CN115444938A - cGAS抑制剂与化疗药物联合在制备治疗肺癌药物中的用途 - Google Patents
cGAS抑制剂与化疗药物联合在制备治疗肺癌药物中的用途 Download PDFInfo
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Abstract
本发明涉及一种药物组合在制备治疗肿瘤药物中的用途。具体而言，cGAS抑制剂选自式(I)所示化合物或其可药用盐。与单药相比，cGAS抑制剂与化疗药物如顺铂联合进一步增强了抗肿瘤效果。可用于有效杀伤肺癌等肿瘤细胞或耐药性肿瘤细胞，并显著降低顺铂的肾毒性。本发明首次在体内、体外水平证实了cGAS抑制剂对抗肿瘤药物的增敏作用，证实了其作为增敏剂在肺癌、乳腺癌、结直肠癌、胃癌、肝癌、胶质瘤等癌症中的治疗增效作用，并具有副作用小的优点。本发明为有效治疗肺癌提供新的途径和手段。
Description
技术领域
本公开属于医药领域，涉及cGAS抑制剂与化疗药物联合在制备治疗肺癌药物中的用途。
背景技术
恶性肿瘤严重威胁着人类健康，近年来肺癌的发病率和死亡率居高不下。肺癌患者的手段包括手术治疗，放疗以及化疗等。对于早期肺癌患者，手术治疗是最佳治疗方案，但多数确诊时处于中晚期的肺癌患者丧失手术机会，化疗成为改善患者生存质量的重要手段。但目前常规化疗药物易产生耐药和副作用，因此增强传统化疗药物的抗癌活性并降低其不良反应具有重要的临床意义。
近年来，随着肿瘤生物学及“精准医疗”的飞速发展，针对肿瘤细胞内特定靶点的特异性抗肿瘤药物是新药研发的焦点。
cGAS是一种核酸转移酶，可以识别胞质中的DNA，激活干扰素刺激蛋白STING，调控机体免疫应答。另一方面，Zhiyong Mao等人研究(Nature，563(7729):131-136)报道，cGAS可从胞质中“逃逸”至细胞核，抑制DNA双链断裂损伤修复，进而增加了基因组的不稳定性，并最终引起肿瘤发生。已有的研究发现cGAS在多种肿瘤中高表达，因此cGAS成为抗肿瘤药物研发热门靶点。
临床上，治疗肺癌的一线药物为铂类(如顺铂)联合其他如表皮生长因子受体抑制剂类药物。但此类治疗方案易产生耐药性及副作用，如顺铂导致的肾毒性在临床中易发，开发新型药物组合以提升疗效或降低副作用具有重要价值。
本发明首次公开了cGAS抑制剂与铂类化疗药物联合在治疗肺癌中的用途。此药物组合可发挥协同抗肺癌作用，并且具有副作用小的优点。
发明内容
为解决上述问题，本发明提供了一种具有抗肿瘤作用的药物组合物，它包括a)cGAS抑制剂，和b)铂类化疗药物。
在某些实施方案中，本公开中所述的cGAS抑制剂可选G140、G150、PF-06928215、IRAK4-IN-4和式(I)所示化合物或其可药用盐中的一种或多种，优选式(I)所示化合物或其可药用盐。
本在某些实施方案中，本公开中所述的铂类药物可选顺铂、奥沙利铂、卡铂、洛铂的一种或多种，优选所述顺铂。
在某些实施方式中，所述肺癌选自非小细胞肺癌和小细胞肺癌。优选非小细胞肺癌。
在某些实施方案中，所述cGAS抑制剂的给药剂量选自1-1000mg，例如5mg、10mg、15mg、20mg、25mg、30mg、35mg、40mg、45mg、50mg、55ng、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、310mg、320mg、330mg、340mg、350mg、360mg、370mg、380mg、390mg、400mg、420mg、440mg、460mg、480mg、500mg、520mg、540mg、560mg、580mg、600mg、620mg、640mg、680mg、700mg、720mg、740mg、760mg、780mg、800mg、820mg、840mg、860mg、880mg、900mg、920mg、940mg、960mg、980mg、1000mg。给药频次为一日两次或一日一次。
在某些实施方案中，所述cGAS的给药剂量选自1-500mg，例如25mg、50mg、100mg、150mg、200mg、250mg、300mg、350mg、400mg、450mg、500mg。给药频次为一日两次。
在某些实施方案中，所述cGAS的给药剂量选自1-500mg，例如25mg、50mg、100mg、150mg、200mg、250mg、300mg、350mg、400mg、450mg、500mg。给药频次为一日一次。
在某些实施方案中，所述铂类给药剂量选自10-100mg/m2，例如10mg/m2、15mg/m2、20mg/m2、25mg/m2、30mg/m2、35mg/m2、40mg/m2、45mg/m2、50mg/m2、55mg/m2、60mg/m2、65mg/m2、70mg/m2、75mg/m2、80mg/m2、85mg/m2、90mg/m2、95mg/m2、100mg/m2。铂类药物的给药频次为一周一次、两周一次、三周一次、一月一次
本公开还提供了一种治疗肺癌的方法，包括向患者施用本公开所述的cGAS抑制剂与铂类、表皮生长因子受体抑制剂。
本本公开还涉及一种包含cGAS抑制剂与铂类以及一种或多种药用载体、赋形剂、稀释剂的药物组合物。所述药物组合物可以制成药学上可接受的任一剂型。例如片剂、胶囊剂、丸剂、颗粒剂、溶液剂、混悬剂、糖浆剂或注射剂(包括注射液、注射用无菌粉末与注射用浓溶液)。
本公开还涉及一种包含cGAS抑制剂与铂类，可以单独给药，或者与一种或多种治疗剂联合使用。
本公开中式(I)所示化合物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。
本公开所述联合的给药方式选自同时给药、独立地配制并共给药或独立地配制并相继给药。
本公开所述联合的给药途径选自经口给药、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。
本公开所述的方案中，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抗肿瘤药等。
本发明具有抗肿瘤作用的药物组合物，将cGAS抑制剂和铂类药物联合用药，可调控机体免疫应答，抑制细胞DNA损伤修复，达到协同增效和抵抗耐药的作用。最终，本发明的联合用药物中cGAS抑制剂可抑制cGAS向细胞核内转位，进而抑制肿瘤细胞DNA损伤修复作用，同时调控肿瘤微环境，其治疗效果显著优于cGAS抑制剂或铂类药物的药物任意一种单独使用，具有临床推广价值。
以下通过实施例形式的具体实施方式，对本发明的上述内容再作进一步的详细说明。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。
具体实施方式
实施例1：式(I)所示化合物联合化疗药物对人肺癌A549荷瘤裸小鼠皮下移植瘤的药效作用研究。
1、受试药物
药物名称：式(I)所示化合物购自Sigma公司；顺铂购买自阿拉丁公司。
2、药物配制：配制方法：式(I)所示化合物用0.5％羧甲基纤维素(CMC)+1％吐温80溶液配制；顺铂用生理盐水配置。
3、实验动物：BALB/c裸小鼠，6-8周龄，雌性。
4、实验步骤：取对数生长期的A549细胞，0.25％胰蛋白酶消化离心后用无血清DMEM高糖培养基重悬，细胞浓度调整为1×107/mL。细胞悬液接种于裸鼠右前肢腋下(200μL/只)，待肿瘤大小平均接近100-150mm3后开始分组给药，每3天测量小鼠肿瘤长度(a)和宽度(b)。给药方法按照表1的实验方案进行，共计给药21天。给药结束后，小鼠安乐死，称体重并剥离皮下瘤块，称瘤重，计算抑瘤率(结果见表2)。
肿瘤体积(V)计算公式为：
V＝1/2×a×b2，其中a代表肿瘤长度，b代表肿瘤宽度。
计算抑瘤率：抑瘤率(％)＝(1-(治疗组瘤体积/对照组瘤体积))×100。
体重：每3天记录小鼠体重，计算小鼠体重变化(W21-W0)，W21代表处死前体重，W0代表第一次给药前体重。
表1，实验方案
备注：p.o.为口服给药；i.p.为腹腔给药；BID为每天2次给药；QW为每周一次给药。
两药合并Q＝E(a+b)/(Ea+Eb-Ea×Eb)，其中E(a+b)为两药合用的抑制率，即实测合并效应，Ea和Eb为两药单用时的抑制率，分母(Ea+Eb-Ea×Eb)为期望合并效应，Q为两者比值。Q值在0.85～1.15时，两药合并效应为相加(+)，Q值在1.15～20时为协同(++)，Q值＞20为明显协同(+++)，Q值在0.05～0.85时为拮抗，Q值＜0.05为明显拮抗。
实验结果见表2。包括平均值和平均值的标准误差(SEM)，组间肿瘤体积的差异统计分析和在最后一次给药(分组后的第42天)后在最佳治疗时间点进行的药物相互作用所获得的数据分析
表2本发明中药物/药物组合对肺癌A549移植瘤生长抑制作用
注：*P<0.05,**P<0.01与组1相比；##P<0.01与组2相比；$P<0.05,$$P<0.01与组5相比。
由结果可知，本发明所公布的药物组合对于肺癌A549小鼠移植瘤具有显著的治疗作用，给药21天后，二者联合肿瘤抑制率达到85.1％。本发明中化合物式(I)对A549移植瘤的抑制率仅为29.3％，顺铂高剂量抑瘤率为56.1％。化合物式(I)与化疗药物顺铂联合治疗Q值均大于1.2，表明联合用药具有协同增效的效果。小鼠体重的变化显示，化合物式(I)与化疗药物顺铂联合治疗可有效减小毒副作用。
实施例2
联合用药安全性评价。实施例2小鼠处死后，眼眶取血并离心去血清，分别检测血清尿素氮和肌酐的含量，评价联合用药的安全性。血清尿素氮和肌酐如表3，结果显示，顺铂给药组显著导致小鼠血清尿素氮和肌酐升高，而联合用药均未造成血清尿素氮和肌酐含量的升高，证明了联合给药具有较低的肾毒性。
| 组别 | 尿素氮(mmol/L) | 肌酐(μmol/L) |
| 1 | 6.85±2.12 | 37.81±5.56 |
| 2 | 7.33±1.56 | 34.61±4.48 |
| 3 | 33.85±6.21** | 122.97±10.12** |
| 4 | 37.53±5.44** | 132.75±11.33** |
| 5 | 41.11±6.62** | 149.26±13.13** |
| 6 | 9.23±2.95 | 43.42±8.80 |
| 7 | 11.82±3.02 | 47.34±6.06 |
| 8 | 10.25±2.69 | 55.28±7.01 |
与组1相比，**P<0.01。
综上实验结果，本发明所公开的cGAS抑制剂与化疗药物如顺铂联合治疗可有效抑制小鼠肺癌移植瘤的生长，且具有显著协同增效作用。安全性评价显示cGAS抑制剂与顺铂联合用药可显著改善顺铂的肾毒性。以上实验均证实本发明的药物组合具有抗肿瘤活性高、安全性高的优点。
Claims (7)
1.cGAS抑制剂与铂类药物联合在制备预防或治疗肺癌的药物中的用途。
2.根据权利要求1所述的用途，其中所述的cGAS抑制剂选自G140、G150、PF-06928215、IRAK4-IN-4和式(I)所示化合物或其可药用盐中的一种或多种，优选式(I)所示化合物或其可药用盐，
3.根据权利要求1所述的用途，其中所述肺癌选自非小细胞肺癌和小细胞肺癌，优选非小细胞肺癌。
4.根据权利要求1所述的用途，还包括cGAS抑制剂与铂类药物或其可药用盐联合在制备预防或治疗肺癌的药物中的用途，铂类药物顺铂、奥沙利铂、卡铂、洛铂的一种或多种，优选所述顺铂。
5.根据权利要求1-4任意一项所述的用途，其中所述cGAS抑制剂的给药剂量选自1-1000mg。
6.根据权利要求1-4任意一项所述的用途，其中所述铂类药物剂量选自10-100mg/m2。
7.药物组合物，其包cGAS抑制剂与铂类药物，以及一种或多种药用载体、赋形剂、稀释剂。
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