CN102172359A - 腺苷与核苷组合在制备治疗肿瘤药物中的应用 - Google Patents

腺苷与核苷组合在制备治疗肿瘤药物中的应用 Download PDF

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CN102172359A
CN102172359A CN2011100490469A CN201110049046A CN102172359A CN 102172359 A CN102172359 A CN 102172359A CN 2011100490469 A CN2011100490469 A CN 2011100490469A CN 201110049046 A CN201110049046 A CN 201110049046A CN 102172359 A CN102172359 A CN 102172359A
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张始状
程鑫
高志芹
韩明
鞠辉军
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
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    • A61P35/02—Antineoplastic agents specific for leukemia

Abstract

本发明公开了腺苷与核苷组合在制备治疗肿瘤药物中的应用，将腺苷与核苷组合作为治疗肿瘤的药物成分使用，将腺苷与核苷按组合用药，能够低毒、抗耐药、高效的治疗不同肿瘤；本发明的优点在于：腺苷与不同的核苷组合用药比单用腺苷的血液浓度降低，毒副作用下降；腺苷与不同的核苷组合用药可延缓肿瘤耐药性的发生。

Description

腺苷与核苷组合在制备治疗肿瘤药物中的应用
技术领域
本发明涉及腺苷与核苷的应用，具体地说是腺苷与核苷组合在制备治疗肿瘤药物中的应用，属于医药领域。
背景技术
核苷(nucleoside)由碱基和五碳糖(核糖或脱氧核糖)连接而成，即嘌呤的N-9或嘧啶的N-1与核糖或脱氧核糖的C-1通过β糖苷键连接而成的化合物，包括核糖核苷和脱氧核糖核苷两类。构成RNA的核苷是核糖核苷，主要有腺苷、鸟苷、胞苷和尿苷。构成DNA的核苷是脱氧核糖核苷，主要有脱氧腺苷、脱氧鸟苷、脱氧胞苷和脱氧胸腺苷。核苷可从水解核酸来制备。用吡啶水溶液、氧化铝或酶促水解核糖核酸RNA，可得到核糖核苷；用氧化铝或酶水解脱氧核糖核酸DNA可得到脱氧核糖核苷。核苷也可用化学方法合成。适当保护的核糖或脱氧核糖与碱基衍生物缩合，可得到相应的核糖核苷和脱氧核糖核苷。
核苷主要包括鸟苷、胞苷、尿苷和胸苷。鸟嘌呤核苷简称鸟苷，化学名：9-beta-D-呋喃核苷鸟嘌，CAS号：118-00-3，分子式：C10H13N5O5，分子量：283.24；胸腺嘧啶脱氧核苷简称胸苷，化学名：9-beta-D-呋喃核苷鸟嘌，CAS号：50-89-5，分子式：C10H14N2O5，分子量为242.023；胞嘧啶核苷简称胞苷，化学名：1-β-D-呋喃核糖基胞嘧啶，CAS号：65-46-3，分子式：C9H13N3O5，分子量243.22；尿嘧啶核苷简称尿苷，化学名：1-β-D-呋喃核糖基尿嘧啶，CAS号：58-96-8，分子式：C9H12N2O6，分子量244.20。
核苷是核酸的主要组分。有些核苷及其衍生物具有显著的生理功能，如次黄嘌呤核苷(肌苷)可治疗急性和慢性肝炎及风湿性心脏病，并有增加白血球等功效。5-氟尿嘧啶脱氧核苷能抗肿瘤，毒性比5-氟尿嘧啶低，对肝癌、胃癌、直肠癌、卵巢癌、膀胱癌有一定疗效。胞嘧啶阿拉伯糖苷对缓解白血病有显著效果。5′-脱氧-5′-碘尿嘧啶核苷是治疗病毒性角膜炎的特效药。但是将核糖核苷应用于抗肿瘤领域中，尚未见相关报道。
腺苷是一种遍布人体细胞的内源性核苷，用于合成三磷酸腺苷(ATP)、腺嘌呤、腺苷酸、阿糖腺苷的重要中间体，可直接进入心肌经磷酸化生成腺苷酸，参与心肌能量代谢，同时还参与扩张冠脉血管，增加血流量。目前的主要用途是作为抗心律失常药，使阵发性室上性心动过速转为窦性心律，用于和房室有关的室上心律失常的诊断和治疗，然而将腺苷作为抗肿瘤药物的组合物应用于肿瘤的治疗领域，尚未见报道。
发明内容
本发明的目的在于，提供了腺苷与核苷组合在制备治疗肿瘤药物中的应用，将腺苷与核苷组合作为治疗肿瘤的药物成分使用，腺苷和其它四种核苷相组合，能够达到在不影响抗肿瘤效果的前提下，降低腺苷浓度，减少毒副作用和延缓耐药性发生的目的。
通过多年的研究发现，不同肿瘤有不同的核酸代谢与组成的特点，对不同肿瘤细胞每种核苷有不同的抑制强度，鸟苷、胞苷、尿苷和胸苷的分子量较接近，嘧啶苷在240D以上，腺嘌呤苷267D、鸟嘌呤苷283D，四种核苷均有的抗肿瘤作用，在浓度为0.1～1.8mmol/L的范围内均出现对肿瘤细胞的抑制作用，且抗肿瘤作用与抑制核酸代谢有关。另外，腺苷的抗肿瘤作用明显，腺苷治疗肿瘤瘤体大小的完全缓解率为6.1％以上，有效率为87.0％以上，且使用剂量低，为3.8～26.5mmol/Kg/天。
本发明的技术方案为：
腺苷与核苷组合在制备治疗肿瘤药物中的应用，所述的核苷包括鸟苷、胞苷、尿苷和胸苷；所述的腺苷为6-氨基-9-β-D-呋喃核糖基-9-H-嘌呤，分子式为C10H13N5O4，分子量267.24，CAS：58-61-7，分子结构式为：
Figure BSA00000442014300031
所述腺苷与核苷组合为腺苷与鸟苷、胞苷、尿苷或胸苷中的一种或多种的组合。
进一步地，所述腺苷与核苷组合为腺苷与鸟苷、胞苷、尿苷和胸苷中的二种的组合。
优选地，所述腺苷与核苷组合为腺苷与鸟苷、胞苷、尿苷或胸苷中的二种核苷的组合，各成分的摩尔比为2∶0.6∶0.4，即腺苷∶第一核苷(第一核苷为四种核苷中的任意一种)∶第二核苷(第二核苷为四种核苷不同于第一核苷的任意一种)的摩尔比2∶0.6∶0.4。通过组合用药，能够降低各成分单一用药时的用药量，而每种具体核苷的绝对浓度明显下降，药物对机体的毒副作用就下降；同时，二种化疗药物组合用药可大大降低耐药性的发生。相比与腺苷与一种核苷用药，腺苷与两种核苷的组合，其耐药性大大降低；相比腺苷与四种核苷组合用药，腺苷与两种核苷的组合，在降低了耐药性的同时，使用起来也方便，容易配制。
所述的肿瘤包括胃癌、肺癌、肝癌、结肠癌、乳腺癌、白血病或生殖系统肿瘤等多种常见恶性肿瘤。
将腺苷与核苷组合后，用在制备治疗上述肿瘤的药物中，制成注射剂，进行注射使用。
本发明的优点在于：
1、通过腺苷与核苷相组合用于制备治疗胃癌、肺癌、肝癌、结肠癌、乳腺癌、生殖系统肿瘤等多种常见恶性肿瘤的药物，抗肿瘤效果明显，具有高效、广谱、低毒的特点；
2、腺苷与核苷组合用药比单一用药的血液浓度降低，从而毒副作用降低；
3、腺苷与核苷组合用药可延缓肿瘤耐药性的发生。
具体实施方式
以下对本发明的优选实施例进行说明，应当理解，此处所描述的优选实施例仅用于说明和解释本发明，并不用于限定本发明。
实施例1
腺苷与一种核苷(胞苷)组合的抑瘤试验
方法：分别设置腺苷组、对照组(5-FU)和试验组(腺苷与核苷组合)三个组。将人胃癌BGC823肿瘤细胞(中国科学院上海细胞所提供)，用含10％新生牛血清的RPMI 1640培养基培养，取对数生长期的细胞，用0.25％胰蛋白酶消化后以3×103个/孔接种于96孔板，置于37℃、5％CO2培养箱中培养24小时，试验组分别加入总浓度为10.0mmol/L的腺苷+胞苷溶液60uL，补充培养液至每孔200μL，两者比例如表中第一列；对照组的5-FU和腺苷组的腺苷与试验组的腺苷的用量(mmol/L)相同，如第一行试验组加2.25mmol/L腺苷+0.75mmol/L胞苷，腺苷组只加2.25mmol/L腺苷，5-FU组加2.25mmol/L的5-FU，试验组腺苷与核苷组合的比例按表1所示，用无血清培养基稀释，0.22μm的无菌微孔滤膜过滤。在拟定的测量时间(48小时)，倒置显微镜观察细胞形态并拍照，然后每孔加入5mg/mL的MTT溶液20μL，置于37℃、5％CO2培养箱中继续培养4小时，终止培养，吸弃孔内培养的上清液，每孔加入150μL DMSO，震荡10分钟，使结晶物充分溶解后，以自动酶标仪(Thermo，型号MULTISKAN MK3)测量570mn处吸光度。
肿瘤细胞生长抑制率计算公式如下：
肿瘤细胞存活率(％)＝加药孔的实际OD值/阴性对照孔的OD值；
肿瘤细胞生长抑制率(％)＝100％-细胞存活率。
表1.腺苷与不同比例胞苷对人胃癌BGC823肿瘤细胞的抑制率(％)
Figure BSA00000442014300051
从表1.中可以看出，加入腺苷与胞苷组合，按照不同比例进行抗肿瘤试验，与单用腺苷和5-FU(5-氟尿嘧啶)相比，均能提高肿瘤抑制率，因其它核苷与腺苷组合与本实施例腺苷和胞苷组合后的抗肿瘤作用原理相同，所以，其它核苷与腺苷组合，也能提高肿瘤抑制率，同时达到降低血液浓度，从而降低毒副作用的效果；通过临床观察发现腺苷与胞苷组合与单一用药相比，基本无毒副作用。
实施例2
腺苷与二种核苷组合的抑瘤试验
细胞培养、MTT检测以及抑瘤率计算等同实施例1，设置腺苷组、对照组(5-FU)和试验组(腺苷与核苷组合)三个组。将人肺癌95C细胞(来自中国科学院武汉细胞所)、人肝癌HepG2细胞(来自中国科学院武汉细胞所)和人乳腺癌Bcap37细胞(来自中国科学院上海细胞所)分别用含10％新生牛血清的RPMI 1640培养基培养，取对数生长期的细胞，0.25％胰蛋白酶消化后以3×103个/孔接种于96孔板，补充培养液至每孔200μL，置于37℃、5％CO2培养箱中培养24小时。试验组为腺苷与两种核苷的组合，即腺苷∶第一核苷∶第二核苷的摩尔比为：2∶0.6∶0.4，组合总浓度为2.0mmol/L，对照组的5-FU和腺苷组的腺苷与试验组的腺苷的用量(mmol/L)相同；用无血清培养基稀释，0.22μm的无菌微孔滤膜过滤。设加入与核苷组合中腺苷等量的腺苷组和5-FU对照组。在拟定的测量时间即培养24小时、48小时、72小时后，首先倒置显微镜观察细胞形态并拍照，然后每孔加入5mg/mL的MTT(噻唑蓝)溶液20μL，置于37℃、5％CO2培养箱中继续培养4小时，终止培养，小心吸弃孔内培养上清液，每孔加入150μL DMSO(二甲基亚砜)，震荡10分钟，使结晶物充分溶解后，以自动酶标仪测量570mn处吸光度。
肿瘤细胞生长抑制率计算公式如下：
肿瘤细胞存活率(％)＝加药孔的实际OD值/阴性对照孔的OD值；
肿瘤细胞生长抑制率(％)＝100％-细胞存活率。
表2.核苷组合对人肺癌95C细胞的抑制率(％)
Figure BSA00000442014300071
表3.核苷组合对人肝癌HepG2细胞的抑制率(％)
Figure BSA00000442014300072
表4.不同核苷组合对人乳腺癌Bcap37细胞的抑制率(％)
从表2-4中可以看出：腺苷与二种不同核苷按照一定比例组合，对人肺癌95C细胞、人肝癌HepG2细胞和人乳腺癌Bcap37的肿瘤抑制试验，与单用腺苷和5-FU(5-氟尿嘧啶)相比，抑制率提高，且因为每种具体核苷的绝对浓度有明显降低，药物对机体的毒副作用也下降；同时，二种化疗药物组合用药可大大降低耐药性的发生，通过临床观察也证明了这一点；因核苷中其它两种与腺苷组合与本实施例腺苷和核苷组合后的抗肿瘤作用原理相同，其它两种核苷与腺苷组合，也能提高肿瘤抑制率，同时达到降低血液浓度，从而降低毒副作用的效果；通过临床观察发现腺苷与胞苷组合与单一用药相比，基本无毒副作用。
实施例3
腺苷与3种核苷的抑瘤试验
细胞培养、MTT检测以及抑瘤率计算等同实施例1，设置腺苷组、对照组(5-FU)和试验组(腺苷与核苷组合)，对照组的5-FU和腺苷组的腺苷与试验组的腺苷的用量(mmol/L)相同；试验组按表5中比例加入其它核苷组合，试验组总浓度为5.0mmol/L，试验用肿瘤细胞为7402人肝癌细胞(中国医学科学院武汉细胞所)。
表5.腺苷与3种不同核苷的不同比例组合对7402人肝癌细胞的48小时抑瘤试验(％)
Figure BSA00000442014300081
注：表中A：腺苷、G：鸟苷、C：胞苷、U：鸟苷、T：胸苷。
从表5中可以看出：腺苷与三种不同核苷按照不同比例组合，对7402人肝癌细胞的肿瘤抑制试验，与单用腺苷和5-FU相比，抑制率提高；因其它三种核苷与腺苷组合与本实施例的腺苷和核苷组合后的抗肿瘤作用原理相同，所以，其它核苷与腺苷组合，也能提高肿瘤抑制率，同时达到降低血液浓度，从而降低毒副作用的效果；通过临床观察发现腺苷与胞苷组合与单一用药相比，基本无毒副作用。
实施例4
腺苷与4种核苷组合的抑瘤试验
细胞培养、MTT检测以及抑瘤率计算等同实施例1，设置腺苷组、对照组(5-FU)和试验组(腺苷与核苷组合)，试验组腺苷与核苷组合的总浓度为4.0mmol/L，对照组的5-FU和腺苷组的腺苷与试验组的腺苷的用量(mmol/L)相同；试验组按表6中比例加入其它核苷组合，试验用肿瘤细胞为宫颈癌Hela细胞(中国医学科学院上海细胞所提供)。
表6.腺苷与4种不同核苷的不同比例组合对宫颈癌Hela细胞的48小时抑瘤试验(％)
Figure BSA00000442014300091
从表6.中可以看出：腺苷与四种核苷按照不同比例组合，对宫颈癌Hela细胞的肿瘤抑制试验，与单用腺苷和5-FU(5-氟尿嘧啶)相比，肿瘤抑制率提高，同时也达到了降低血液浓度，从而降低毒副作用的效果；通过临床观察发现腺苷与胞苷组合与单一用药相比，基本无毒副作用。
最后应说明的是：以上所述仅为本发明的优选实施例而已，并不用于限制本发明，尽管参照前述实施例对本发明进行了详细的说明，对于本领域的技术人员来说，其依然可以对前述各实施例所记载的技术方案进行修改，或者对其中部分技术特征进行等同替换。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (10)

1.腺苷与核苷组合在制备治疗肿瘤药物中的应用，所述的核苷包括鸟苷、胞苷、尿苷和胸苷；所述的腺苷为6-氨基-9-β-D-呋喃核糖基-9-H-嘌呤，分子式为C10H13N5O4，分子量267.24，CAS：58-61-7，分子结构式为：
Figure FSA00000442014200011
2.根据权利要求1所述的腺苷与核苷组合在制备治疗肿瘤药物中的应用，所述腺苷与核苷组合为腺苷与鸟苷、胞苷、尿苷或胸苷中的一种或多种的组合。
3.根据权利要求2所述的腺苷与核苷组合在制备治疗肿瘤药物中的应用，所述腺苷与核苷组合为腺苷与鸟苷、胞苷、尿苷或胸苷中的二种的组合。
4.根据权利要求3所述的腺苷与核苷组合在制备治疗肿瘤药物中的应用，所述腺苷与鸟苷、胞苷、尿苷或胸苷中的二种按照摩尔比为2∶0.6∶0.4的比例组合。
5.根据权利要求1所述的腺苷与核苷组合在制备治疗肿瘤药物中的应用，所述的肿瘤为肺癌。
6.根据权利要求1所述的腺苷与核苷组合在制备治疗肿瘤药物中的应用，所述的肿瘤为肝癌。
7.根据权利要求1所述的腺苷与核苷组合在制备治疗肿瘤药物中的应用，所述的肿瘤为结肠癌。
8.根据权利要求1所述的腺苷与核苷组合在制备治疗肿瘤药物中的应用，所述的肿瘤为乳腺癌。
9.根据权利要求1所述的腺苷与核苷组合在制备治疗肿瘤药物中的应用，所述的肿瘤为生殖系统肿瘤。
10.根据权利要求1所述的腺苷与核苷组合在制备治疗肿瘤药物中的应用，所述的肿瘤为胃癌。
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