CN114010624B - 双硫仑和甲氨蝶呤在制备抗肝癌药物中的应用 - Google Patents

双硫仑和甲氨蝶呤在制备抗肝癌药物中的应用 Download PDF

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CN114010624B
CN114010624B CN202111516373.0A CN202111516373A CN114010624B CN 114010624 B CN114010624 B CN 114010624B CN 202111516373 A CN202111516373 A CN 202111516373A CN 114010624 B CN114010624 B CN 114010624B
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methotrexate
disulfiram
liver cancer
drug
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CN114010624A (zh
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崔大祥
崔明青
梁辉
陈晓敏
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Shanghai National Engineering Research Center for Nanotechnology Co Ltd
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Abstract

本发明公开了一种双硫仑在增敏甲氨蝶呤对治疗肝癌药物中的应用，双硫仑与靶向DHFR的药物甲氨蝶呤药物复配使用，作为抗肿瘤药物复方。双硫仑与甲氨蝶呤合用，增强了甲氨蝶呤治疗肝癌药效。化疗药物甲氨蝶呤通过抑制二氢叶酸还原酶DHFR的活性，抑制肝癌细胞的生长，双硫仑通过抑制肝癌细胞的干性，增加肝癌细胞对甲氨蝶呤治疗的敏感性，起到药物增效的作用。本发明所述双硫仑与甲氨蝶呤合用，可以提高甲氨蝶呤化疗效果，提高药物疗效，为临床治疗肝癌提供了一个方便、经济、高效的增敏剂。

Description

双硫仑和甲氨蝶呤在制备抗肝癌药物中的应用
技术领域
本发明属于肿瘤化疗的增敏药物领域，涉及到双硫仑的一种新用途，即双硫仑用于增强甲氨蝶呤治疗肝癌的药效及其应用。
技术背景
肝癌是全球常见的恶性肿瘤之一，也是肿瘤导致死亡的第二大原因。世界范围内，每年肝癌新发病例约为70万，其发病率和死亡率高居恶性肿瘤前三位，仅次于肺癌和胃癌。早期或部位局限的肝癌患者通常采用手术切除术，中晚期及复发肝癌患者通常采用化疗手段。然而，耐药性和肿瘤异质性限制了药物的疗效，导致患者对化疗的短暂反应甚至无反应。
叶酸是嘌呤和胸腺嘧啶脱氧核苷酸从头合成途径中重要的辅助因子，在DNA合成和复制中发挥重要。叶酸通过一系列酶促反应生成四氢叶酸，四氢叶酸是叶酸在胞内的活化形式，传递一碳单位，参与一碳代谢，对于嘌呤和胸腺嘧啶的合成、同型半胱氨酸的甲基化等生物学过程起着重要作用。肿瘤的增殖需要大量营养和能量的供给。研究发现，为了满足肿瘤增殖所需的DNA合成，叶酸代谢关键酶的表达上调。二氢叶酸还原酶DHFR是叶酸代谢的关键限速酶。DHFR在多种肿瘤中表达异常，促进叶酸代谢和DNA合成。靶向DHFR的药物如甲氨蝶呤(MTX)已经广泛应用于多种肿瘤的临床治疗，主要通过抑制DHFR的活性，进而阻碍肿瘤细胞的生长与繁殖。但其副作用明显，不仅会导致病人造血功能和胃肠上皮损伤，也会由于病人自身DHFR高表达对药物产生耐药性。因此，增加甲氨蝶呤治疗的敏感性，对肝癌患者的治疗具有重要意义。
乙醛脱氢酶（ALDHs）是NADP+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，ALDH1A1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。
发明内容
本发明目的在于，提供一种双硫仑在抗肿瘤药物中的应用。
本发明提供了一种ALDH1A1抑制剂双硫仑（disulfiram）在抗肿瘤药物中的应用，其与靶向DHFR的药物甲氨蝶呤药物复配使用，作为抗肿瘤药物复方。
本发明提出了双硫仑与抗肿瘤药物甲氨蝶呤药物联用，可增强化疗药物敏感性，提高临床疗效。
本发明原理是：化疗药物甲氨蝶呤通过抑制二氢叶酸还原酶DHFR的活性，抑制肝癌细胞的生长，双硫仑通过抑制肝癌细胞的干性，增加肝癌细胞对甲氨蝶呤治疗的敏感性，起到药物增效的作用。
进一步的，所述双硫仑与甲氨蝶呤的质量比为1:1。
优选的，双硫仑在增强甲氨蝶呤抗肿瘤药效中的应用，所涉及的肿瘤为肝癌。
以小鼠肝癌细胞Hep1-6接种的荷瘤小鼠为模型动物，通过腹腔注射给予甲氨蝶呤和双硫仑联合用药，测定小鼠肿瘤体积的变化评价双硫仑对甲氨蝶呤的增敏作用。研究发现，双硫仑单用组与甲氨蝶呤单用组均呈现一定的抑瘤作用，双硫仑与甲氨蝶呤联用可显著增强甲氨蝶呤的抗肿瘤药效。
本发明提出了一种双硫仑在抗肿瘤药物中的应用，所述双硫仑与甲氨蝶呤合用，可以提高甲氨蝶呤化疗效果，提高药物疗效，为临床治疗肝癌提供了一个方便、经济、高效的增敏剂。
附图说明
附图1为肝癌荷瘤小鼠肿瘤大小对比图；
附图2 为肝癌荷瘤小鼠肿瘤重量对比图；
附图3 为肝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
双硫仑在肝癌荷瘤小鼠对甲氨蝶呤增敏作用。
实验如下：
细胞来源与培养：小鼠肝癌细胞Hep1-6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；
肝癌荷瘤小鼠模型的建立：培养小鼠肝癌细胞Hep1-6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。
肝癌荷瘤小鼠设计和分组如下：对照组腹腔注射DMSO，甲氨蝶呤单用组采取10mg/kg.day腹腔注射，双硫仑单用组采取10mg/kg.day腹腔注射，甲氨蝶呤+双硫仑为药物联用组，两种药物均采取10mg/kg.day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、图2、图3所示，其中，如图1所示，肝癌荷瘤小鼠接受治疗后，甲氨蝶呤＋双硫仑联合用药组别的小鼠肿瘤明显小于其他组别；如图2所示，肝癌荷瘤小鼠接受治疗后，甲氨蝶呤＋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3所示，肝癌荷瘤小鼠接受治疗后，甲氨蝶呤＋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。
小鼠接受甲氨蝶呤与双硫仑联合用药，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，说明甲氨蝶呤与双硫仑联合用药显著抑制肿瘤的生长，即双硫仑可增强甲氨蝶呤的抗肿瘤药效。

Claims (2)

1.一种双硫仑和甲氨蝶呤在制备抗肿瘤药物中的应用，其特征在于，所述的药物由双硫仑和甲氨蝶呤组成，所涉及的肿瘤为肝癌。
2.根据权利要求1所述的应用，其特征在于：所述双硫仑与甲氨蝶呤的质量比为1:1。
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