CN115227688A - 双硫仑在增敏紫杉醇对肺癌治疗效果中的应用 - Google Patents
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Abstract
本发明涉及双硫仑在增敏紫杉醇对肺癌治疗效果中的应用。即双硫仑与紫杉醇组合物用于增强紫杉醇治疗肺癌的药效，提供了一种双硫仑的新用途。化疗药物紫杉醇通过抑制肿瘤细胞的有丝分裂，减慢肿瘤细胞增殖，达到抗肿瘤的作用效果，合用双硫仑对增强紫杉醇治疗肺癌药效的应用。双硫仑是乙醛脱氢酶1A1的抑制剂，双硫仑与紫杉醇联合用药可以增加肺癌细胞对紫杉醇治疗的敏感性。提高紫杉醇化疗效果和药物疗效，为临床治疗肺癌提供了一个高效的增敏剂。
Description
技术领域
本发明属于肿瘤化疗的增敏药物领域，涉及双硫仑在增敏紫杉醇对肺癌治疗效果中的应用。即双硫仑与紫杉醇组合物用于增强紫杉醇治疗肺癌的药效，提供了一种双硫仑的一种新用途。
技术背景
肺癌是全球常见的恶性肿瘤之一，严重危害人类的生命健康。据2018年世界卫生组织的流行病学数据表明，肺癌的发病率和死亡率均高居恶性肿瘤榜首。在我国，肺癌的发病人数也在逐年增加。非小细胞肺癌是肺癌的主要类型，占肺癌总数的85%。约70%的肺癌患者在被诊断为肺癌的时候处于进展期。化疗是此类肺癌治疗的常用治疗手段，可以有效延长患者的生命。然而，肿瘤耐药的存在，导致许多患者化疗后很快复发或者进展，限制了治疗效果，成为肺癌临床治疗的瓶颈，需要尽快突破。
紫杉醇是肺癌化疗的常用药物。紫杉醇是一种微管抑制剂，直接作用于细胞分裂过程中组成纺锤体的微管蛋白，与多聚β-Tubilin结合，从而干扰微管动态平衡，防止其解聚。结果，细胞被纺锤体检查点阻滞在G2/M期，无法完成复制，最终发生程序性细胞凋亡。已有研究报道，包括RAS，MYC依赖的信号途径以及非受体型酪氨酸激酶途径等多种信号传导通路参与紫杉醇诱导肿瘤细胞凋亡的过程。紫杉醇联合铂类或者紫杉醇单药治疗是肺癌治疗的一线方案，但其同样面临产生耐药性的问题。因此，增加紫杉醇治疗的敏感性，对肺癌患者的治疗具有重要意义。
乙醛脱氢酶（ALDHs）是NADP+（脱氢酶的辅酶）依赖酶的一个超家族，负责将内源性和外源性醛代谢为相应的羧酸。ALDH1是乙醛脱氢酶家族中的成员之一，超过90%的ALDH1的活性与其亚型ALDH1A1相关。研究发现，醛脱氢酶1A1（Aldehyde dehydrogenas 1A1，ALDH1A1）是乳腺肿瘤干细胞（Breast Cancer Stem Cells，BCSCs）的重要生物标志物之一。不仅可作为乳腺癌、肺癌、肝癌等恶性肿瘤的肿瘤干细胞分子标记物，也与肿瘤多重耐药性的产生密切相关。
双硫仑（Disulfiram）是一种古老的解酒药，商业上称之为戒酒硫，临床已经使用了60多年，廉价且安全。
发明内容
本发明目的在于：提供一种包括双硫仑的组合物。
本发明的再一目的在于，提供所述组合物的用途。以及
本发明的又一目的在于，提供所述组合物的使用方法。
本发明目的通过下述方案实现：
一种双硫仑和抗肿瘤药物的组合物，由双硫仑和抗肿瘤药物紫杉醇组成。
进一步的，所述双硫仑与紫杉醇的质量比为2:1。
本发明也提供了一种根据上述的组合物的用途，双硫仑作为抗肿瘤药物的增敏剂，用于肿瘤的化疗。ALDH1A1抑制剂双硫仑与化疗药物紫杉醇联用可增强化疗药物敏感性，提高临床疗效。
所述肿瘤为肺癌。
本发明还提供了一种根据上述的组合物的使用方法，双硫仑作为单独成分与紫杉醇合并使用，所述双硫仑与紫杉醇的质量比为2:1。
化疗药物紫杉醇通过抑制肿瘤细胞的有丝分裂，减慢肿瘤细胞增殖，达到抗肿瘤的作用效果。双硫仑是乙醛脱氢酶1A1的抑制剂，双硫仑与紫杉醇联合用药可以增加肺癌细胞对紫杉醇治疗的敏感性。
本发明提供了一种双硫仑的新用途，可以用于与紫杉醇合用，以提高紫杉醇化疗效果，提高药物疗效，为临床治疗肺癌提供了一个高效的增敏剂。
本发明以肺癌细胞A549接种的荷瘤小鼠为模型动物，通过腹腔注射给予双硫仑和紫杉醇联合用药，测定小鼠肿瘤体积的变化评价双硫仑对紫杉醇的增敏作用。研究发现，紫杉醇的单用组呈现一定的抑瘤作用，双硫仑与紫杉醇联用可显著增强紫杉醇的抗肿瘤药效。以此为基础，本发明提出，双硫仑与紫杉醇联用可应用于肺癌的临床治疗。
附图说明
图1 肺癌荷瘤小鼠肿瘤重量对比图；
图2 肺癌荷瘤小鼠肿瘤体积变化对比图。
具体实施方式
本发明通过下面的实施例进行详细解释，但不仅限于此。
实施例：
双硫仑在肺癌荷瘤小鼠对紫杉醇增敏作用实验：
细胞来源与培养：肺癌细胞A549购于上海中科院细胞库，细胞采用含10%胎牛血清、100U/ml青霉素和100μg/ml链霉素的DMEM培养基培养于37℃、5%CO2培养箱中。
动物来源与饲养：采用Balb/c-Nude小鼠进行实验。在标准饲养环境下（自由饮食与饮水，昼夜交替，各12小时），适应性饲养一周。
肺癌荷瘤小鼠模型的建立：培养肺癌细胞A549至对数生长期，消化细胞，无菌PBS重悬并计数细胞，以1×106/点注射到裸鼠的双侧腹股沟处，一周后开始计量肿瘤生长体积。当肿瘤体积达到50mm3左右时，将小鼠随机分为4组，按照需要给药处理。
肺癌荷瘤小鼠设计和分组如下：
对照组：腹腔注射DMSO；
紫杉醇的单用组：采取5mg/kg.day腹腔注射；
紫杉醇+双硫仑为药物联用组：紫杉醇采取5mg/kg.day，双硫仑采取10mg/kg.day；
上述各组均为腹腔注射，每隔3天注射一次。每隔3天测量小鼠的肿瘤的体积大小，记录并绘制曲线。15天后处死小鼠，取出肿瘤，比较肿瘤的体积。
动物实验结果如图1所示，肿瘤的重量与各组的关系图，肺癌荷瘤小鼠接受治疗后，紫杉醇＋双硫仑联合用药组别的小鼠肿瘤重量明显轻于其他组别。
如图2所示，各组随着天数的增加，肿瘤体积（mm3）的变化曲线，肺癌荷瘤小鼠接受治疗后，紫杉醇＋双硫仑联合用药组别的小鼠肿瘤生长速度明显慢于其他组别。
小鼠接受紫杉醇与双硫仑联合用药，肿瘤体积、重量显著小于其他组别，肿瘤的生长速度显著慢于其他组别，说明紫杉醇与双硫仑联合用药显著抑制肿瘤的生长，即双硫仑可增强紫杉醇的抗肿瘤药效。
Claims (5)
1.一种双硫仑和抗肿瘤药物的组合物，其特征在于，由双硫仑和抗肿瘤药物紫杉醇组成。
2.根据权利要求1所述的组合物，其特征在于，所述双硫仑与紫杉醇的质量比为2:1。
3.一种根据权利要求1或2所述的组合物的用途，其特征在于，双硫仑作为抗肿瘤药物的增敏剂，用于肿瘤的化疗。
4.根据权利要求3所述的组合物的用途，其特征在于，所述肿瘤为肺癌。
5.一种根据权利要求1或2所述的组合物的使用方法，其特征在于，双硫仑作为单独成分与紫杉醇合并使用，所述双硫仑与紫杉醇的质量比为2:1。
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