CN115068495A - 核苷单体在制备抗肿瘤的药物中的用途 - Google Patents
核苷单体在制备抗肿瘤的药物中的用途 Download PDFInfo
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Abstract
本发明提供了核苷单体在制备抗肿瘤的药物中的用途,属于生物医药材料技术领域。本发明中所述的核苷单体为鸟嘌呤核苷或鸟嘌呤核苷和胞嘧啶核苷组成的组合物。本发明通过研究意外的发现鸟嘌呤核苷(G)对于Kras突变的肺癌细胞具有选择性杀伤效果,有望用于治疗Kras突变型肺癌;并且鸟嘌呤核苷(G)与胞嘧啶核苷(C)混合使用对于肺癌细胞活性抑制可以发挥协同增效作用,提高肺癌治疗效果。本发明为临床肺癌治疗提供了新的治疗思路和方法,具有重要意义。
Description
技术领域
本发明属于生物医药材料技术领域,具体涉及核苷单体在制备抗肿瘤的药物中的用途。
背景技术
肺癌是世界范围内死亡率最高的恶性肿瘤,占所有癌症相关死亡的27%,2021年全球有超过180万人死于肺癌。迄今为止,肺癌一般分为两大类:非小细胞肺癌(NSCLC,80%)和小细胞肺癌(SCLC,20%)。目前,肺癌的总体5年生存率低于18%,其原因在于肺癌是一类异质性很强的恶性肿瘤,不同病因、不同驱动基因的肺癌都必须使用不同的治疗手段。但是,目前针对肺癌的手术切除、放射疗法和药物治疗(靶向与免疫疗法)等都不能完全满足临床需求。因此,对于肺癌药物进行研发,对于提高肺癌患者的总体生存率具有重要意义。
在肺癌中,KRAS是肺癌中一种最常见的突变基因,发生在大约25%的肺腺癌中。KRAS基因突变主要发生在外显子2、3、4上。近年来的研究越来越明确认定KRAS基因突变对NSCLC患者是一个不良的治疗和预后因素。KRAS基因突变会导致对上游EGFR靶点耐药,同时KRAS基因突变会导致肺癌发生脑转移及在肺内转移的风险上升。KRAS突变型非小细胞肺癌的耐药性和高转移性导致患者总体生存率明显低于野生型KRAS患者。并且,由于KRAS突变型非小细胞肺癌的耐药性和高转移性,普通治疗肺癌的药物效果欠佳。而现有技术中,缺乏针对性治疗KRAS突变型非小细胞肺癌的药物。
核苷是一类糖苷的总称,核苷都是由D-核糖或D-Z-脱氧核糖与嘧啶碱或嘌呤碱缩合而成。核苷一般为无色结晶,不溶于普通有机溶剂,易溶于热水,熔点为160~240℃。由D-核糖生成的核苷称核糖核苷,参与RNA组成,由D-α-脱氧核糖生成的核苷称脱氧核糖核苷,参与DNA组成。常见的核苷有:尿嘧啶核苷、腺嘌呤核苷、胞嘧啶核苷、鸟嘌呤核苷、胸腺嘧啶核苷。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。
目前尚未见有研究表明鸟嘌呤核苷(G)与胞嘧啶核苷(C)单体对肺癌细胞活性有抑制作用,更未见鸟嘌呤核苷与胞嘧啶核苷用于治疗KRAS突变型非小细胞肺癌。
发明内容
本发明的目的是提供核苷单体在制备抗肿瘤的药物中的用途。
本发明提供了鸟嘌呤核苷在制备抗肿瘤药物中的用途。
进一步地,所述药物为预防和/或治疗肺癌的药物;
优选地,所述肺癌为非小细胞肺癌;
更优选地,所述肺癌为Kras突变型非小细胞肺癌。
本发明还提供了一种抗肿瘤的组合物,它包括鸟嘌呤核苷。
进一步地,前述的组合物是由鸟嘌呤核苷和胞嘧啶核苷组成。
进一步地,所述鸟嘌呤核苷和胞嘧啶核苷的摩尔比为(1~10):(1~10);
优选地,所述鸟嘌呤核苷和胞嘧啶核苷的摩尔比为1:1。
本发明还提供了前述的组合物的制备方法,它包括如下步骤:将鸟嘌呤核苷和胞嘧啶核苷混合,即得。
本发明还提供了前述的组合物在制备抗肿瘤药物中的用途。
进一步地,所述药物为预防和/或治疗肺癌的药物;
优选地,所述肺癌为非小细胞肺癌;
更优选地,所述肺癌为Kras突变型非小细胞肺癌。
本发明还提供了鸟嘌呤核苷和胞嘧啶核苷联用在制备抗肿瘤药物中的用途;
优选地,所述鸟嘌呤核苷和胞嘧啶核苷的摩尔比为(1~10):(1~10);
更优选地,所述鸟嘌呤核苷和胞嘧啶核苷的摩尔比为1:1。
进一步地,所述药物为预防和/或治疗肺癌的药物;
优选地,所述肺癌为非小细胞肺癌;
更优选地,所述肺癌为Kras突变型非小细胞肺癌。
本发明通过研究意外的发现鸟嘌呤核苷(G)对于Kras突变的肺癌细胞具有选择性杀伤效果,有望用于治疗Kras突变型肺癌;并且鸟嘌呤核苷(G)与胞嘧啶核苷(C)混合使用对于肺癌细胞活性抑制可以发挥协同增效作用,提高肺癌治疗效果。本发明为临床肺癌治疗提供了新的治疗思路和方法,具有重要意义。
显然,根据本发明的上述内容,按照本领域的普通技术知识和惯用手段,在不脱离本发明上述基本技术思想前提下,还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式,对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
具体实施方式
本发明具体实施方式中使用的原料、设备均为已知产品,通过购买市售产品获得。
实施例1、核苷单体的抗癌活性研究
1、实验方法
1.1肺癌细胞系培养
在A549细胞(Kras突变型肺癌细胞)、H1299细胞以及H1975细胞中加入含10%FBS和1%的双抗RPMI-1640培养基,并在37℃下,含有5%的CO2细胞培养箱中进行培养。
1.2核苷单体在细胞增殖抑制实验中的预处理
首先分别精确称量2.8mg鸟苷(G)、2.4mg胞苷(C)以及G和C混合物(混合物中,G为2.8mg,C为2.4mg,摩尔比为1:1),并分别加入600μL纯水溶解。然后在85℃下加热5min,待溶液冷却至室温后,在-20℃下冷冻。加药前,将核苷溶液在室温下解冻后,于在95℃下加热5min。等待溶液冷却至室温后,加药(整个操作中尽量避光)。
1.3细胞增殖抑制实验
将A549细胞、H1299细胞以及H1975细胞(4000个/孔)分别接种于96孔板,并加入相同体积的不同药物(G、C、G/C混合物),各药物均用培养基稀释至不同浓度,药物浓度设为0、3.15、6.25、12.5、25、50以及100μM,培养48h。然后弃去上清液,并用PBS洗去残余药物,每孔加入100μL CCK8工作液,并继续孵育2h,通过酶标仪在450nm处检测各孔的吸光度值。通过公式:细胞存活率=[A(药液)-A(空白)]/[A(对照)-A(空白)]来评估药物对细胞的增殖抑制能力。
2、实验结果
C、G以及G/C混合物对A549细胞、H1299细胞以及H1975细胞的抗肺癌细胞结果如表1所示(表1中NA表示在所设置的最高浓度范围内,核苷单体对细胞没有抑制活性)。本发明研究发现:胞苷(C)对三种细胞均不敏感,无抑制细胞增殖的效果;鸟苷(G)对H1299细胞不敏感,无抑制细胞增殖的效果,对H1975细胞增殖活性抑制效果一般(IC50>100μM),但是出乎意料的是G对A549细胞的杀伤力较强,其IC50值为66.1μM,因此G可以选择性抑制A549细胞增殖活性。
此外,本发明研究还发现:G/C混合物抑制A549细胞增殖活性的IC50值为51.27μM,显著优于单独使用G;同时,与单独使用G和C相比,G/C混合物显著提高了对H1975细胞及H1299细胞增殖活性的抑制效果。说明G和C混合使用可以发挥协同增效作用,增强对肺癌细胞的杀伤效果。
表1.核苷单体的抗肺癌细胞活性
上述实验结果意外发现G对于特殊的突变类型肺癌细胞(A549细胞,Kras突变)具有选择性杀伤效果,同时G和C混合使用对于抑制肺癌细胞活性发挥了协同增效作用。因此,核苷单体G或G/C混合物有望用于治疗肺癌。
综上,本发明通过研究意外的发现鸟嘌呤核苷(G)对于Kras突变的肺癌细胞具有选择性杀伤效果,有望用于治疗Kras突变型肺癌;并且鸟嘌呤核苷(G)与胞嘧啶核苷(C)混合使用对于肺癌细胞活性抑制可以发挥协同增效作用,提高肺癌治疗效果。本发明为临床肺癌治疗提供了新的治疗思路和方法,具有重要意义。
Claims (10)
1.鸟嘌呤核苷在制备抗肿瘤药物中的用途。
2.根据权利要求1所述的用途,其特征在于:所述药物为预防和/或治疗肺癌的药物;
优选地,所述肺癌为非小细胞肺癌;
更优选地,所述肺癌为Kras突变型非小细胞肺癌。
3.一种抗肿瘤的组合物,其特征在于:它包括鸟嘌呤核苷。
4.根据权利要求3所述的组合物,其特征在于:它是由鸟嘌呤核苷和胞嘧啶核苷组成。
5.根据权利要求4所述的组合物,其特征在于:所述鸟嘌呤核苷和胞嘧啶核苷的摩尔比为(1~10):(1~10);
优选地,所述鸟嘌呤核苷和胞嘧啶核苷的摩尔比为1:1。
6.权利要求3~5任一项所述的组合物的制备方法,其特征在于:它包括如下步骤:将鸟嘌呤核苷和胞嘧啶核苷混合,即得。
7.权利要求3~5任一项所述的组合物在制备抗肿瘤药物中的用途。
8.根据权利要求7所述的用途,其特征在于:所述药物为预防和/或治疗肺癌的药物;
优选地,所述肺癌为非小细胞肺癌;
更优选地,所述肺癌为Kras突变型非小细胞肺癌。
9.鸟嘌呤核苷和胞嘧啶核苷联用在制备抗肿瘤药物中的用途;
优选地,所述鸟嘌呤核苷和胞嘧啶核苷的摩尔比为(1~10):(1~10);
更优选地,所述鸟嘌呤核苷和胞嘧啶核苷的摩尔比为1:1。
10.根据权利要求9所述的用途,其特征在于:所述药物为预防和/或治疗肺癌的药物;
优选地,所述肺癌为非小细胞肺癌;
更优选地,所述肺癌为Kras突变型非小细胞肺癌。
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