CN115006414A - 人参皂苷Rg3的新用途 - Google Patents
人参皂苷Rg3的新用途 Download PDFInfo
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- CN115006414A CN115006414A CN202210666535.7A CN202210666535A CN115006414A CN 115006414 A CN115006414 A CN 115006414A CN 202210666535 A CN202210666535 A CN 202210666535A CN 115006414 A CN115006414 A CN 115006414A
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Abstract
本发明提供一种人参皂苷Rg3的新用途,具体涉及该化合物或它们的衍生物在制备预防和/或治疗耐药的BRAF(V600E)突变型肿瘤的药物中的用途。本发明的发明人发现,人参皂苷Rg3能有效抑制对BRAF(V600E)靶向药物耐受的肿瘤细胞的增殖,包括固有和获得性耐受的肿瘤细胞,抑制肿瘤生长。该结果显示,人参皂苷Rg3有潜力被开发成为安全有效的、治疗耐药BRAF(V600E)突变型肿瘤的药物。
Description
本申请是申请号为2020106191489、申请日为2020年07月01日、发明名称为“小白菊内酯、木犀草素、金圣草素和人参皂苷Rg3的新用途”的分案申请。
技术领域
本发明属于医药领域,具体涉及天然产物人参皂苷Rg3在制备预防和/或治疗耐药BRAF(V600E)突变型肿瘤的药物中的应用。
背景技术
丝裂原活化蛋白激酶(MAPK)是许多癌症中的关键信号传导途径。BRAF是MAPK途径的一个重要信号分子。对于BRAF突变的描述最初在2002年,其中V600E(第600位缬氨酸被谷氨酸替代)是其最常见的突变。据报道,在甲状腺***状癌(60.83%)、毛细胞白血病(58.33%)、黑色素瘤(48%)、甲状腺未分化癌(35.96%)、浆液性卵巢癌(35%)、乳腺癌(13%)、大肠癌(8.04%)、胶质瘤(6.5%)、非小细胞肺癌(3%)等肿瘤中存在BRAF(V600E)突变。这种突变会导致BRAF的持续活化,从而激活RAF-MEK-ERK信号级联反应,促进细胞增殖和存活,抑制细胞凋亡,最终促进了癌症的进展。
目前,BRAF(V600E)靶向抑制剂维罗非尼(Vemurafenib)、达拉非尼(Dabrafenib)以及BRAF下游MEK的抑制剂曲美替尼(Trametinib)、考比替尼(Cobimetinib)被批准用于治疗黑色素瘤和Erdheim-Chester血癌。虽然这些抑制剂的临床疗效显著,但患者往往在6-8月内出现耐药。联合使用BRAF(V600E)抑制剂和MEK抑制剂能有效提高耐药患者的临床疗效,但患者在接受治疗数月后也对该药物组合产生耐药。此外,BRAF(V600E)突变型大肠癌患者对BRAF(V600E)抑制剂固有耐药,对靶向治疗不敏感。尚无能逆转BRAF(V600E)突变型肿瘤耐药的理想药物。耐药性问题是治疗BRAF(V600E)突变型恶性肿瘤过程中急需解决的难题。
小白菊内酯(Parthenolide)属于倍半萜类化合物,其分子式是C15H20O3,分子量是248.32,结构式如式(I):
以小白菊内酯作为主要活性成分的小白菊提取物是缓解偏头痛、皮肤或其他器官感染症状的常用保健品,提示小白菊内酯有较好的安全性。然而,至今尚未见小白菊內酯对耐药的BRAF(V600E)突变型肿瘤作用的报道。
木犀草素(Luteolin)属于黄酮类化合物,其分子式是C15H10O6,分子量是286.24,结构式如式(II):
木犀草素在金银花、菊花、紫苏等中草药及芹菜、香菜等蔬菜中含量较高。以木犀草素为主要成分的木犀草素复合片、木犀草素复合物胶囊是用于增强人体免疫力的保健品,提示木犀草素均具有较好的安全性。然而尚无有关木犀草素逆转BRAF(V600E)突变型肿瘤耐药作用的报道。
金圣草素(又名金圣草黄素,chrysoeriol)属于黄酮类化合物,其分子式是C16H12O6,分子量是300.3,结构式如式(III):
金圣草素主要存在于青蒿、菊花、金银花等一些清热解毒类中药中。在人体内,金圣草素可由木犀草素经儿茶酚-O-甲基转移酶代谢转化而成。据报道,金圣草素在乳腺癌、肺癌及多发性骨髓瘤模型上具有抗肿瘤作用。但其是否具有逆转BRAF(V600E)突变型肿瘤耐药的作用,国内外尚无报道。
人参皂苷Rg3(Ginsenoside Rg3)属于三萜类化合物,其分子式是C42H72O13,分子量是785.01,结构式如式(IV)。
人参皂苷Rg3可从人参中提取。以人参皂苷Rg3为主要成分的参一胶囊已被国家食品药品监督管理局批准用于肿瘤患者的辅助治疗。然而,尚不清楚人参皂苷Rg3是否能逆转BRAF(V600E)突变型肿瘤细胞的耐药。
目前,关于天然产物小白菊内酯、木犀草素、金圣草素、人参皂苷Rg3是否可逆转肿瘤细胞对BRAF(V600E)抑制剂耐药,国内外均无报导。
发明内容
基于此,本发明的目的在于提供小白菊内酯、木犀草素、金圣草素、人参皂苷Rg3或者它们的衍生物在制备预防和/或治疗耐药BRAF(V600E)突变型肿瘤的药物中的用途。
化合物在制备预防和/或治疗耐药的BRAF(V600E)突变型肿瘤的药物中的用途;所述化合物选自小白菊内酯或其衍生物、木犀草素或其衍生物、金圣草素或其衍生物以及人参皂苷Rg3或其衍生物中的至少一种。
在其中一些实施例中,所述耐药的BRAF(V600E)突变型肿瘤为获得性耐药的BRAF(V600E)突变型肿瘤。
在其中一些实施例中,所述耐药的BRAF(V600E)突变型肿瘤为固有耐药的BRAF(V600E)突变型肿瘤。
在其中一些实施例中,所述耐药的BRAF(V600E)突变型肿瘤耐受BRAF(V600E)靶向药物。
在其中一些实施例中,所述耐药的BRAF(V600E)突变型肿瘤耐受BRAF下游MEK靶向药物。
在其中一些实施例中,所述肿瘤为甲状腺***状癌、白血病、黑色素瘤、甲状腺未分化癌、浆液性卵巢癌、乳腺癌、大肠癌、胶质瘤或者非小细胞肺癌。
在其中一些实施例中,所述药物包含所述化合物以及药学上可接受的辅料。
在其中一些实施例中,所述药物包含质量百分含量为0.1-99%的所述化合物。
在其中一些实施例中,所述药物的剂型为片剂、胶囊剂、颗粒剂、混悬剂、口服液、注射剂或者膏剂。
在其中一些实施例中,所述药物的给药方式为注射给药、口服给药或外用给药。
本发明的有益效果:
本发明的发明人发现,小白菊内酯、木犀草素、金圣草素、人参皂苷Rg3能有效抑制对BRAF(V600E)靶向药物耐受的肿瘤细胞的增殖,包括固有和获得性耐受的肿瘤细胞,抑制肿瘤生长。该结果显示,小白菊内酯、木犀草素、金圣草素、人参皂苷Rg3有潜力被开发成为安全有效的、治疗耐药BRAF(V600E)突变型肿瘤的药物。
附图说明
图1为不同浓度的小白菊内酯对耐药BRAF(V600E)突变型黑色素瘤细胞增殖的影响;
图2为不同浓度的木犀草素对耐药BRAF(V600E)突变型黑色素瘤细胞增殖的影响;
图3为不同浓度的金圣草素对耐药BRAF(V600E)突变型黑色素瘤细胞增殖的影响;
图4为不同浓度的人参皂苷Rg3对耐药BRAF(V600E)突变型黑色素瘤细胞增殖的影响;
图5为小白菊内酯对裸鼠体内耐药的BRAF(V600E)突变型黑色素瘤生长的影响;
图6为金圣草素对裸鼠体内耐药的BRAF(V600E)突变型黑色素瘤生长的影响。
具体实施方式
为了便于理解本发明,下面将对本发明进行更全面的描述。但是,本发明可以以许多不同的形式来实现,并不限于本文所描述的实施例。相反地,提供这些实施例的目的是使对本发明的公开内容的理解更加透彻全面。
除非另有定义,本文所使用的所有的技术和科学术语与属于本发明的技术领域的技术人员通常理解的含义相同。本文中在本发明的说明书中所使用的术语只是为了描述具体的实施例的目的,不是旨在于限制本发明。本文所使用的术语“和/或”包括一个或多个相关的所列项目的任意的和所有的组合。
本发明实施例涉及化合物在制备预防和/或治疗耐药的BRAF(V600E)突变型肿瘤的药物中的用途;所述化合物选自小白菊内酯或其衍生物、木犀草素或其衍生物、金圣草素或其衍生物以及人参皂苷Rg3或其衍生物中的至少一种。例如单独选用小白菊内酯或其衍生物,单独选用木犀草素或其衍生物,单独选用金圣草素或其衍生物,单独选用人参皂苷Rg3或其衍生物,当然并不限于此,也可以将上述化合物结合使用。
优选地,所述耐药的BRAF(V600E)突变型肿瘤为获得性耐药的BRAF(V600E)突变型肿瘤。
优选地,所述耐药的BRAF(V600E)突变型肿瘤为固有耐药的BRAF(V600E)突变型肿瘤。
优选地,所述耐药的BRAF(V600E)突变型肿瘤耐受BRAF(V600E)靶向药物。
优选地,所述BRAF(V600E)靶向药物选自维罗非尼以及达拉非尼中的至少一种。
优选地,所述耐药的BRAF(V600E)突变型肿瘤耐受BRAF下游MEK靶向药物。
优选地,所述BRAF下游MEK靶向药物选自曲美替尼以及考比替尼中的至少一种。
可以理解的是,本发明实施例所述的肿瘤的种类不受限制,可以是存在BRAF(V600E)突变的任何肿瘤,包括但不限于:甲状腺***状癌、白血病、黑色素瘤、甲状腺未分化癌、浆液性卵巢癌、乳腺癌、大肠癌、胶质瘤或者非小细胞肺癌,等等。
优选地,所述药物包含所述化合物以及药学上可接受的辅料。可以理解的是,此处所述的“辅料”可以是根据制备剂型等的要求添加的各种载体、各种助剂等,包括但不限于稀释剂、润湿剂、黏合剂、崩解剂、润滑剂、色香味调节剂、溶剂、增溶剂、助溶剂、乳化剂、抗氧剂、金属络合剂、惰性气体、防腐剂、局部止痛剂、pH调节剂、等渗或等张调节剂,等等。进一步地:稀释剂,如淀粉、蔗糖、纤维素类、无机盐类等;润湿剂,如水、乙醇等;黏合剂,如淀粉浆、糊精、糖、纤维素衍生物、明胶、聚维酮、聚乙二醇等;崩解剂,如淀粉、羧甲基淀粉钠、低取代羟丙基纤维素、联羧甲基纤维素钠、交联聚维酮、表面活性剂、跑腾崩解剂等;润滑剂,如滑石粉、硬脂酸钙、硬脂酸镁、十二烷基硫酸镁、微粉硅胶、聚乙二醇等;色香味调节剂,如色素、香料、甜味剂、胶浆剂、矫臭剂等,具体如品红、木糖醇;溶剂,如水、油、乙醇、甘油、丙二醇、聚乙二醇、二甲基亚砜、液体石蜡、脂肪油、乙酸乙酯等;增溶剂,如吐温类、卖泽类、聚氧乙烯脂肪醇醚类、肥皂类、硫酸化物、磺酸化物等;助溶剂,如有机酸(如枸橼酸)及其盐类、酰胺及胺类化合物、无机盐、聚乙二醇、聚维酮以、甘油等;乳化剂,如司盘类、吐温类、卖泽类、苄泽类、甘油脂肪酸酯、高级脂肪酸盐、硫酸化物、磺酸化物、***胶、西黄耆胶、明胶、果胶、磷脂、琼脂、海藻酸钠、氢氧化物、二氧化硅、皂土等;助悬剂,如甘油、糖浆、***胶、西黄耆胶、琼脂、海藻酸钠、纤维素衍生物、聚维酮、卡波普、聚乙烯醇、触变胶等;抗氧剂,如亚硫酸盐、焦亚硫酸盐、亚硫酸氢盐、抗坏血酸、没食子酸及其酯类等;金属络合剂,如乙二胺四乙酸二钠、多羧酸化合物等;惰性气体,如氮气、二氧化碳等;防腐剂,如尼泊金类、有机酸及其盐(如苯甲酸钠)、季铵类化合物、醋酸氯己定、醇类、酚类以及挥发油等;局部止痛剂,如苯甲醇、三氯叔丁醇、利多卡因以及普鲁卡因等;pH调节剂,如盐酸、硫酸、磷酸、酒石酸、醋酸、氢氧化钠、碳酸氢钠、乙二胺、葡甲胺、磷酸盐、醋酸盐、枸橼酸、枸橼酸盐等;等渗或等张调节剂,如葡萄糖、氯化钠、枸橼酸钠、山梨醇以及木糖醇等。
优选地,所述药物包含质量百分含量为0.1-99%的所述化合物。
本发明所涉可被制成片剂、胶囊剂、颗粒剂、混悬剂、口服液、注射剂、膏剂等任何一种剂型。上述各种剂型的药物均可以按照药学领域的常规方法制备。本发明不受上述所列剂型所限制。
本发明所涉药物可经注射、口服或外用形式给药,给药途径不受上述例子所限制。
本实施例所用小白菊内酯、木犀草素、人参皂苷Rg3购于成都曼思特生物科技有限公司(中国),金圣草素购于Extrasynthese公司(法国)。四种天然产物经HPLC检测,纯度均大于98%。
下面结合具体实施例对本发明作更进一步的说明,以便本领域的技术人员更了解本发明,但不应将此理解为本发明上述主题的范围仅限于以下的实例,凡基于本发明上述内容所实现的技术均属于本发明的范围。
实施例1、不同浓度的小白菊内酯、木犀草素、金圣草素以及人参皂苷Rg3对耐药
BRAF突变型黑色素瘤细胞增殖的影响
1.1、实验材料
(1)小白菊内酯:购于成都曼思特生物科技有限公司;精密称取一定量小白菊内酯,用二甲基亚砜(DMSO)溶解为20mM的小白菊内酯溶液(母液),分装,放-20℃冰箱备用。
(2)木犀草素:购于成都曼思特生物科技有限公司;精密称取一定量木犀草素,用二甲基亚砜(DMSO)溶解为80mM的木犀草素溶液(母液),分装,放-20℃冰箱备用。
(3)金圣草素:购于Extrasynthese公司;精密称取一定量金圣草素,用二甲基亚砜(DMSO)溶解为40mM的金圣草素溶液(母液),分装,放-20℃冰箱备用。
(4)人参皂苷Rg3:购于成都曼思特生物科技有限公司;精密称取一定量人参皂苷Rg3,用二甲基亚砜(DMSO)溶解为60mM的人参皂苷Rg3溶液(母液),分装,放-20℃冰箱备用。
(5)维罗非尼:由LC Laboratories公司生产;精密称取一定量维罗非尼,用DMSO溶解为1mM的维罗非尼溶液(母液),分装,放-20℃冰箱备用。
(6)A375细胞株【携带BRAF(V600E)突变的人黑色素瘤细胞】:购于美国ATCC细胞库,液氮保存。
(7)对维罗非尼获得性耐药的细胞A375-VR:在含有5%FBS和递增浓度(0.1μM→1μM)的维罗非尼的DMEM中培养A375细胞3个月,得到对维罗非尼耐药的黑素瘤细胞A375-VR,后续用含有1μM维罗非尼和5%FBS的DMEM培养细胞,维持其耐药性。
(8)A2058细胞株【携带BRAF(V600E)突变的人黑色素瘤细胞;对BRAF(V600E)抑制剂固有耐药】:购于美国ATCC细胞库,液氮保存。
(9)HaCaT人永生化角质形成细胞:购于美国ATCC细胞库,液氮保存。
(10)HDFa人真皮成纤维细胞:购于美国ATCC细胞库,液氮保存。
(11)成纤维细胞生长试剂盒:购于美国ATCC公司。
(12)DMEM培养基粉末:美国Gibco公司生产。
(13)0.5%胰蛋白酶-EDTA(10X)(Trypsin):100mL/瓶,美国Gibco公司生产。
(14)胎牛血清:500mL/瓶,美国Gibco公司生产。
(15)96孔平底培养板:韩国SPL公司生产;
(16)MTT试剂粉末:Affymetrix公司生产。
1.2、实验仪器
(1)二氧化碳培养箱:nu-4750e型,Nuaire公司生产。
(2)离心机:centrifuge 5702型,Eppendorf公司生产。
(3)生物安全柜:nu-425-400e型,Nuaire公司生产。
(4)电子天平:Mettler Toledo公司生产。
(5)倒置显微镜:Leica公司生产。
(6)水浴器:WNB 14,Memmert GmbH+Co公司生产。
(7)微孔板阅读仪:BIO-RAD公司生产。
1.3、实验方法及结果
(1)调整细胞悬液浓度为3×103/孔,加入96孔培养板内,每孔100μL,置37℃、5%的CO2细胞培养箱培养24小时。
(2)吸除旧培养基,加入含不同药物浓度的5%FBS相应细胞培养基,并设对照组和调零组,每组均设5复孔,继续培养24小时。
小白菊内酯加药组:培养基中药物的终浓度分别为1.25μM、2.5μM、5μM、10μM、20μM。
木犀草素加药组:培养基中药物的终浓度分别为5μM、10μM、20μM、40μM、80μM。
金圣草素加药组:培养基中药物的终浓度分别为5μM、10μM、20μM、30μM、40μM。
人参皂苷Rg3加药组:培养基中药物的终浓度分别为20μM、30μM、40μM、50μM、60μM。
对照组:采用含1‰DMSO的培养基。
调零组:无细胞,只添加与加药组及对照组等体积的不同药物浓度培养基或含1‰DMSO的培养基。
(3)给药结束后按10μL每孔加入浓度为5mg/mL的MTT溶液,4小时后吸出上清液,加入100μL的DMSO溶液,振荡10分钟,使结晶充分溶解。在570nm处检测各孔的OD值。
用以下公式计算细胞存活率:
细胞存活率=【(加药组OD平均值-调零孔OD平均值)/(对照组OD平均值-调零孔OD平均值)×100%】;其中:
加药组OD平均值=各加药组OD值总和/加药组组数;
调零孔OD平均值=各调零孔OD值总和/调零孔数;
对照组OD平均值=各对照组OD值/空白对照组组数;
所述OD值为被检测物吸收掉的光密度,为仪器上直接读取数据。
实验重复3遍。结果见图1、图2、图3、图4。
由图1可见,小白菊内酯显著抑制对维罗非尼获得性耐药(A375-VR)和固有耐药(A2058)的黑色素瘤细胞的增殖,且具有量效关系;而对人正常真皮成纤维细胞HDFa的杀伤作用较小。
由图2可见,木犀草素显著抑制对维罗非尼获得性耐药的A375-VR黑色素瘤细胞的增殖,且具有量效关系;而对人正常真皮成纤维细胞HDFa的杀伤作用较小。
由图3可见,金圣草素显著抑制对维罗非尼获得性耐药的A375-VR黑色素瘤细胞的增殖,且具有量效关系;而对人角质形成细胞HaCaT的杀伤作用较小。
由图4可见,人参皂苷Rg3显著抑制对维罗非尼获得性耐药的A375-VR黑色素瘤细胞的增殖,且具有量效关系;而对人角质形成细胞HaCaT的杀伤作用较小。
实施例2、小白菊内酯对裸鼠体内耐药的BRAF(V600E)突变型黑色素瘤生长的影响
2.1、实验材料
实验动物:雄性BALB/c-nu/nu裸鼠(约8周大小),由香港中文大学动物实验中心提供。在香港浸会大学实验动物中心恒温恒压无菌环境中,自由摄食饮水1周后用于实验。
对维罗非尼获得性耐药的A375-VR细胞:对维罗非尼耐药的黑素瘤细胞A375-VR在实施例1建立,后续用含有1μM维罗非尼和5%FBS的DMEM培养细胞,维持其耐药性。
小白菊内酯腹腔注射液:称取5mg小白菊内酯溶解于1mL的DMSO中,再用PBS稀释至20mL,得到0.25mg/mL小白菊内酯溶液,过滤灭菌,分装,放4℃冰箱保存。
维罗非尼腹腔注射液:称取12.5mg维罗非尼溶解于0.5mL的DMSO中,再用PBS稀释至10mL,得到1.25mg/mL维罗非尼溶液,过滤灭菌,分装,放4℃冰箱保存。
2.2、实验方法与结果:
将A375-VR细胞(浓度为3×106)重悬于0.1mL磷酸盐缓冲盐水(PBS)中并接种到BALB/c-nu/nu裸鼠的背部皮下。
在肿瘤生长至约50mm3时,将小鼠随机分成3组,每组4只,并开始给药。其中:一组为维罗非尼组,每日给予小鼠腹腔注射10mg/kg/天的维罗非尼;一组为小白菊内酯组,每日给予小鼠腹腔注射2mg/kg/天的小白菊内酯;一组为对照组:每日给予小鼠腹腔注射含5%DMSO的PBS溶液;持续给药21天。
在实验期结束时,称体重,处死小鼠、剥离实体瘤、称瘤重,计算抑瘤率(%),结果见图5。
小白菊内酯组裸鼠的瘤重明显低于对照组(P<0.01),小白菊内酯对A375-VR肿瘤生长的抑制率为86.61%,而对小鼠体重无明显影响,说明小白菊内酯可安全有效抑制对维罗非尼耐药的黑色素瘤的生长。
实施例3、金圣草素对裸鼠体内耐药的BRAF(V600E)突变型黑色素瘤生长的影响
3.1、实验材料
实验动物:雄性BALB/c-nu/nu裸鼠(约8周大小),由香港中文大学动物实验中心提供。在香港浸会大学实验动物中心恒温恒压无菌环境中,自由摄食饮水1周后用于实验。
对维罗非尼获得性耐药的A375-VR细胞:对维罗非尼耐药的黑素瘤细胞A375-VR在实施例1建立,后续用含有1μM维罗非尼和5%FBS的DMEM培养细胞,维持其耐药性。
金圣草素腹腔注射液:称取25mg金圣草素溶解于20mL含5%PEG400及5%Tween 80的PBS溶液,得到1.25mg/mL金圣草素溶液,过滤灭菌,分装,放4℃冰箱保存。
曲美替尼腹腔注射液:称取2.5mg曲美替尼溶解于10mL含5%PEG400及5%Tween80的PBS溶液,得到0.25mg/mL曲美替尼溶液,过滤灭菌,分装,放4℃冰箱保存。
3.2、实验方法与结果:
将A375-VR细胞(浓度为3×106)重悬于0.1mL磷酸盐缓冲盐水(PBS)中并接种到BALB/c-nu/nu裸鼠的背部皮下。
于细胞接种后第一天将小鼠随机分成4组,每组4只,并开始给药。其中:一组为金圣草素组,每日给予小鼠腹腔注射10mg/kg的金圣草素;一组为曲美替尼组,每日给予小鼠腹腔注射2mg/kg的曲美替尼(阳性对照组);一组为对照组,每日给予小鼠腹腔注射2mg/kg的含5%PEG400及5%Tween 80的PBS溶液;持续给药14天。
在实验期结束时,称体重,处死小鼠、剥离实体瘤、称瘤重,计算抑瘤率(%)。图6所示为每组最大和最小的肿瘤。
金圣草素组和曲美替尼组裸鼠的瘤重明显低于对照组(P<0.05),金圣草素对A375-VR肿瘤生长的抑制率为59.8%,而对小鼠体重无明显影响,说明金圣草素可安全有效抑制对维罗非尼耐药的黑色素瘤的生长。
以上所述实施例的各技术特征可以进行任意的组合,为使描述简洁,未对上述实施例中的各个技术特征所有可能的组合都进行描述,然而,只要这些技术特征的组合不存在矛盾,都应当认为是本说明书记载的范围。
以上所述实施例仅表达了本发明的几种实施方式,其描述较为具体和详细,但并不能因此而理解为对发明专利范围的限制。应当指出的是,对于本领域的普通技术人员来说,在不脱离本发明构思的前提下,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。因此,本发明专利的保护范围应以所附权利要求为准。
Claims (10)
1.人参皂苷Rg3或其衍生物在制备预防和/或治疗耐药的BRAF(V600E)突变型肿瘤的药物中的用途。
2.根据权利要求1所述的用途,其特征在于,所述耐药的BRAF(V600E)突变型肿瘤为获得性耐药的BRAF(V600E)突变型肿瘤。
3.根据权利要求1所述的用途,其特征在于,所述耐药的BRAF(V600E)突变型肿瘤为固有耐药的BRAF(V600E)突变型肿瘤。
4.根据权利要求1至3任一项所述的用途,其特征在于,所述耐药的BRAF(V600E)突变型肿瘤耐受BRAF(V600E)靶向药物。
5.根据权利要求1至3任一项所述的用途,其特征在于,所述耐药的BRAF(V600E)突变型肿瘤耐受BRAF下游MEK靶向药物。
6.根据权利要求1至3任一项所述的用途,其特征在于,所述肿瘤为甲状腺***状癌、白血病、黑色素瘤、甲状腺未分化癌、浆液性卵巢癌、乳腺癌、大肠癌、胶质瘤或者非小细胞肺癌。
7.根据权利要求1至3任一项所述的用途,其特征在于,所述药物包含所述化合物以及药学上可接受的辅料。
8.根据权利要求7所述的用途,其特征在于,所述药物包含质量百分含量为0.1-99%的所述化合物。
9.根据权利要求1至3以及8任一项所述的用途,其特征在于,所述药物的剂型为片剂、胶囊剂、颗粒剂、混悬剂、口服液、注射剂或者膏剂。
10.根据权利要求1至3以及8任一项所述的用途,其特征在于,所述药物的给药方式为注射给药、口服给药或外用给药。
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