CN111202743A - 马杜霉素和长春新碱联用的抗癌药物组合物 - Google Patents
马杜霉素和长春新碱联用的抗癌药物组合物 Download PDFInfo
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Abstract
本发明公开了马杜霉素和长春新碱联用的抗癌药物组合物,所述组合物的组分为马杜霉素和长春新碱;马杜霉素和长春新碱的比例为1:1‑1:10。本发明的优点在于提供了一种新型的抗癌药物组合物,马杜霉素与长春新碱联用,此组合物提高了抗癌效果,毒副作用降低。
Description
技术领域
本发明涉及医药领域,具体涉及马杜霉素和长春新碱联用的抗癌药物组合物。
背景技术
由于现在生活环境污染的加剧以及生活压力的增大,癌症的发病率逐年升高并有年轻化的趋势。相关统计显示我国因患癌致死的人数就高达281万人,已经超过了因心脑血管疾病死亡的人数,因此癌症对于我国人民的生命安全构成了严重威胁。同时肺癌又是我国发病率最高的恶性肿瘤,每年新增肺癌的病例约39.9万人,每年因肺癌死亡病例约59.1万人。肺癌分为非小细胞肺癌(NSCLC)和小细胞肺癌(SCLC),其中非小细胞肺癌发病率最高,占所有肺癌发病率的85%以上。在过去的二十多年时间中,肺癌的患病率不断攀升。有科学家预计在2025年每年患病人数将会达到100万人左右,那时我国的肺癌患病人数将跃居世界第一位,所以对于肺癌治疗手段的研究成为了现如今亟待解决的问题。
到目前为止,对于肺癌的主要治疗方法有三种,分别是手术切除、放疗与化疗。手术治疗是最为有效的方法,但也仅限于肺癌发病的早期,而近些年来新纳米药物载体的研发以及免疫治疗法为治疗肺癌提供了新的途径。非小细胞肺癌(NSCLC)在发病前期症状不明显并且具有一定的隐蔽性,因此当病人发现病情后,癌症往往已经到了不可控的地步甚至已经到了癌症晚期,只能采用放疗及化疗的方法进行治疗。而放疗和化疗又存在着许多的弊端,比如说:药物副作用大;对病人身体健康有极大的负面影响;病人术后生活将面临免疫力低下,体质弱等问题。尽管近年来肺癌个性化治疗方案有了进一步的发展,但肺癌患者的预后依然很差,术后5年的生存率仅为16%。随着治疗的深入,会对正常细胞产生严重的副作用。因此需要寻找一种新的具有低毒、高效等特点的新型抗癌药物。
马杜霉素( Maduramicin) 是美国氰胺公司开发的一种聚醚类离子载体抗生素,之前广泛应用于饲料添加, 它对禽类所患的球虫病都有很好的杀灭活性。因其抗球虫谱广、高效、耐药性小、价格相对便宜等优点,应用十分广泛。但是马杜霉素对于兔子和马等动物具有明显毒性,在使用时需注意用量。马杜霉素分子量为934.163,分子式为C47H83NO17,其化学结构如图1;从结构上说马杜霉素能与金属离子选择性的结合,从而影响细胞内的Na+/K+离子的浓度、打破了细胞膜上电荷平衡,进而引发了细胞的凋亡。
马杜霉素可以抑制鸡心肌细胞系的增殖,并诱导此细胞系阻滞在G1期,从而促使心肌细胞凋亡,产生自噬等现象,这证明了马杜霉素可以抑制心肌细胞的增殖能力。
长春新碱,英文名称Vincristine;CAS号57-22-7;分子式C46H56N4O10;分子量824.96。长春新碱是一种双吲哚型生物碱。具有使细胞分裂(有丝分裂)在中期停止的作用,这与秋水仙素相似,但其作用比秋水仙素更强。与秋水仙素一样可以与微管蛋白结合而抑制其生物活性,但结合部位不同。另外它与秋水仙素不同的是对微管蛋白以外的蛋白质如肌动蛋白及10纳米细丝蛋白等也起作用。在临床医学上作为抗癌剂之一而被应用,特别是对造血器官的肿瘤比较有效。长春碱硫酸盐可用于治疗何杰金氏病和绒毛膜上皮癌,疗效较好;对淋巴肉瘤、网状细胞肉瘤、急性白血病、乳腺癌、肾母细胞瘤、卵巢癌、睾丸癌、神经母细胞瘤和恶性黑色素瘤等也有一定疗效。具有以下毒副作用:1、剂量限制性毒性是神经系统毒性,主要引起外周神经症状,如手指、神经毒性等,与累积量有关。足趾麻木、腱反射迟钝或消失,外周神经炎。腹痛、便秘,麻痹性肠梗阻偶见。运动神经、感觉神经和脑神经也可受到破环,并产生相应症状。神经毒性常发生于40岁以上者,儿童的耐受性好于成人,恶性淋巴瘤病人出现神经毒性的倾向高于其他肿瘤病人。2、骨髓抑制和消化道反应较轻。3、有局部组织刺激作用,药液不能外漏,否则可引起局部坏死。4、可见脱发,偶见血压的改变。。毒副反应限制了长春新碱的临床应用。
因此,尝试使用马杜霉素和长春新碱联合使用,提高治疗效果,降低毒副反应。
发明内容
为解决以上技术上的不足,本发明提供了马杜霉素和长春新碱在制备抗癌药物中的应用。
本发明是通过以下技术方案实现的:
本发明提供了一种马杜霉素和长春新碱联用的抗癌药物组合物,所述组合物的组分为马杜霉素和长春新碱。
优选的,所述马杜霉素和长春新碱的比例为1:1-1:10。
更优选的,所述马杜霉素和长春新碱的比例为1:1或1:2.5、1:5、1:10。
更优选的,所述马杜霉素和长春新碱的剂量为6mg/kg马杜霉素+6mg/kg长春新碱。
本发明提供了所述一种马杜霉素和长春新碱联用的抗癌药物组合物在制备抗癌药物中的应用。
本发明提供了一种马杜霉素和长春新碱联用的抗癌药物组合物的在制备抗肺癌或宫颈癌药物中的应用。
本发明的有益效果是:本发明的优点在于提供了一种新型的抗癌药物组合物,马杜霉素与长春新碱联用,此组合物提高了抗癌效果,毒副作用降低。
附图说明
图1表示马杜霉素分子结构。
具体实施方式
实施例1 马杜霉素与长春新碱联合使用对肿瘤细胞增殖的抑制作用
将处于对数生长期且形态良好的人肺腺癌细胞系A549、人宫颈癌细胞系Hela进行PBS冲洗、0.25%胰酶消化并吹打为单细胞悬液。常规计数后,调整细胞浓度为4×104个/mL,按照100µL/孔接种于96孔板。于37℃、5% CO2饱和湿度培养箱中培养24h后,加入待测药物,继续培养一段时间后加入20µL MTT,孵育4h后,于酶标仪中检测570nm处的吸光值。
存活率=(实验组OD-空白组OD)/(溶剂对照组OD-空白组OD)×100%。
两药相互作用系数CDI值Q=E(A+B)/(EA+EB-EA×EB),E(A+B)指A、B两药联合对细胞的抑制率,EA和EB指A、B药分别对细胞的抑制率。Q>1.15时,两药有协同作用;Q=0.85~1.15时,两药有相加作用;Q<0.85时,两药表现为拮抗作用。
结果表明:
(1)人肺腺癌细胞系A549
从表1中可以得出,马杜霉素与不同浓度的长春新碱组合对人肺腺癌细胞系A549的增殖抑制作用明显强于等浓度的马杜霉素和长春新碱的单独作用,但通过计算两药相互作用系数Q(表1),发现马杜霉素与低浓度(2μg/mL)及高浓度(4μg/mL)的长春新碱相互作用为协同作用(表1),因此马杜霉素联合长春新碱对A549细胞增殖的抑制作用表现为明显的协同作用。
表1、马杜霉素与长春新碱联用对A549细胞增殖的抑制作用
(2)人宫颈癌细胞系Hela
从表2中可以得出,马杜霉素与不同浓度的长春新碱组合对人宫颈癌细胞系Hela的增殖抑制作用明显强于等浓度的马杜霉素和长春新碱的单独作用,但通过计算两药相互作用系数Q(表2),发现马杜霉素与低浓度2μg/mL的长春新碱相互作用为相加作用,而马杜霉素+4μg/mL长春新碱组合作用其Q值(表2)显示二者对Hela细胞为协同作用,因此马杜霉素联合长春新碱对Hela细胞表现为明显的协同作用。
表2、马杜霉素与长春新碱联用对Hela细胞增殖的抑制作用
实施例2 马杜霉素与长春新碱联用高效诱导肿瘤细胞凋亡的作用
将处于对数生长期且生长状态良好的A549细胞消化计数后接种于60mm培养皿中,每皿分别加入5mL细胞培养液,个细胞。置于37℃、5%CO2饱和湿度培养箱中培养。处理细胞:接板24h后弃各孔中旧培养液。向对照组各孔中分别加入5mL细胞培养液;向实验组各孔中分别加入5mL含一定浓度马杜霉素、长春新碱的细胞培养液,置于37℃、5%CO2饱和湿度培养箱中继续培养。收集细胞:分别继续培养6h、12h、24h、48h后吸弃各孔中旧培养液,每孔用1×PBS轻轻冲洗两遍,然后用0.25%胰酶+0.02% EDTA Na2消化,并收集细胞。样品处理:按照Nucleosome ELISA试剂盒说明书操作步骤处理样品。检测:样品于酶标仪405nm条件下测吸光值,记录结果。
加强系数=加药处理组的DNA碎片OD值/对照组细胞的DNA碎片OD值。
结果表明:
(1)人肺腺癌细胞系A549
从表3中可以得出,马杜霉素与不同浓度的长春新碱组合对人肺腺癌A549细胞的凋亡诱导作用明显强于等浓度的马杜霉素和长春新碱的单独作用,特别是马杜霉素与高浓度(4μg/mL)的长春新碱联合其凋亡诱导效果大于单药相加,因此马杜霉素联合长春新碱对A549细胞表现为明显的协同作用。
表3、马杜霉素与长春新碱联用诱导A549细胞凋亡的作用
(2)人宫颈癌细胞系Hela
从表3中可以得出,马杜霉素与不同浓度的长春新碱组合对人宫颈癌细胞系Hela细胞的凋亡诱导作用明显强于等浓度的马杜霉素和长春新碱的单独作用,特别是马杜霉素与高浓度(4μg/mL)的长春新碱联合其凋亡诱导效果大于单药相加,因此马杜霉素联合长春新碱对Hela细胞表现为明显的协同作用。
表4、马杜霉素与长春新碱联用诱导Hela细胞凋亡的作用
实施例3 马杜霉素与长春新碱联用对小鼠移植瘤的抑制作用
将裸鼠肺癌移植瘤模型的建立:用生理盐水稀释A549细胞至1.2×107/mL,取0.2mL分别接种于实验用雄性裸鼠上肢腋下,建立裸鼠的移植瘤模型,然后将荷瘤的雄性裸鼠随机分成对照组,长春新碱组、马杜霉素组以及联合治疗组,每组10只。
药物处理,待瘤长到大小约1.0cm时,采用尾静脉注射的方式给药。我们向对照组的裸鼠上肢的腋下注射生理盐水0.2mL/只,长春新碱组的裸鼠上肢腋下加入抗肿瘤药物长春新碱的浓度为6mg/kg,马杜霉素组的裸鼠上肢腋下加入马杜霉素的浓度为6mg/kg。两种药物联合作用组的裸鼠上肢腋下加入相应的联合药物浓度。每隔三天用游标卡尺测量一次肿瘤的直径(A)和肿瘤的横径(B),按照公式V=π/6×(A/2+B/2)3计算肿瘤的体积大小,统计肿瘤大小。
结果表明,长春新碱或者马杜霉素8单独对癌细胞作用后,肿瘤的抑制率分别为29.1%和13.1%,显著抑制了肿瘤的生长。马杜霉素和长春新碱联合作用增强了对肿瘤的抑制作用,肿瘤抑制率达到62.05%,Q值为1.62,两药表现为明显协同作用(表5)。
表5、马杜霉素与长春新碱联用对小鼠移植瘤的抑制作用
实施例4 马杜霉素与长春新碱联用对荷瘤小鼠血常规的影响
实验动物造模和分组给药方法同上。末次给药后24 h,对裸鼠称重,每只腹腔注射 0.5% 肝素0. 5 mL,使肝素化后摘除眼球取血,全血检测血常规中白细胞、红细胞 和血小板的浓度。
结果表明,对照组与联合治疗组白细胞、红细胞、血小板数量接近明显高于长春新碱治疗组以及马杜霉素治疗组(表6)。
表6、马杜霉素与长春新碱联用对荷瘤小鼠血常规的影响
说明联合用药毒副反应较小。
以上所述仅是本专利的优选实施方式,应当指出,对于本技术领域的普通技术人员来说,在不脱离本专利技术原理的前提下,还可以做出若干改进和替换,这些改进和替换也应视为本专利的保护范围。
Claims (6)
1.一种马杜霉素和长春新碱联用的抗癌药物组合物,其特征在于:所述组合物的组分为马杜霉素和长春新碱。
2.根据权利要求1所述的一种马杜霉素和长春新碱联用的抗癌药物组合物,其特征在于:所述马杜霉素和长春新碱的比例为1:1-1:10。
3.根据权利要求2所述的的一种马杜霉素和长春新碱联用的抗癌药物组合物,其特征在于:所述马杜霉素和长春新碱的比例为1:1或1:2.5、1:5、1:10。
4.根据权利要求2所述的的一种马杜霉素和长春新碱联用的抗癌药物组合物,其特征在于:所述马杜霉素和长春新碱的剂量为6mg/kg马杜霉素+6mg/kg长春新碱。
5.根据权利要求1-4任一项所述一种马杜霉素和长春新碱联用的抗癌药物组合物在制备抗癌药物中的应用。
6.根据权利要求5所述一种马杜霉素和长春新碱联用的抗癌药物组合物的在制备抗肺癌或宫颈癌药物中的应用。
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朱俊等: "长春新碱对非小细胞肺癌中Livin基因表达的影响", 《现代肿瘤医学》 * |
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