋形剂和共佐剂。
为实现本发明的目的，术语去纤苷酸(DF)因而应理解为任何从动物和/或植物组织特别是哺乳动物器官提取产生的寡核苷酸和/或多核苷酸。优选地，DF将依照本文并入作为参考的美国专利(6，7)中所述的方法生产。
参考书目：
1、US-3,770,720
2、US-3,899,481
3、US-3,829,567
4、US-4,694,134
5、US-4,693,995
6、US-4,985,552
7、US-5,223,609
8、Carlo-Stella，C.，Di Nicola，M.，Magni M.等人，去纤苷酸与粒细胞集落刺激因子联合显著增强小鼠原代和定向外周血祖细胞的募集。《癌症研究》(Cancer Research)，2002，62：6152-6157(2002年11月1日)。
9、Hazlehurst，L.，Damiano，J.，Buyuksal，I.，Pledger，W.J.，Dalton，W.S.，介由b1整联蛋白的纤粘连蛋白的粘附调节p27kip1水平并促成了细胞粘附介导的药物抗性(CAM-DR)。《致癌基因》(Oncogene)，2000；19：4319-4327。
10、Richardson，P.G.，Elias，A.D.，Krishnan，A.等人，用去纤苷酸治疗重症静脉闭塞病：在高危人群中知情使用产生没有显著毒性的反应。《血液》(Blood)，1998；92：737-44。
11、Richardson，P.，Murakami，C.，Jin，Z.等人，在88名患有重症静脉闭塞病和多系统器官衰竭的患者中经干细胞移植后多机构使用去纤苷酸：在高危人群中没有显著毒性的反应以及可预测结果的因素。《血液》(Blood)，2002；100(13)：4337-4343。
12、Eissner，G.，Multhoff，G.，Gerbitz，A.等人，氟达拉滨在人内皮和上皮细胞中诱导细胞凋亡、激活和异体抗原性：去纤苷酸的保护效应。《血液》(Blood)，2002；100：334-340。
13、Falanga，A.，Vignoli，A.，Marchetti，M.，Barbui，T.，去纤苷酸降低促凝血活性并提高内皮细胞纤维蛋白溶解特性。《白血病》(Leukemia)，2003；待刊。

Claims (6)

1、去纤苷酸在制备具有抗肿瘤作用的制剂中的用途。
2、如权利要求1所述的用途，特征在于去纤苷酸与至少一种其它具有抗肿瘤作用的活性成分联合使用。
3、如权利要求2所述的用途，特征在于所述其它具有抗肿瘤作用的活性成分选自紫杉醇、野百合碱、卡氮芥、苯丙氨酸氮芥和/或环磷酰胺。
4、如权利要求1-3中任一项所述的用途，特征在于向哺乳动物给药所述制剂。
5、如权利要求4所述的用途，特征在于所述哺乳动物为人。
6、如权利要求4所述的用途，特征在于所述哺乳动物患有乳腺癌。
CNB2004800253315A 2003-09-05 2004-08-27 单独包含去纤苷酸或与其它抗肿瘤剂联合的抗肿瘤制剂 Expired - Fee Related CN100490820C (zh)

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