CN114432446A - 抗组胺药在制备抗肿瘤药物中的应用 - Google Patents
抗组胺药在制备抗肿瘤药物中的应用 Download PDFInfo
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Abstract
本发明属于医药技术领域，具体涉及抗组胺药在制备抗肿瘤药物中的应用。所述肿瘤具体可为人脑胶质瘤。动物实验表明，抗组胺药(苯海拉明、异丙嗪)在动物原位肿瘤模型中能抑制脑胶质瘤的生长，延缓荷瘤小鼠的生存，有望成为一种新的治疗肿瘤的药物，尤其是治疗脑胶质瘤的药物。
Description
技术领域
本发明属于医药技术领域，具体涉及抗组胺药在制备抗肿瘤药物中的应用。
背景技术
肿瘤(tumour)是指机体在各种致瘤因子作用下，局部组织细胞增生所形成的新生物(neogrowth)，因为这种新生物多呈占位性块状突起，也称赘生物(neoplasm)。
脑胶质瘤是由于大脑和脊髓胶质细胞癌变所产生的、最常见的原发性颅脑肿瘤。年发病率约为3-8人/10万人口。如同其他肿瘤(疾病)一样，胶质瘤也是由于先天的遗传高危因素和环境的致癌因素相互作用所导致的。一些已知的遗传疾病，例如神经纤维瘤病(I型)以及结核性硬化疾病等，为脑胶质瘤的遗传易感因素。
目前用于治疗脑胶质瘤的方法主要有：外科手术治疗：外科手术切除主要达到减少胶质瘤细胞数量、缓解荷瘤症状、暂时降低颅内压。手术治疗基于胶质瘤的生长特点，理论上手术不可能完全切除，生长在脑干等重要部位的肿瘤有的则根本不能手术，所以手术的治疗目的有局限性。放射治疗：放射治疗几乎是各型胶质瘤的常规治疗，但疗效评价不一，除髓母细胞瘤对放疗高度敏感，室管膜瘤中度敏感外，其他类型对放疗均不敏感，有观察认为放疗与非放疗者预后相同。此外射线引起的放射性坏死对于脑功能的影响亦不可低估。化疗：原则上用于恶性肿瘤，但化疗药物限于血脑屏障及药物的毒副作用，疗效尚不肯定，常用BCNU、CCNU、VM-26等有效率均在30％以下。
组胺是体内重要的生物活性物质之一，是平滑肌收缩、免疫反应、血管通透性、神经传递和刺激胃酸分泌的调节子。近年来有研究报导组胺还具有调控细胞增殖和血管生成的新功能。组胺酸脱羧酶HDC(Histidine decarboxylase)是催化组胺合成的关键酶，主要存在于肥大细胞、嗜碱性细胞、巨噬细胞、中性粒细胞和淋巴细胞。
组胺通过激活组胺受体发挥其功能。目前组胺受体分为H1，H2，H3，H4四种亚型。不同亚型被激活后介导不同的信号通路从而调控不同的功能。抗组胺药是一类特异性阻断组胺受体的临床药物，其中阻断H1受体的抗组胺药在治疗过敏性疾病、晕动病、放疗及手术后、妊娠、药物、梅尼埃病、内耳迷路炎症所致的恶心、呕吐、眩晕中有明确疗效，使用十分广泛。其中苯海拉明(Diphenhydramine hydrochloride，DPH)和异丙嗪(promethazine)是两种最为常见的阻断H1受体的抗组胺药物。苯海拉明适用于治疗皮肤粘膜的过敏性疾病，如荨麻疹、枯草热，过敏性鼻炎等。异丙嗪用于治疗皮肤及黏膜过敏、过敏性鼻炎、哮喘、食物过敏。两种药物因较易进入脑组织，故有明显的镇静作用；能加强催眠药、镇痛药及麻醉药的中枢抑制作用。目前尚未发现抗组胺药在肿瘤治疗领域尤其是治疗脑胶质瘤中的应用。
发明内容
本发明的目的是提供抗组胺药的药物新用途。
本发明所提供的抗组胺药的药物新用途，是：抗组胺药及其药学上可接受的盐和/或其溶剂化物和/或其水合物在下述方面的应用：
1)在制备真核生物肿瘤细胞增殖抑制剂中的应用；2)在制备预防和/或治疗肿瘤药物中的应用。
上述应用中，所述肿瘤为HDC高表达的肿瘤；
所述肿瘤具体可为人脑胶质瘤、黑色素瘤或结直肠癌；所述肿瘤细胞具体可为人脑胶质瘤干细胞、黑色素瘤细胞、结直肠癌细胞。
所述抗组胺药包括但不局限于苯海拉明、异丙嗪、扑尔敏、曲吡那敏、氯苯那敏、赛庚啶、羟嗪、溴苯那敏，二甲茚定，非尼拉敏，曲普利啶、曲美苄胺，卡比沙明，多西拉敏、美吡拉敏，氯吡啉，安他唑林，希司洛啶、帕拉塞嗪、丙酰马嗪、美喹他嗪、布克利嗪、美克洛嗪、阿扎他啶、特非那啶、阿伐司丁、巴米品、氯雷他定。
所述抗组胺药包括各种剂型的抗组胺药，如片剂，胶囊剂，注射剂，喷雾剂，气雾剂，滴鼻剂，粉雾剂，栓剂、贴剂、凝胶剂等。
所述片剂选自普通片剂、速释片、缓释片、控释片、薄膜衣片、糖衣片、口含片、舌下片、生物粘附片；所述胶囊剂选自硬胶囊、软胶囊；所述注射剂选自无菌或者含抑菌剂的水性注射剂、油性注射剂、冷冻干粉针剂、注射用微球；所述喷雾剂选自口腔喷雾剂、鼻腔喷雾剂、局部皮肤喷雾剂；所述气雾剂选自肺吸入用气雾剂、局部皮肤气雾剂；所述滴鼻剂选自滴鼻用溶液、滴鼻用凝胶；所述粉雾剂选自空腔用粉雾剂、鼻腔用粉雾剂、局部皮肤用粉雾剂。
本发明还提供一种真核生物肿瘤细胞增殖抑制剂、预防和/或治疗肿瘤的药物，含有抗组胺药。
所述肿瘤为HDC高表达的肿瘤；
所述肿瘤具体可为人脑胶质瘤、黑色素瘤或结直肠癌；所述肿瘤细胞具体可为人脑胶质瘤干细胞、黑色素瘤细胞、结直肠癌细胞。
本发明还提供抗组胺药及其药学上可接受的盐和/或其溶剂化物和/或其水合物与放疗联用在治疗HDC高表达的肿瘤中的应用。
所述肿瘤为人脑胶质瘤、黑色素瘤或结直肠癌。
我们发现HDC在胶质瘤干细胞中高表达，并促进原位脑胶质移植瘤的生长。动物实验表明，抗组胺药(如苯海拉明、异丙嗪)在动物原位肿瘤模型中能抑制脑胶质瘤的生长，延缓荷瘤小鼠的生存，有望成为一种新的治疗肿瘤的药物，尤其是治疗脑胶质瘤的药物。抗组胺药(苯海拉明)与放疗联用对肿瘤的生长有更好的抑制作用，苯海拉明与放疗联用较单独用药能够更显著的延长荷瘤小鼠的生存。此外，有研究表明HDC在黑色素瘤、结直肠癌中高表达，因此抗组胺药同样具有治疗这些肿瘤的潜力。
附图说明
图1表明本发明实施例1通过活体成像检测动物原位肿瘤模型给药(DMSO、苯海拉明、异丙嗪)后的肿瘤大小；
图2表明喂食抗组胺药对荷瘤小鼠生存的影响；
图3表明本发明实施例1通过活体成像检测动物原位肿瘤模型给药(DMSO、苯海拉明、放疗、苯海拉明与放疗联用)后不同时间点下的肿瘤大小；
图4表明喂食抗组胺药与放疗联用对荷瘤小鼠生存的影响。
具体实施方式
下面通过具体实施例对本发明进行说明，但本发明并不局限于此。
下述实施例中所使用的实验方法如无特殊说明，均为常规方法；下述实施例中所用的试剂、生物材料等，如无特殊说明，均可从商业途径得到。
下述实施例中所采用的DPH购自Sigma-Aldrich公司，商品名为Diphenhydraminehydrochloride，批号为D3630。
实施例1：抗组胺药在动物水平对脑胶质瘤移植瘤生长抑制效果的评价
将病人来源的胶质瘤干细胞系GSC 5×104个(GSC由加州大学圣地亚哥分校的Jeremy Rich教授和克利夫兰医学中心的Jennifer S.Yu教授馈赠)，接种进野生型雌性4周龄裸鼠大脑的右额叶处(裸鼠购自北京维通利华实验动物技术有限公司)。
接种10天后，将小鼠分为四组：DMSO组；苯海拉明DPH组(货号：D3630，购自Sigma-Aldrich公司)；异丙嗪Promethazine组(货号：T0445L，购自TargetMol公司)；西替利嗪Cetirizine组(货号：2577，购自Tocris公司)。每组按每天每只小鼠摄入10mg/kg的剂量，将药物添加到小鼠饮用水中。每周更换新鲜饮用水两次。
开始给药后，每7天通过活体成像仪(Caliper公司)监测小鼠颅内肿瘤的生长情况。记录荷瘤小鼠从接种肿瘤到至小鼠出现背弓、消瘦等因负荷肿瘤引起的神经症状的生存时间。
实验结果：
活体成像结果显示与对照组DMSO相比，抗组胺药苯海拉明DPH和异丙嗪Promethazine能够显著抑制移植瘤的生长，但是不能通过血脑屏障的抗组胺药西替利嗪Cetirizine则对移植瘤的生长无明显影响，见图1。
苯海拉明和异丙嗪显著延长荷瘤小鼠的生存时间，而西替利嗪对荷瘤小鼠生存时间无明显影响，见图2。
实施例2：抗组胺药与放疗联用在动物水平对脑胶质瘤移植瘤生长抑制效果的评价
将5×104个GSC接种进野生型雌性4周龄裸鼠大脑的右额叶处。接种10天后，将小鼠分为四组：DMSO组；苯海拉明DPH组(货号：D3630，购自Sigma-Aldrich公司)；放疗组；放疗与苯海拉明DPH联用组。
对于单独用药组，按每天每只小鼠摄入10mg/kg的剂量，将药物添加到小鼠饮用水中。每周更换新鲜饮用水两次。对于放疗组，每周对小鼠脑部进行一次3Gy剂量的钴-60电离辐射，并且添加与单独用药组等量的DMSO于饮用水中。对于联用组，周对小鼠脑部进行一次3Gy剂量的钴-60电离辐射，并且添加与单独用药组等量的DPH于饮用水中。
开始给药后，每7天通过活体成像仪(Caliper公司)监测小鼠颅内肿瘤的生长情况。记录荷瘤小鼠从接种肿瘤到至小鼠出现背弓、消瘦等因负荷肿瘤引起的神经症状的生存时间。
实验结果
苯海拉明DPH对肿瘤生长的抑制效果与放疗相近，且DPH与放疗联用时对移植瘤的生长有更好的抑制作用，见图3。
苯海拉明与放疗联用较单独用药组更显著的延长荷瘤小鼠的生存，见图4。
Claims (8)
1.抗组胺药及其药学上可接受的盐和/或其溶剂化物和/或其水合物在在如下方面的应用：
1)在制备真核生物肿瘤细胞增殖抑制剂中的应用；2)在制备预防和/或治疗肿瘤药物中的应用；
所述肿瘤为HDC高表达的肿瘤。
2.根据权利要求1所述的应用，其特征在于：所述抗组胺药为苯海拉明、异丙嗪、扑尔敏、曲吡那敏、氯苯那敏、赛庚啶、羟嗪、溴苯那敏，二甲茚定，非尼拉敏，曲普利啶、曲美苄胺，卡比沙明，多西拉敏、美吡拉敏，氯吡啉，安他唑林，希司洛啶、帕拉塞嗪、丙酰马嗪、美喹他嗪、布克利嗪、美克洛嗪、阿扎他啶、特非那啶、阿伐司丁、巴米品、氯雷他定中的至少一种。
3.根据权利要求1或2所述的应用，其特征在于：所述肿瘤为人脑胶质瘤、黑色素瘤或结直肠癌。
4.根据权利要求1或2所述的应用，其特征在于：所述的抗组胺药为苯海拉明或异丙嗪。
5.根据权利要求1或2所述的应用，其特征在于：所述抗组胺药包括如下剂型的抗组胺药：片剂、胶囊剂、注射剂、喷雾剂、气雾剂、滴鼻剂、粉雾剂、栓剂、贴剂、凝胶剂。
6.根据权利要求5所述的应用，其特征在于：
所述片剂选自普通片剂、速释片、缓释片、控释片、薄膜衣片、糖衣片、口含片、舌下片、生物粘附片；
所述胶囊剂选自硬胶囊、软胶囊；
所述注射剂选自无菌或者含抑菌剂的水性注射剂、油性注射剂、冷冻干粉针剂、注射用微球；
所述喷雾剂选自口腔喷雾剂、鼻腔喷雾剂、局部皮肤喷雾剂；
所述气雾剂选自肺吸入用气雾剂、局部皮肤气雾剂；
所述滴鼻剂选自滴鼻用溶液、滴鼻用凝胶；
所述粉雾剂选自空腔用粉雾剂、鼻腔用粉雾剂、局部皮肤用粉雾剂。
7.抗组胺药及其药学上可接受的盐和/或其溶剂化物和/或其水合物与放疗联用在治疗HDC高表达的肿瘤中的应用。
8.根据权利要求7所述的应用，其特征在于：所述肿瘤为人脑胶质瘤、黑色素瘤或结直肠癌。
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| WO2014018563A2 (en) * | 2012-07-23 | 2014-01-30 | The Board Of Trustees Of The Leland Stanford Junior University | Methods for the treatment of cancer |
| US20180008588A1 (en) * | 2015-01-19 | 2018-01-11 | Belina Pharma Ab | Antihistamine for use in treatment of breast cancer |
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