CN111818925B - Cdk4/6抑制剂与egfr抑制剂联合在制备治疗肿瘤疾病的药物中的用途 - Google Patents
Cdk4/6抑制剂与egfr抑制剂联合在制备治疗肿瘤疾病的药物中的用途 Download PDFInfo
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- CN111818925B CN111818925B CN201980017473.3A CN201980017473A CN111818925B CN 111818925 B CN111818925 B CN 111818925B CN 201980017473 A CN201980017473 A CN 201980017473A CN 111818925 B CN111818925 B CN 111818925B
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Abstract
本发明提供了CDK4/6抑制剂与EGFR抑制剂联合在制备治疗肿瘤疾病的药物中的用途。具体而言,本发明提供一种细胞周期蛋白依赖性激酶4和6抑制剂(CDK4/6i)与人表皮生长因子受体抑制剂(EGFRi)联合在制备预防或治疗肿瘤疾病的药物中的用途。
Description
本申请要求申请日为2018年05月23日的中国专利申请CN201810499596.2、申请日为2018年09月18日的中国专利申请CN201811086544.9和申请日为2018年10月11日的中国专利申请CN201811182296.8的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明属于医药领域,涉及细胞周期蛋白依赖性激酶4和6(CDK4/6)抑制剂(CDK4/6i)与人表皮生长因子受体抑制剂(EGFRi)联合在制备预防或治疗非小细胞肺癌(NSCLC)的药物中的用途。
背景技术
在世界范围内,肺癌已成为癌症死亡的主要原因。在中国,不论是癌症发生率还是死亡率,肺癌都占据了首位。尽管在过去20年内推出了更新的几代细胞毒性药物和靶向治疗,但是晚期肺癌患者、特别是没有已知的驱动突变基因的患者生存预后仍很差,晚期或转移性肺癌仍是一种有大量医疗需求未被满足的致死性疾病。
非小细胞肺癌(NSCLC)约占所有肺癌的85%,约75%的NSCLC患者发现时已处于中晚期,5年生存率很低。对于晚期或转移性NSCLC患者选择合适的系统性治疗方式仍在临床上存在很大的需求。NSCLC又可分为鳞状细胞癌与非鳞状细胞癌。非鳞状细胞癌包括腺癌、大细胞癌及其他亚型细胞癌。非鳞状细胞癌患者再按照有无驱动突变基因(EGFR突变或ALK基因重排)进一步分类。
EGFR(Epidermal Growth Factor Receptor)是跨膜蛋白酪氨酸激酶erbB受体家族的一员。通过与其配体-例如表皮生长因子(EGF)的结合,EGFR在细胞膜上可以形成同源二聚体,或者与家族中其他的受体(比如erbB2,erbB3,或erbB4)形成异源二聚体。这些二聚体的形成,可引起EGFR细胞内关键的酪氨酸残基磷酸化,从而激活细胞内多个下游的信号通路。这些细胞内信号通路在细胞增殖、生存及抗凋亡中起重要作用。EGFR信号传导通路失调,包括配体及受体的表达增高、EGFR基因扩增以及突变等,可促进细胞向恶性转化,并在肿瘤细胞的增殖、侵袭、转移以及血管形成中起重要作用。EGFR的过度表达已在许多人类恶性疾病中报道,包括膀胱癌、脑肿瘤、头颈癌、胰腺癌、肺癌、乳腺癌、卵巢癌、结肠癌、前列腺癌和肾脏癌。在许多情况下,EGFR的过度表达与患者的预后不良有关。
另外,已有大量研究发现肿瘤与细胞周期反常相关,大部分肿瘤都存在有丝分裂信号蛋白的大量突变/抗有丝分裂信号蛋白缺陷,基因组不稳定性(GIN)和染色体组不稳定性(CIN),这三种基本的细胞周期缺陷都直接或间接由细胞周期蛋白依赖性激酶(CDK)的失控引起。细胞周期蛋白Cyclin B/CDK1、Cyclin A/CDK2、Cyclin E/CDK2、Cyclin D/CDK4、Cyclin D/CDK6和其它杂二聚物(包括CDK3和CDK7)是细胞周期进展的重要调节剂。目前已公开了一些CDK抑制剂,其中CDK4/6抑制剂有abemaciclib、ribociclib、palbociclib等。
现有技术公开了一些CDK激酶抑制剂与EGFR激酶抑制剂联合在制备治疗非小细胞肺癌的的药物中的用途,例如,报告Synergistic combinations between the oral CDKinhibitor,seliciclib,and either EGFR inhibitors or DNA damaging agents inNSCLC(AACR Annual Meeting--Apr 14-18,2007;Los Angeles,CA)中公开CDK激酶seliciclib与EGFR激酶抑制剂联用治疗NSCLC起到了协同的作用,其中seliciclib是靶向CDK2、CDK7和CDK9的抑制剂。
WO2017160568A公开了一种重组人源性lgG1单克隆抗体necitumumab与一种细胞周期蛋白依赖性激酶CDK4和CDK 6抑制剂abemaciclib联用治疗非小细胞肺癌的用途。文献PD 0332991,a selective cyclin D kinase 4/6 inhibitor,sensitizes lung cancercells to treatment with epidermal growth factor receptor tyrosine kinaseinhibitors(Oncotarget.2016 Dec 20;7(51):84951-84964)公开PD 0332991即palbociclib与吉非替尼用于抑制肺腺癌细胞系中的生长。
W02014183520提供了一种有效的CDK4/6抑制剂,其结构如式I所示,WO2016124067公开了上述新的CDK4/6抑制剂的羟乙基磺酸盐,
WO2016054987A公开了一种式(II)结构所示的4-取代-2-(N-(5-烯丙酰胺基)苯基)氨基)嘧啶衍生物,该化合物具有抑制L858R EGFR突变体、T790M EGFR突变体和外显子19缺失激活突变体的活性,可以用来治疗单独或部分地由EGFR突变体活性介导疾病,WO2017161937A公开了式(II)所示EGFR抑制剂的甲磺酸盐,
本发明提供了一种新的CDK4/6抑制剂联合EGFR抑制剂在制备预防或治疗非小细胞肺癌的药物中的用途,并显示了良好的效果。。
发明内容
本发明提供一种CDK4/6抑制剂与EGFR抑制剂联合在制备预防或治疗肿瘤疾病的药物中的用途。
本发明所述肿瘤疾病可以选自乳腺癌、卵巢癌、前列腺癌、黑色素瘤、脑瘤、食管癌、胃癌、肝癌、胰腺癌、结肠直肠癌、肺癌、肾癌、皮肤癌、成胶质细胞瘤、神经母细胞瘤、肉瘤、脂肪肉瘤、骨软骨瘤、骨瘤、骨肉瘤、精原细胞瘤、睾丸肿瘤、子宫癌、头颈肿瘤、多发性骨髓瘤、恶性淋巴瘤、真性红细胞增多症、白血病、甲状腺肿瘤、输尿管肿瘤、膀胱肿瘤、胆囊癌、胆管癌或绒毛膜上皮癌,优选非小细胞肺癌。
本发明提供一种CDK4/6抑制剂与EGFR抑制剂联合在制备预防或治疗肿瘤疾病的药物中的用途,所述肿瘤疾病为EGFR突变的肿瘤疾病。
本发明所述的EGFR突变的肿瘤疾病优选为非小细胞肺癌,优选的EGFR突变体选自L858R EGFR突变体和/或T790M EGFR突变体。
在可选实施方案中,本发明所述的非小细胞肺癌选自鳞状细胞癌和非鳞状细胞癌,优选非磷状细胞癌,其中所述非磷状细胞癌可以是腺癌、大细胞癌及其他亚型细胞癌。
在可选实施方案中,所述的CDK4/6抑制剂可以选自abemaciclib、ribociclib、palbociclib、alvocidib、trilaciclib、voruciclib、AT-7519、G1T-38、FLX-925、INOC-005、G1T28-1、BPI-1178、gossypin、G1T30-1、GZ-38-1、P-276-00、staurosporine、R-547、PAN-1215、PD-0183812、AG-024322、NSC-625987、CGP-82996、PD-171851或式(I)所示化合物或其复合物或其可药用盐,优选abemaciclib、ribociclib、palbociclib、alvocidib或式(I)所示化合物或其复合物或其可药用盐,最优选式(I)所示化合物或其复合物或其可药用盐,
在可选实施方案中,所述的EGFR抑制剂可以选自osimertinib、gefitinib、erlotinib、olmutinib、icotinib、pyrotinib、vandetanib、brigatinib、dacomitinib、afatinib、neratinib、lapatinib、ABT-414、varlitinib、HLX-07、tesevatinib、theliatinib、epitinib succinate、S-222611、poziotinib、AST-2818、GNS-1480、mavelertinib、AP-32788、AZD-3759、nazartinib、Sym-013、allitinib tosylate、tarloxotinib bromide、CK-101、QL-1203、JNJ-61186372、SKLB-1028、TAS-121、Hemay-020、Hemay-022、NRC-2694-A、simotinib hydrochloride、SPH-1188-11、GR-1401、SYN-004、ABBV-221、MP-0274、GC-1118、BPI-15000、DBPR-112、Pirotinib、PB-357、lifirafenib、SCT-200、QLNC-120、agerafenib hydrochloride或式(II)化合物或其立体异构体、其复合物或其可药用盐,优选olmutinib、afatinib、osimertinib、CK-101、erlotinib、icotinib、gefitinib或式(II)化合物或其立体异构体、其复合物或其可药用盐,最优选式(II)化合物或其立体异构体、复合物或其可药用盐,
本发明所述药物的可药用盐可以是盐酸盐、磷酸盐、磷酸氢盐、硫酸盐、硫酸氢盐、亚硫酸盐、乙酸盐、草酸盐、丙二酸盐、戊酸盐、谷氨酸盐、油酸盐、棕榈酸盐、硬脂酸盐、月桂酸盐、硼酸盐、对甲苯磺酸盐、甲磺酸盐、羟乙基磺酸盐、马来酸盐、苹果酸盐、酒石酸盐、苯甲酸盐、双羟萘酸盐、水杨酸盐、香草酸盐、扁桃酸盐、琥珀酸盐、葡萄糖酸盐、乳糖酸盐或月桂基磺酸盐等。
在优选的实施方案中,所述式(I)所示化合物的可药用盐为羟乙基磺酸盐。
在优选的实施方案中,所述式(II)所示化合物的可药用盐为甲磺酸盐。
本发明涉及的CDK4/6抑制剂与EGFR抑制剂在制备预防或治疗肿瘤疾病的药物中的用途,其中所述CDK4/6抑制剂给药频次可以是一日一次、一日二次、一日三次;所述EGFR抑制剂的给药频次可以是一日一次、一日二次、一日三次。
本发明的可选实施方案中,所述CDK4/6抑制剂的剂量选自1-1000mg,给药频次可以是一日一次、一日二次、一日三次;所述EGFR抑制剂的剂量范围选自1-1000mg,给药频次可以是一日一次、一日二次、一日三次。
本发明所述CDK4/6抑制剂的剂量可以选自5mg、10mg、15mg、20mg、25mg、30mg、35mg、40mg、45mg、50mg、55mg、60mg、65mg、70mg、75mg、80mg、85mg、90mg、100mg、125mg、150mg、175mg、200mg、250mg、300mg、350mg、400mg、450mg、500mg,600mg、700mg、750mg、800mg、900mg、1000mg。
本发明所述EGFR抑制剂的剂量可以选自1mg、2.5mg、5mg、7.5mg、10mg、12.5mg、15mg、17.5mg、20mg、22.5mg、25mg、27.5mg、30mg、32.5mg、35mg、37.5mg、40mg、42.5mg、45mg、47.5mg、50mg、52.5mg、55mg、60mg、65mg、70mg、75mg、80mg、85mg、90mg、95mg、100mg、105mg、110mg、120mg、130mg、140mg、150mg、160mg、170mg、180mg、190mg、200mg、210mg、220mg、230mg、240mg、250mg、260mg、270mg、280mg、290mg、300mg、350mg、400mg、450mg、500mg、550mg、600mg、650mg、700mg、750mg、800mg、850mg、900mg、950mg、100mg。
本发明优选的实施方案中,所述CDK4/6抑制剂一日一次给药,给药剂量优选自25mg、50mg、75mg、100mg、125mg、150mg、175mg;所述EGFR抑制剂一日一次给药,给药剂量优选自55mg、110mg、220mg、260mg。
本发明优选的实施方案中,所述CDK4/6抑制剂为式(I)所示化合物或其复合物或其可药用盐,一日一次给药,给药剂量优选自25mg、50mg、75mg、100mg、125mg、150mg、175mg;所述EGFR抑制剂为式(II)化合物或其立体异构体、其复合物或其可药用盐,一日一次给药,给药剂量优选自55mg、110mg、220mg、260mg。
本发明的可选实施方案中,所述CDK4/6抑制剂为式(I)所示化合物羟乙基磺酸盐,一日一次给药,给药剂量可以为25mg、50mg、75mg、100mg、125mg、150mg、175mg,所述EGFR抑制剂为式(II)化合物甲磺酸盐,一日一次给药,给药剂量可选自55mg、110mg、220mg、260mg。
在优选的实施方案中,所述CDK4/6抑制剂为式(I)所示化合物羟乙基磺酸盐,一日一次给药,给药剂量为25mg,所述EGFR抑制剂为式(II)化合物甲磺酸盐,一日一次给药,给药剂量优选自55mg、110mg、220mg、260mg。
在优选的实施方案中,所述CDK4/6抑制剂为式(I)所示化合物羟乙基磺酸盐,一日一次给药,给药剂量为50mg,所述EGFR抑制剂为式(II)化合物甲磺酸盐,一日一次给药,给药剂量优选自55mg、110mg、220mg、260mg。
在优选的实施方案中,所述CDK4/6抑制剂为式(I)所示化合物羟乙基磺酸盐,一日一次给药,给药剂量为75mg,所述EGFR抑制剂为式(II)化合物甲磺酸盐,一日一次给药,给药剂量优选自55mg、110mg、220mg、260mg。
在优选的实施方案中,所述CDK4/6抑制剂为式(I)所示化合物羟乙基磺酸盐,一日一次给药,给药剂量为100mg,所述EGFR抑制剂为式(II)化合物甲磺酸盐,一日一次给药,给药剂量优选自55mg、110mg、220mg、260mg。
在优选的实施方案中,所述CDK4/6抑制剂为式(I)所示化合物羟乙基磺酸盐,一日一次给药,给药剂量为125mg,所述EGFR抑制剂为式(II)化合物甲磺酸盐,一日一次给药,给药剂量优选自55mg、110mg、220mg、260mg。
在优选的实施方案中,所述CDK4/6抑制剂为式(I)所示化合物羟乙基磺酸盐,一日一次给药,给药剂量为150mg,所述EGFR抑制剂为式(II)化合物甲磺酸盐,一日一次给药,给药剂量优选自55mg、110mg、220mg、260mg。
在优选的实施方案中,所述CDK4/6抑制剂为式(I)所示化合物羟乙基磺酸盐,一日一次给药,给药剂量为175mg,所述EGFR抑制剂为式(II)化合物甲磺酸盐,一日一次给药,给药剂量优选自55mg、110mg、220mg、260mg。
本发明优选的实施方式中,所述CDK4/6抑制剂与所述EGFR抑制剂重量比为0.001∶1-1000∶1,优选0.01∶1-100∶1,最优选0.05∶1-50∶1,具体可选500∶1、400∶1、300∶1、200∶1、100∶1、50∶1、25∶1、12.5∶1、10∶1、8∶1、6∶1、5∶1、3.18∶1、2.72∶1、2.27∶1、2∶1、1.81∶1、1.59∶1、1.36∶1、1.14∶1、1∶1、1∶1.1、1∶1.5、1∶1.26、1∶1.47、1∶1.49、1∶1.73、1∶1.76、1∶2、1∶2.08、1∶2.2、1∶2.6、1∶2.93、1∶3.47、1∶3.5、1∶4.4、1∶5、1∶5.2、1∶7.5、1∶8.8、1∶10、1∶10.4、1∶12.5、1∶15、1∶20、1∶25、1∶30、1∶50、1∶75、1∶100、1∶125、1∶150、1∶200、1∶250、1∶300、1∶400、1∶500、1∶600、1∶700、1∶800。
本发明所述联合的给药途径可以选自经口给药、胃肠外给药、经皮给药,所述胃肠外给药包括但不限于静脉注射、皮下注射、肌肉注射,优选口服给药。
本发明所述的方案中,所述的联合任选的还包含其他组分,所述其他组分包括但不限于其他治疗肿瘤疾病的药物中的用途。
本发明还提供了一种治疗肿瘤疾病的药物中的方法,包括向患者施用有效量所述CDK4/6抑制剂与有效量所述EGFR抑制剂。
本发明还涉及一种药物组合物,其包含所述CDK4/6抑制剂与所述EGFR抑制剂以及一种或多种药用载体、赋形剂、稀释剂。所述药物组合物可以制成药学上可接受的任一剂型。例如,可以配制为片剂、胶囊剂、丸剂、颗粒剂、溶液剂、混悬剂、糖浆剂、注射剂(包括注射液、注射用无菌粉末与注射用浓溶液)、栓剂、吸入剂或喷雾剂。
本发明的包含所述CDK4/6抑制剂与所述EGFR抑制剂的药物组合物,可以单独给药,或者与一种或多种治疗剂联合使用。
本发明还提供了一种用于治疗肿瘤疾病的药物中的用途的药物试剂盒,其中包装有本发明所述的药物组合物,其包含所述CDK4/6抑制剂与所述EGFR抑制剂。
本发明将所述CDK4/6抑制剂与所述EGFR抑制剂联合给药,从而增强了肿瘤疾病的药物中的用途,以及改善了治疗效果。
本发明中所述的“联合”是一种给药方式,是指在一定时间期限内给予至少一种剂量的所述CDK4/6抑制剂和至少一种剂量的所述EGFR抑制剂,其中两种物质都显示药理学作用。所述的时间期限可以是一个给药周期内,优选4周内,3周内,2周内,1周内,或24小时以内。可以同时或依次给予所述CDK4/6抑制剂和所述EGFR抑制剂。这种期限包括这样的治疗,其中通过相同给药途径或不同给药途径给予所述CDK4/6抑制剂和所述EGFR抑制剂。
术语“有效量”指在哺乳动物中有效治疗疾病或病症的药物量。在癌症的情况中,治疗有效量的药物可减少癌细胞的数目;缩小肿瘤的尺寸;抑制(即一定程度的减缓和优选阻止)癌细胞浸润到周围器官中;抑制(即一定程度的减缓和优选阻止)肿瘤转移;一定程度的抑制肿瘤生长;和/或一定程度的减轻一种或多种与该病症有关的症状。根据药物可阻止现有癌细胞生长和/或杀死现有癌细胞的程度,它可以是细胞抑制性的和/或细胞毒性的。对于癌症治疗,可通过评估存活持续时间、无进展存活(PFS)持续时间、响应率(RR)、响应持续时间和/或生活质量来测量体内功效。
附图说明
图1.药物A与药物B联用对裸小鼠体重的影响;
图2.药物A与药物B联用对人肺癌细胞NCI-H1975皮下移植瘤模型瘤体积的影响;
图3.药物A与药物B联用对人肺癌细胞NCI-H1975皮下移植瘤模型相对瘤体积的影响。
具体实施方式
以下将结合实施例更详细地解释本发明,本发明的实施例仅用于说明本发明的技术方案,并非限定本发明的实质和范围。
实施例1.评价式(I)所示化合物羟乙基磺酸盐(药物A)与式(II)所示化合物甲磺酸盐(药物B)联用对人非小细胞肺腺癌细胞(NCI-H1975)的增殖抑制作用。
1.实验材料
人肺腺癌细胞NCI-H1975(携带EGFR21外显子L858R突变和20外显子T790M突变)由浙江大学药学院肿瘤与内分泌药理研究室培养并保存于液氮中;
药物A采用WO2016124067A公开的方法制备;
药物B采用WO2017161937A中公开的方法制备。
2.实验方法
将生长状态良好的NCI-H1975细胞接种于96孔板,过夜贴壁生长后,分别给予不同浓度的受试物,每个浓度设三个复孔。受试物式(I)所示化合物羟乙基磺酸盐终浓度设置为0.125、0.25、0.5、1、2μM式(II)所示化合物终浓度设置为5、10nM。受试物单用或合用作用NCI-H1975细胞7d后,用SRB法检测受试物对NCI-H1975细胞的体外增殖抑制作用。
3.结果处理
根据酶标仪测定的OD值,按下列公式计算抑制率:
抑制率(%)=(1-OD给药/OD对照)×100%
4.实验结果
化合物式(I)所示化合物羟乙基磺酸盐在0.125-2μM浓度范围内能浓度依赖性地抑制NCI-H1975细胞生长。药物A与5nM或10nM药物B合用能够增加两种药物分别单用对NCI-H1975细胞的增殖抑制率,具体见表1。
更正页(细则第91条)
表1.
更正页(细则第91条)
实施例2.评价药物A与药物B联用对人肺癌NCI-H1975裸小鼠移植瘤的实验治疗作用
1.实验材料
实验动物:裸小鼠,雌性;8周,接种24只,实际使用18只,提供单位为上海西普尔-必凯实验动物有限公司;
受试药物:药物A、药物B同实施例1;对照药物吉非替尼,由浙江大学药学院提供。
2.实验方法
1)给药剂量和频率
吉非替尼:30mg/kg,一天一次;药物A:100(50)mg/kg,一天一次;药物B:5mg/kg,一天一次。
2)药品配置
称取6mg吉非替尼,加入适量0.5%CMC-Na研磨均匀,转移至EP管,再加入0.5%CMC-Na补至2ml,混匀,得3mg/ml的吉非替尼溶液,现配现用。
称取20mg药物A,加入适量0.5%MC研磨均匀,转移至EP管,再加入0.5%MC补至2ml,混匀,得10mg/ml的药物A溶液,现配现用。
称取1mg药物B,加入适量0.5%MC研磨均匀,转移至EP管,再加入0.5%MC补至2ml,混匀,得0.5mg/ml的药物B溶液,现配现用。
3)模型建立
将1×107人肺癌细胞NCI-H1975细胞注入裸小鼠腋下,待瘤块生长至合适大小后剖取NCI-H1975种鼠瘤块,放入盛有生理盐水的器皿内,剥弃表面血管,切开,去除坏死区域后,将瘤块切成1~2mm3,用套管针将瘤块接入裸小鼠左腋下,待肿瘤生长至平均体积50~150mm3后,18只小鼠分为6组(每组3只),分别为阴性对照组(Control)、吉非替尼30mg/kg组、药物A100(50)mg/kg组、药物B 5mg/kg组、药物A与药物B联用组和药物A与吉非替尼联用组。
4)具体操作方式
所有裸小鼠通过灌胃方式给药,给药容量为10ml/kg,每周称重和测量肿瘤体积2次,给药周期21天,于第22天称量体重测量肿瘤体积后处死小鼠取瘤块称重,计算相对肿瘤体积(RTV)、相对肿瘤增值率(T/C)和肿瘤抑制百分率(IR),做统计学检测(SPSS检验)。
计算公式如下:
(1)TV(tumor volume)=1/2×a×b2,其中a、b分别表示肿瘤的长和宽;
(2)RTV(relative tumor volume)=Vt/V0,其中V0为分组给药时(即d0)所测得的肿瘤体积,Vt为每一次测量时的肿瘤体积;
(3)T/C(%)=TRTV/CRTV×100%,其中TRTV为治疗组的RTV,CRTV为对照组的RTV;
(4)IR(%)=(1-TWt/TWc)×100%,其中TWt为治疗组的瘤重,TWc为对照组的瘤重。
3.实验结果
实验结束时,与阴性对照组相比,各给药组小鼠体重均无明显变化。(详见表2和图1)。
表2.药物A与药物B联用对裸小鼠体重的影响
D1到D12药物A组及合用组的药物A给药剂量为100mg/kg,D13到D21更改为50mg/kg。与阴性对照相比,各组均无显著性差异。
实验结束时,与阴性对照组肿瘤体积732±200mm3相比,第2组到第6组的肿瘤体积分别为477±162mm3、136±83mm3、125±58mm3、17±3mm3和233±104mm3(详见表3和图2)。与阴性对照组RTV值4.77±0.48相比,第2组到第6组RTV值分别为3.18±0.65、0.81±0.33、1.25±0.53、0.18±0.07和1.71±0.71;T/C值分别为66.81%、17.00%、26.14%、3.86%和35.91%(详见表3和图3)。
表3.药物A与药物B联用对皮下移植瘤的作用
实验结束时,与阴性对照组瘤块重量0.5958±0.1900g相比,第2组到第6组的的瘤块重量分别为0.4097±0.1605、0.1269±0.0839、0.1091±0.0621、0.0061±0.0002和0.2153±0.1119g;IR分别为31.24%、78.69%、81.69%、98.98%和63.86%(详见表4)。
表4.药物A与药物B联用对皮下移植瘤肿瘤重量的影响
D1到D12药物A组及合用组的药物A给药剂量为100mg/kg,D13到D21更改为50mg/kg。
本实验条件下,药物A 100(50)mg/kg与药物B 5mg/kg联合用药(q.d.,共21天)能够抑制人肺癌NCI-H1975裸小鼠移植瘤的生长,且作用优于药物A与吉非替尼联用。
Claims (14)
1.一种CDK4/6抑制剂与EGFR抑制剂联合在制备预防或治疗肿瘤疾病的药物中的用途,
所述CDK4/6抑制剂为式(I)所示化合物或其可药用盐,
所述EGFR抑制剂为式(II)化合物或其可药用盐,
所述肿瘤疾病为非小细胞肺癌。
2.根据权利要求1所述的用途,其特征在于:所述的肿瘤疾病为EGFR突变的肿瘤疾病。
3.根据权利要求2所述的用途,其特征在于:所述的EGFR突变体选自L858R EGFR突变体和/或T790M EGFR突变体。
4.根据权利要求1所述的用途,其特征在于:所述的非小细胞肺癌选自鳞状细胞癌和非鳞状细胞癌。
5.根据权利要求4所述的用途,所述非小细胞肺癌为非磷状细胞癌。
6.根据权利要求1所述的用途,其特征在于:所述式(I)所示化合物的可药用盐为羟乙基磺酸盐。
7.根据权利要求1所述的用途,其特征在于:所述式(II)所示化合物的可药用盐为甲磺酸盐。
8.根据权利要求1-7中任一项所述的用途,其特征在于:所述CDK4/6抑制剂的剂量选自1-1000mg,给药频次为一日一次、一日二次、一日三次;所述EGFR抑制剂的剂量范围选自1-1000mg,给药频次为一日一次、一日二次、一日三次。
9.根据权利要求8所述的用途,其特征在于:所述CDK4/6抑制剂与所述EGFR抑制剂重量比选自0.001:1-1000:1。
10.根据权利要求9所述的用途,所述CDK4/6抑制剂与所述EGFR抑制剂重量比选自0.01:1-100:1。
11.根据权利要求10所述的用途,所述CDK4/6抑制剂与所述EGFR抑制剂重量比选自0.05:1-50:1。
12.根据权利要求10所述的用途,其特征在于:所述CDK4/6抑制剂一日一次给药,给药剂量选自25mg、50mg、75mg、100mg、125mg、150mg、175mg;所述EGFR抑制剂一日一次给药,给药剂量选自55mg、110mg、220mg、260mg。
13.一种药物组合物,其包含根据权利要求1-12中任一项所述的CDK4/6抑制剂与EGFR抑制剂,以及一种或多种可药用载体、赋形剂、稀释剂。
14.一种药物试剂盒,其包含根据权利要求13所述的药物组合物。
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