CN116077505A - Kpt-330联合5-fu或奥沙利铂在抗胃癌肿瘤药物中的应用 - Google Patents
Kpt-330联合5-fu或奥沙利铂在抗胃癌肿瘤药物中的应用 Download PDFInfo
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- CN116077505A CN116077505A CN202310060503.7A CN202310060503A CN116077505A CN 116077505 A CN116077505 A CN 116077505A CN 202310060503 A CN202310060503 A CN 202310060503A CN 116077505 A CN116077505 A CN 116077505A
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Abstract
本发明属于医药技术领域，涉及KPT‑330联合5‑FU或奥沙利铂在抗胃癌肿瘤药物中的应用。胃癌原位种植转移模型关键是注入部位，在胃黏膜和肌层之间，不易漏出腹腔及胃腔，使肿瘤形成在胃黏膜组织下，接种2周后原位成瘤率为100％，4‑5周出现血性腹水以及肝脾转移，肝转移率为80％，脾转移为80％；此模型更真实客观地模拟了临床胃癌黏膜原位癌发生发展演变过程，且模型成瘤率和转移率极高，操作简便，术中小鼠死亡率极低，可推荐采用本文这种较为理想的动物模型来研究KPT‑330与奥沙利铂和5‑FU联合药物干预及治疗效果。KPT‑330与奥沙利铂和5‑FU在胃癌中的联合应用，与单药处理组比，可促进肿瘤细胞凋亡以提高化疗敏感性，改善由奥沙利铂和5‑FU耐药。
Description
技术领域
本发明属于医药技术领域，涉及KPT-330联合5-FU或奥沙利铂在抗胃癌肿瘤药物中的应用。
背景技术
胃癌是全球癌症死亡最常见的原因之一，在目前胃癌的治疗中，对可手术的胃癌依据临床分期进行治疗选择。对于符合适应症的早期胃癌，首选内镜治疗，即内镜下黏膜切除术(EMR)和内镜下黏膜下层切除术(ESD)。对于不适合内镜治疗的非食管胃结合部的进展期胃癌患者，目前的治疗标准是D2手术切除联合术后辅助化疗，而对于分期较晚(临床分期Ⅲ期或以上)者，可选择围手术期化疗模式。对于进展期的胃食管结合部癌，可选择新辅助化疗或术前化疗。多种细胞毒性药物，包括铂类化合物、氟尿嘧啶类、紫杉类、蒽环类和伊立替康对胃癌的治疗均有疗效。联合化疗比单药化疗更能延长患者的总生存期。铂类(顺铂或奥沙利铂)联合氟嘧啶(5-FU，卡培他滨或S-1)是目前全球一线治疗晚期胃癌的标准方案。另外，胃癌术前化疗方案包括：奥沙利铂联合卡培他滨(XELOX)，奥沙利铂联合氟尿嘧啶(FOLFOX)，顺铂联合S-1(SP)，奥沙利铂联合S-1(SOX)。但由于胃癌细胞对化疗药物存在多药耐药性，导致化疗的有效率并不理想。化疗药物杀死肿瘤细胞的重要机制之一是诱导细胞凋亡，因此肿瘤细胞凋亡减少是产生多药耐药的主要原因。
本发明旨在通过寻找有效的胃癌靶点，抑制抗凋亡因子的表达，从而增加化疗药物诱导细胞凋亡，增加肿瘤细胞对化疗药的敏感性。
发明内容
为了抑制抗凋亡因子的表达，增加化疗药物诱导细胞凋亡，增加肿瘤细胞对化疗药的敏感性，本发明提供了KPT-330联合5-FU或奥沙利铂在抗胃癌肿瘤药物中的应用。
进一步地，所述KPT-330与所述5-FU的质量比为(3-10)：(3-50)，所述KPT-330和所述奥沙利铂的质量比为(3-10)：(3-10)。
本发明的一个目的是提供一种抗胃癌肿瘤的药物组合物，包括KPT-330以及5-FU和奥沙利铂中的一种。
进一步地，抗胃癌肿瘤的药物组合物中，所述KPT-330与所述5-FU的质量比为(3-10)：(3-50)，所述KPT-330和所述奥沙利铂的质量比为(3-10)：(3-10)。
本发明的一个目的是提供一种筛选和评价抗胃癌肿瘤药物组合物体内有效的办法，将如上任一项所述的抗胃癌肿瘤的药物组合物施用于胃癌原位种植转移模型或异种移植裸鼠皮下瘤模型，若肿瘤发生减小、肿瘤生长速度减慢或小鼠受体生存时间延长，则表明该药物或疗法有效，可将该药物组合物作为胃癌肿瘤的治疗药物。
进一步地，构建胃癌原位种植转移模型的方法包括以下步骤：
裸鼠剑突下方约5mm处沿腹中线左侧横向依次切开左上腹皮肤、腹壁和腹膜，将胃壁暴露于腹腔外，将MKN45-luc细胞悬液注射于胃壁的黏膜和肌层之间，可见透明小皮丘，退针，然后将胃送入腹腔内，缝合腹壁和皮肤，约3-5天后，经生物发光实验观察成功建立了稳定表达荧光素酶luciferase的细胞系，即获得胃癌原位种植转移模型。
进一步地，构建异种移植裸鼠皮下瘤模型的方法包括以下步骤：
将胃癌细胞MKN45注射入无胸腺小鼠的右侧上臂皮下，约3-5天后，待裸鼠腹部或者右侧上臂出现硬结，即获得异种移植裸鼠皮下瘤模型。
进一步地，所述的抗胃癌肿瘤的药物组合物中KPT-330通过灌胃给药，奥沙利铂通过腹腔注射给药，5-FU通过腹腔注射给药。
奥沙利铂或5-FU和KPT-330在胃癌中的联合应用，与单药处理组比，改善由奥沙利铂或5-FU产生的耐药性，可促进肿瘤细胞凋亡以提高化疗敏感性。
附图说明
图1为本发明提供的裸鼠胃原位种植转移模型建立流程图；
图2为本发明提供的裸鼠胃原位种植转移模型结果分析；
图3为实施例1提供的细胞存活曲线；
图4为实施例2提供的对照组、单独给药组和联合给药组肿瘤体积对比图；
图5为实施例2提供的对照组、单独给药组和联合给药组肿瘤体积对比图、肿瘤体积随时间的变化图和平均肿瘤体积对比图。
具体实施方式
为了使本发明的上述目的、特征和优点能够更加明显易懂，下面结合附图对本发明的具体实施方式做详细的说明，但不能理解为对本发明的可实施范围的限定。
常见的裸鼠胃癌原位种植转移模型按部位分为皮下移植和原位种植；按接种肿瘤组织块法类型分为胃囊法、包埋法、OB法和挂线法；还用一种方法是将肿瘤细胞悬液注射入裸鼠脾脏引发肝转移，这种方法不能模拟胃癌胃黏膜演变及浸润转移的过程，且术中由于大出血导致死亡的可能性极高。以上方法转移率极低，浪费大量动物和经费，未能有效建立一种简便、稳定的裸鼠胃癌转移模型。本发明使用裸鼠胃黏膜下注射高侵袭性的MKN45人胃癌细胞悬液的造模方法，可以快速建立大批量小鼠胃癌原位种植转移模型和皮下瘤种植模型。
本发明提供一种筛选和评价抗胃癌肿瘤药物组合物体内有效的办法，将抗胃癌肿瘤的药物组合物施用于胃癌原位种植转移模型或异种移植裸鼠皮下瘤模型，若肿瘤发生减小、肿瘤生长速度减慢或小鼠受体生存时间延长，则表明该药物或疗法有效，可将该药物组合物作为胃癌肿瘤的治疗药物。
进一步地，构建胃癌原位种植转移模型的方法包括以下步骤：
裸鼠剑突下方约5mm处沿腹中线左侧横向依次切开左上腹皮肤、腹壁和腹膜，将胃壁暴露于腹腔外，将MKN45-luc细胞悬液注射于胃壁的黏膜和肌层之间，可见透明小皮丘，退针，然后将胃送入腹腔内，缝合腹壁和皮肤，约3-5天后，经生物发光实验观察成功建立了稳定表达荧光素酶luciferase的细胞系，即获得胃癌原位种植转移模型。
进一步地，构建异种移植裸鼠皮下瘤模型的方法包括以下步骤：
将胃癌细胞MKN45注射入无胸腺小鼠的右侧上臂皮下，约3-5天后，待裸鼠腹部或者右侧上臂出现硬结，即获得异种移植裸鼠皮下瘤模型。
在一个实施例中，构建胃癌原位种植转移模型和异种移植裸鼠皮下瘤模型，用以评价抗胃癌肿瘤的药物组合物体内的有效性。
1、胃癌原位种植转移模型的构建包括以下步骤：
1.1、细胞培养
MKN45人胃癌细胞，用含10％胎牛血清、1％青链霉素双抗混合液的培养基培养于37℃、5％CO2饱和湿度下，常规传代培养。选取处于对数生长且状态良好的MKN45细胞，用0.25％胰蛋白酶消化细胞，将细胞转移至15m离心管中，以4℃，1000rpm，5分钟的条件进行离心，舍弃上层清液。向EP管中加入1ml已预冷的PBS溶液，使用移液枪轻微吹打细胞团块，使其重新悬浮并混匀。再以同样的条件进行离心，舍弃上层清液。上述PBS清洗细胞及离心的步骤重复2次。最后一次离心前进行细胞计数，离心后弃上清，PBS缓冲液重悬并充分混匀细胞，调整细胞浓度为5×1010/L备用，注射的细胞数为5×106个/只。
1.2、慢病毒转染和体外检测MKN45-luc活性
MKN45人胃癌细胞于转染前1d铺于24孔板，将病毒与polybrene(10ug/ml)混合后加入细胞培养液，72h加带有Purmycin培基筛选2周建立稳定表达荧光素酶的细胞系MKN45-luc。倍比稀释法将MKN45-luc铺于24孔板，毎孔加入3ul D-luciferin(150ug/ml),进行生物学发光检测，结果用Bruker MISE软件分析。
1.3、裸鼠胃原位种植转移模型建立
裸鼠术前禁食12h，无菌条件下以1％戊巴比妥钠腹腔注射麻醉，固定小鼠，常规消毒皮肤，剑突下方约5mm处沿腹中线左侧横向用眼科剪依次切开左上腹皮肤、腹壁和腹膜，开口约1.5cm，将胃壁暴露于腹腔外，用胰岛素针与腹壁呈30°倾斜进针，进针深度约为1cm，将100μl的MKN45-luc细胞悬液缓慢注射于胃壁的黏膜和肌层之间，可见透明小皮丘，快速退针，然后将胃送入腹腔内，用0号丝线一次缝合腹壁和皮肤，术后观察动物麻醉情况，直至全部动物全部清醒后，送至饲养室。上述步骤参见图1的步骤A-步骤F，其中，步骤A表示固定体位；步骤B表示定位手术切口；步骤C表示暴露腺胃前壁大弯侧；步骤D表示注射细胞；步骤E表示胃复位；步骤F表示缝合。
1.4、结果
1.4.1术后一般情况及原位瘤生长速度
小鼠于术后20-30min左右开始苏醒，活动自如，术中无牺牲小鼠，术后无大出血、皮肤溃疡及肠梗阻等并发症。逐日观察裸鼠全身状况，运动情况，腹部特征。接种成功2周后的裸鼠上腹可触及直径0.5-0.8cm的硬质肿块；接种部位肿瘤随接种时间的延长呈浸润性增长，1-3周增长缓慢，4-5周时逐渐增大1.0-1.2cm，瘤体浸润壁外，裸鼠进食明显减少，大便呈黏液稀便，出现消瘦、弓背、衰竭等恶病质表征。(见图2C)。
1.4.2成功构建胃癌细胞系MKN45-luc和生物活性分析
胃癌细胞经慢病毒感染和含嘌呤霉素的培基筛选2周后，经生物发光实验观察成功建立了稳定表达荧光素酶luciferase的细胞系(见图2A)；CCK8检测证明与亲本细胞生长无差异(见图2B)。
1.4.3直观解剖观察原位瘤生长情况
胃癌原位裸鼠观察期为5周，结束观察麻醉处死，剖腹取胃，可见整个胃壁全层被肿瘤组织浸润，分不清解剖结构，表面呈不规则的结节状，向周围组织浸润生长，胃壁与网膜粘连，部分裸鼠瘤体与肝脾及腹壁粘连，腹腔内有少量血性腹水；胃壁无弹性，黏膜色深，皱襞表面不平整，走向紊乱，可见出血点和溃疡面，被覆盖较多黏液(见图2F-G)。
胃癌原位种植转移模型关键是注入部位，在胃黏膜和肌层之间，不易漏出腹腔及胃腔，使肿瘤形成在胃黏膜组织下，接种2周后原位成瘤率为100％，4-5周出现血性腹水以及肝脾转移，肝转移率为80％，脾转移为80％；显然，此模型更真实客观地模拟了临床胃癌黏膜原位癌发生发展演变过程，且模型成瘤率和转移率极高，操作简便，术中小鼠死亡率极低，可推荐采用本文这种较为理想的动物模型来研究KPT-330与奥沙利铂和5-FU联合药物干预及治疗效果。
2、异种移植裸鼠皮下瘤模型的构建包括以下步骤：
选取处于对数生长期且细胞状态良好的胃癌细胞MKN45，用0.25％胰蛋白酶消化细胞，将细胞转移至15m离心管中，在常温下，以1000rpm，5分钟的条件进行离心，舍弃上层清液。向EP管中加入1ml已预冷的PBS溶液，使用移液枪轻轻吹打细胞团块，使其重新悬浮并混匀。再次在常温下，以1000rpm，5分钟的条件进行离心，舍弃上层清液。上述PBS清洗及离心的步骤重复3次。最后一次离心前进行细胞计数，离心后弃上清，根据计数结果加入相应体积的不含血清的RMPI-1640培养基，重悬并充分混匀细胞。将胃癌细胞MKN45注射入无胸腺小鼠的右侧上臂皮下，注射的细胞数为5×106个/只。
上述模型构建成功后每日观察成瘤情况，约3-5天后，待裸鼠腹部或者右侧上臂出现硬结。
Exportin-1(XPO1,CRM1，chromosome region maintenance-1)，即染色体区域维持蛋白1，介导约285个不同的蛋白质的核输出，包括一些生长调节蛋白和大部分的肿瘤抑制蛋白如P53、P21、FOXO、BRCA1等，且它们核质运输只能依赖于协助蛋白XPO1，导致其靶蛋白的细胞质错误定位和活性异常。癌细胞通常过度表达XPO1，选择性核输出抑制剂(Selective Inhibitors of Nuclear Export,SINEs)可与XPO1结合，不可逆地抑制其输出蛋白质的能力。KPT-330(selinexor)化合物在血液型肿瘤和软组织以及骨肉瘤中进行临床一二期的研究，通过结合并抑制核输出蛋白XPO1起作用，导致一些肿瘤抑制蛋白在细胞核中的积累，重新启动并放大了它们的肿瘤抑制功能，并能选择性诱导癌细胞凋亡，同时在很大程度上避免损伤正常细胞，本发明利用KPT-330联合5-FU或奥沙利铂为寻求高效低毒胃癌化疗方案提供新策略。
实施例1：为了探究KPT-330是否与胃癌常用化疗药物(5-FU和Oxaplatin)有协同作用，我们测定了联合药物指数(Combination Index,CI)。通过设置如图3所示浓度比例的KPT-330和5-FU/Oxa联合用药处理MKN45细胞后，用CCK8法检测细胞存活数，绘制细胞存活曲线，用CompuSyn软件计算各组CI值。结果显示，KPT-330和5-FU/Oxa联合用药各组CI值均小于1，提示KPT-330对5-FU和Oxaplatin均有协同增敏作用(见图3)。
实施例2：
在胃癌原位种植转移模型中的小鼠接种后小鼠腹部第10天可见到明显的瘤块，分为空白组、奥沙利铂(OXA)组、5-FU组、KPT-330组、KPT330+5-FU组和KPT330+OXA组。
参阅图4，控制组注射生理盐水，奥沙利铂(OXA)组按照5mg/kg的标准给药，5-FU组按照40mg/kg的标准给药，KPT-330组按照3mg/kg的标准给药，KPT330+5-FU组按照3mg/kgKPT-330+40mg/kg 5-FU的标准给药，KPT330+OXA组按照3mg/kg KPT-330+5mg/kg OXA的标准给药，每周两次。奥沙利铂和5FU通过腹腔注射，KPT-330通过灌胃给药，至35天后剥出胃癌原位肿瘤后大体观察，通过测量肿瘤重量，重复测量方差分析显示，联合给药比任一单独给药组肿瘤重量减小差异更显著，提示KPT-330具有杀伤胃癌肿瘤及增强化疗药物敏感性作用(见图4)。
实施例3
异种移植裸鼠皮下瘤模型中的小鼠约3-5天后，待裸鼠腹部或者右侧上臂出现硬结，分为Control组、奥沙利铂(OXA)组、5-FU组、KPT-330组、KPT330+5-FU组和KPT330+OXA组，开始给药，参阅图5控制组注射生理盐水，奥沙利铂(OXA)组按照5mg/kg的标准给药，5-FU组按照40mg/kg的标准给药，KPT-330组按照3mg/kg的标准给药，KPT330+5-FU组按照3mg/kg KPT-330+40mg/kg 5-FU的标准给药，KPT330+OXA组按照3mg/kg KPT-330+5mg/kg OXA的标准给药，每周两次。其中KPT-330通过灌胃给药，OXA通过腹腔注射给药，5-FU通过腹腔注射给药。每7天测量并记录肿瘤的生长体积，一共记录5次。第5周应用脊髓离断技术处死无胸腺小鼠，剥离小鼠背部肿瘤组织进行称量体积重量和拍照记录，应用SPSS软件分析各组之间的差异。通过测量肿瘤重量，计算肿瘤体积，绘制生长曲线，重复测量方差分析显示，与对照相比，单独给药与联合给药组的生长速度明显减慢，且联合给药组更显著，与原位瘤结果一致，单独给药组与联合给药组肿瘤体积明显小于对照组，且联合给药比任一单独给药组肿瘤体积减小差异更显著，提示KPT-330具有杀伤胃癌肿瘤及增强化疗药物敏感性作用(见图5)。
实施例4：实施例4和实施例2基本相同，区别在于，奥沙利铂(OXA)组按照3mg/kg的标准给药，5-FU组按照30mg/kg的标准给药，KPT-330组按照5mg/kg的标准给药，KPT330+5-FU组按照5mg/kg KPT-330+30mg/kg 5-FU的标准给药，KPT330+OXA组按照5mg/kg KPT-330+3mg/kg OXA的标准给药，每周两次。
实施例5：实施例5和实施例3基本相同，奥沙利铂(OXA)组按照3mg/kg的标准给药，5-FU组按照30mg/kg的标准给药，KPT-330组按照5mg/kg的标准给药，KPT330+5-FU组按照5mg/kg KPT-330+30mg/kg 5-FU的标准给药，KPT330+OXA组按照5mg/kg KPT-330+3mg/kgOXA的标准给药，每周两次。
实施例6：实施例6和实施例2基本相同，区别在于，奥沙利铂(OXA)组按照10mg/kg的标准给药，5-FU组按照50mg/kg的标准给药，KPT-330组按照10mg/kg的标准给药，KPT330+5-FU组按照10mg/kg KPT-330+50mg/kg 5-FU的标准给药，KPT330+OXA组按照10mg/kg KPT-330+10mg/kg OXA的标准给药，每周两次。
实施例7，实施例7和实施例3基本相同，奥沙利铂(OXA)组按照10mg/kg的标准给药，5-FU组按照50mg/kg的标准给药，KPT-330组按照10mg/kg的标准给药，KPT330+5-FU组按照10mg/kg KPT-330+50mg/kg 5-FU的标准给药，KPT330+OXA组按照10mg/kg KPT-330+10mg/kg OXA的标准给药，每周两次。
实施例8，实施例8和实施例2基本相同，区别在于，奥沙利铂(OXA)组按照10mg/kg的标准给药，5-FU组按照40mg/kg的标准给药，KPT-330组按照3mg/kg的标准给药，KPT330+5-FU组按照3mg/kg KPT-330+40mg/kg 5-FU的标准给药，KPT330+OXA组按照3mg/kg KPT-330+10mg/kg OXA的标准给药，每周两次。
实施例9，实施例9和实施例3基本相同，区别在于，奥沙利铂(OXA)组按照10mg/kg的标准给药，5-FU组按照40mg/kg的标准给药，KPT-330组按照3mg/kg的标准给药，KPT330+5-FU组按照3mg/kg KPT-330+40mg/kg 5-FU的标准给药，KPT330+OXA组按照3mg/kg KPT-330+10mg/kg OXA的标准给药，每周两次。
本发明建立最接近人体胃癌发生发展过程的动物模型可以真实模拟胃癌的生长及肿瘤转移的过程，是研究该病发病机制及治疗的重要前提和保障，这也必将为筛选KPT-330提高胃癌化疗敏感性的探索提供途径。
KPT-330和奥沙利铂或5-FU在胃癌中的联合应用，与单药处理组比，改善由奥沙利铂或5-FU产生耐药性，可促进肿瘤细胞凋亡以提高化疗敏感性。
Claims (8)
1.KPT-330联合5-FU或奥沙利铂在抗胃癌肿瘤药物中的应用。
2.如权利要求1所述的KPT-330联合5-FU或奥沙利铂在抗胃癌肿瘤药物中的应用，其特征在于，所述KPT-330与所述5-FU的质量比为3-10：3-50，所述KPT-330和所述奥沙利铂的质量比为3-10：3-10。
3.一种抗胃癌肿瘤的药物组合物，其特征在于，包括KPT-330以及5-FU和奥沙利铂中的一种。
4.如权利要求3所述的抗胃癌肿瘤的药物组合物，其特征在于，所述KPT-330与所述5-FU的质量比为3-10：3-50，所述KPT-330和所述奥沙利铂的质量比为3-10：3-10。
5.一种筛选和评价抗胃癌肿瘤药物组合物体内有效的办法，其特征在于，将如权利要求3或4所述的抗胃癌肿瘤的药物组合物施用于胃癌原位种植转移模型或异种移植裸鼠皮下瘤模型，若肿瘤发生减小、肿瘤生长速度减慢或小鼠受体生存时间延长，则表明该药物或疗法有效，可将该药物组合物作为胃癌肿瘤的治疗药物。
6.如权利要求5所述的筛选和评价抗胃癌肿瘤药物组合物体内有效的办法，其特征在于，构建胃癌原位种植转移模型的方法包括以下步骤：
裸鼠剑突下方约5mm处沿腹中线左侧横向依次切开左上腹皮肤、腹壁和腹膜，将胃壁暴露于腹腔外，将MKN45-luc细胞悬液注射于胃壁的黏膜和肌层之间，可见透明小皮丘，退针，然后将胃送入腹腔内，缝合腹壁和皮肤，约3-5天后，经生物发光实验观察成功建立了稳定表达荧光素酶luciferase的细胞系，即获得胃癌原位种植转移模型。
7.如权利要求5所述的筛选和评价抗胃癌肿瘤药物组合物体内有效的办法，其特征在于，构建异种移植裸鼠皮下瘤模型的方法包括以下步骤：
将胃癌细胞MKN45注射入无胸腺小鼠的右侧上臂皮下，约3-5天后，待裸鼠腹部或者右侧上臂出现硬结，即获得异种移植裸鼠皮下瘤模型。
8.如权利要求5所述的筛选和评价抗胃癌肿瘤药物组合物体内有效的办法，其特征在于，所述的抗胃癌肿瘤的药物组合物中KPT-330通过灌胃给药，奥沙利铂通过腹腔注射给药，5-FU通过腹腔注射给药。
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| CN118021819B (zh) * | 2024-04-15 | 2024-07-09 | 中国医学科学院基础医学研究所 | Xpo1抑制剂和mettl3抑制剂联合在制备治疗胃癌的药物中的应用 |
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