CN111939159A - Nsc 23766辅助肿瘤放射治疗的用途 - Google Patents
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Abstract
本发明涉及生物医药领域，具体涉及NSC 23766在辅助肿瘤放射治疗的用途。本发明的有益效果在于首次发现并证实了NSC 23766增加肿瘤的放疗敏感性。
Description
技术领域
本发明涉及生物医药领域，具体涉及NSC 23766在辅助肿瘤放射治疗的用途。
背景技术
肺癌在全球范围都是发病率较高的肿瘤，在中国，肺癌相关死亡率和致病率逐年增长。最常见的肺癌类型是非小细胞肺癌(non-small cell lung cancers,NSCLCs)占人类肺癌的85％，其常用治疗手段为放疗(radiation therapy,RT)。但是，放疗用于肺癌的治疗仍然并不理想，原因在于癌细胞存在辐射抗性、以及常规治疗剂量下即可出现的对非肿瘤细胞的严重细胞毒性。经过高剂量放疗联合化疗或手术治疗，NSCLC的局部治疗失败率仍然很高，药物或辐射抵抗仍是限制患者预后的主要因素。近年来，局部晚期肺癌的放化疗取得一些进展，尽管如此，大部分患者的疾病仍会复发或进展。其中很大一个原因在于肺癌干细胞的存在，此类细胞能自我更新、增殖并转移，具有明显的辐射抗性。
此外，小细胞肺癌(small cell lung cancer,SCLC)占肺癌的13～15％，是全世界造成癌症相关死亡率的第六大原因。过去几十年中，SCLC的预后几乎没有得到改善，广泛期SCLC(extensive stage SCLC，ES-SCLC)患者的5年生存率低至1～5％。因此，迫切需要新的治疗手段来补充增强现有治疗，改善局限期及广泛期SCLC患者的肿瘤控制。
以上现状都表明，目前仍迫切需要研发高效能、低毒性的新型辐射增敏剂，与放疗联合可有效增强肿瘤细胞死亡，以进一步改善肺癌患者的放疗效果，提高患者治愈率与生存率。
Rho家族成员Ras相关C3肉毒毒素底物1(Ras-related C3 botulinum toxinsubstrate1,Rac1)是一种小分子鸟苷三磷酸(guanosine triphosphate,GTP)酶，在多种细胞事件中起重要作用。NSC 23766(CAS号1177865-17-6)是一种Rac1激活的抑制剂，发明人惊奇的发现，NSC 23766还能够增加肿瘤的放疗敏感性，下式为NSC 23766的结构式。
发明内容
本发明要解决的技术问题是：提供一种NSC 23766的新用途。
在本发明的第一方面，提供了NSC 23766或其药学上可接受的盐在制备肿瘤放射治疗辅助药物中的用途。
在本发明的第二方面，提供了NSC 23766或其药学上可接受的盐在制备肿瘤放射治疗增敏药物中的用途。
具体的，所述用途是指将NSC 23766或其药学上可接受的盐制备成药物从而给进行放射治疗的肿瘤患者施用。
优选的，所述肿瘤选自肺癌；更进一步的，所述肺癌为非小细胞肺癌或小细胞肺癌。
在本发明的第三方面，提供了一种药物组合物，其含有治疗量的NSC 23766及药学上可接受的辅料。
本发明的有益效果在于首次发现并证实了NSC 23766增加肿瘤的放疗敏感性。
附图说明
图1为不同浓度的NSC23766对LLC细胞增殖活力抑制柱状图；
图2为100μM NSC 23766增敏LLC细胞照射后凋亡示意图和统计图；
图3为肺部荷瘤1周后小鼠肿瘤照片；
图4A为肺部荷瘤2周、给药1周后PBS组、NSC组小鼠肿瘤照片；
图4B为图4A的柱状统计图；
图5A为肺部荷瘤3周、给药2周，照射1周后PBS组、NSC组小鼠肿瘤照片；
图5B为图5A的柱状统计图；
图6A为肺部荷瘤4周、给药3周，照射2周后PBS组、NSC组小鼠肿瘤照片；
图6B为图6A的柱状统计图。
具体实施方式
以下结合实例说明本发明，但不限制本发明。在本领域内，技术人员对本发明所做的简单替换或改进均属于本发明所保护的技术方案内。
具体实施方式中雄性野生型C57 BL/6小鼠(6-8周)购于中国科学院(上海)。所有小鼠均饲养于中国人民解放军第二军医大学(上海)动物实验中心无特殊病原体(SPF)实验室。NSC 23766采购自MedChemExpress公司。
实验例1验证NSC 23766抑制LLC细胞增殖活力
使用10μM、50μM、100μM NSC23766孵育小鼠肺癌细胞LLC 2h，随后进行0Gy(未照射)、4Gy和8Gy照射处理，24h后通过CCK-8检测LLC细胞增殖活力。实验结果表明：①抑制Rac1本身可显著降低LLC细胞增殖活力；②50μM及100μM给药组均可显著降低不同剂量照射后LLC的细胞增殖活力，即增敏照射对LLC细胞的损伤效应。
如图1所示，不同剂量Rac1抑制剂NSC23766对LLC细胞系细胞增殖活力CCK-8检测。***代表对应分组与同照射剂量下PBS对照组相比，P＜0.001。误差值采用mean±SEM，N＝6。
实验例2验证NSC 23766促进小鼠肺癌细胞照射后凋亡
PBS或100μM NSC23766孵育小鼠肺癌细胞LLC 2h，0Gy(未照射)或10Gy照射处理，24h后使用流式细胞仪Annexin V/PI法检测细胞凋亡情况。实验结果表明：①0Gy未照射条件下，给药组与对照组LLC细胞凋亡率无明显差异；②10Gy照射后，各组细胞凋亡率显著增加；③10Gy照射后，给药组细胞凋亡率显著高于对照组(P＜0.05)。以上结果表明，照射引起小鼠肺癌细胞LLC凋亡，NSC 23766可增加LLC细胞照射后凋亡，即对小鼠肺癌细胞的放射性损伤存在一定增敏效应。
图2为Annexin V/PI法流式细胞仪凋亡检测示意图，其中图2中B部分为A部分的统计图。n.s.代表两组相比差异无统计学意义，即P＞0.05，*代表两组相比P＜0.05。
实验例3动物实验
取6～8周C57BL/6雄性小鼠共33只。将肿瘤细胞用含EDTA胰酶消化后，加入培养基重悬并行细胞计数。将细胞悬液稀释至4×107个细胞/ml。培养基与基质胶1:1，每只小鼠于右侧腋窝下切口向右肺部注射50ul，即每只小鼠肺部荷瘤细胞数为1×106个。肺部荷瘤1周后，颈椎脱臼法处死3只，剥除右侧肺上肿瘤，采用称重法测量肺部成瘤大小，肿瘤照片及重量如图3所示。
第2周起，肺部荷瘤小鼠随机分为2组：腹腔注射PBS组、腹腔注射3mg/kg NSC23766组，每组15只，均为隔日注射一次；分别记为PBS组、NSC组。给药一周后，再次每组取材3只，剥除右侧肺部肿瘤，测量各组肺部成瘤大小，肿瘤照片及重量如图4A所示，图4B为图4A的统计图(n＝3)。随后，各组小鼠再随机分为2个亚组：肺部局部照射组(IR)、未照射对照组(noIR)。肺部局部照射剂量为25Gy。此时共产生4组小鼠：NC+PBS+no IR组、NC+PBS+IR组、NC+NSC+no IR组、NC+NSC+IR组，每组6只。照射1周后再次取材，每组3只，剥除右侧肺部肿瘤，测量肿瘤大小，其照片如图5A所示，图5B为图5A的统计图(n＝3)。荷瘤后第4周，即照射后2周，未照射4组均无存活，剩余照射4组进行最后一次取材观察，每组3只，剥除右侧肺部肿瘤，测量肿瘤大小，其照片如图6A所示，图6B为图6A的统计图(n＝3)。
以上所述的仅是本发明的优选实施方式，应当指出，对于本领域的普通技术人员来说，在不脱离本发明创造构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。
Claims (5)
1.NSC 23766或其药学上可接受的盐在肿瘤放射辅助治疗中的用途。
2.NSC 23766或其药学上可接受的盐在制备肿瘤放射治疗增敏药物中的用途。
3.如权利要求1或2所述的用途，其特征在于，所述肿瘤选自肺癌。
4.如权利要求3所述的用途，其特征在于，所述肺癌为非小细胞肺癌或小细胞肺癌。
5.一种药物组合物，其含有治疗量的NSC 23766或其药学上可接受的盐及药学上可接受的辅料。
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| CN112618549A (zh) * | 2020-11-27 | 2021-04-09 | 中国人民解放军第二军医大学 | Nsc 23766在防护肝缺血再灌注损伤中的用途 |
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Non-Patent Citations (2)
| Title |
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| NI AN 等: "Inhibition of Rac1 Attenuates Radiation-Induced Lung Injury while Sensitizes Lung Tumor to Radiotherapy", 《RESEARCH SQUARE》 * |
| SHIMING TAN 等: "RAC1 Involves in the Radioresistance by Mediating Epithelial-Mesenchymal Transition in Lung Cancer", 《FRONTIERS IN ONCOLOGY》 * |
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| CN112618549A (zh) * | 2020-11-27 | 2021-04-09 | 中国人民解放军第二军医大学 | Nsc 23766在防护肝缺血再灌注损伤中的用途 |
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