CN112569342A - 卡泊芬净和/或其可药用盐在制备抗肿瘤药物中的应用及抗肿瘤药物 - Google Patents
卡泊芬净和/或其可药用盐在制备抗肿瘤药物中的应用及抗肿瘤药物 Download PDFInfo
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Abstract
本发明涉及卡泊芬净和/或其可药用盐在制备抗肿瘤药物中的应用及抗肿瘤药物。本发明将卡泊芬净用于制备抗肿瘤药物,尤其是抗慢性髓细胞白血病、Ph染色体阳性的急性淋巴细胞白血病、肺癌、乳腺癌、肾细胞癌、胰腺癌、脑肿瘤、黑色素瘤、卵巢癌、甲状腺癌、结直肠癌等肿瘤,效果明显。卡泊芬净联合其他抗肿瘤药物,可增强抗瘤药物的抗肿瘤作用,特别与普纳替尼、多柔比星、顺铂、紫杉醇联合应用,可增强这些药物的抗肿瘤作用。
Description
技术领域
本发明涉及卡泊芬净和/或其可药用盐在制备抗肿瘤药物中的应用及抗肿瘤药物,属于生物医药领域。
背景技术
酪氨酸激酶是一种分布在细胞质膜表面的酶偶联型受体,可催化多种底物蛋白质酪氨酸残基磷酸化,在细胞生长、增殖、分化中具有重要作用。与多种肿瘤的发生、发展密切相关,是肿瘤治疗重要靶点之一。酪氨酸激酶抑制剂通过抑制其活性,抑制肿瘤细胞的生长。如酪氨酸激酶抑制剂通过抑制酪氨酸激酶ABL-1(Abelson Tyrosine Kinase-1)、PDGFR((Platelet-Derived Growth Factor Receptor)、VEGFR(Vascular Endothelial GrowthFactor Receptor)、FGFR(Fibroblast Growth Factor)、EGFR(Epidermal Growth FactorReceptor)、ALK(Anaplastic Lymphoma Kinase)等分子抑制慢性粒细胞白血病、非小细胞肺癌、乳腺癌、淋巴瘤等肿瘤细胞的增殖和生长,促进肿瘤细胞死亡。
卡泊芬净为抗真菌药,能抑制真菌细胞壁生成,通过非竞争性抑制葡聚糖合成酶,导致真菌细胞生长过程中细胞壁葡聚糖缺乏,渗透压失常,最终产生真菌细胞溶解。卡泊芬净对于念珠菌、曲霉菌等有良好的抑制活性,目前主要用于侵袭性曲霉菌的治疗。目前尚未有卡泊芬净抗肿瘤作用的报道。
一般的,卡泊芬净的结构式如下式所示:
发明内容
针对现有技术的不足,本发明的目的之一在于提供卡泊芬净和/或其可药用盐在制备抗肿瘤药物中的应用;本发明的目的之二在于提供一种抗肿瘤药物。
本发明采用的技术方案如下:
卡泊芬净和/或其可药用盐在制备抗肿瘤药物中的应用。
进一步地,所述肿瘤包括白血病、肺癌、肾细胞癌、乳腺癌、胰腺癌、脑肿瘤、黑色素瘤、卵巢癌、结直肠癌、甲状腺癌、胃肠道间质瘤、淋巴瘤、肝癌、骨肉瘤、食管癌、头颈癌、前列腺癌、宫颈癌中的一种或几种。
进一步地,所述白血病包括慢性髓细胞白血病、Ph染色体阳性的急性淋巴细胞白血病中的至少一种。
进一步地,所述肺癌包括非小细胞肺癌。
进一步地,所述乳腺癌包括Her2阳性的乳腺癌。
进一步地,所述抗肿瘤药物是抑制人慢性髓细胞白血病细胞(K562)、人非小细胞肺癌细胞(NCI-H358)中的一种或几种生长的药物。
可选的,所述抗肿瘤药物可以制备成药剂学上可以接受的任意一种剂型。
进一步地,所述抗肿瘤药物的剂型包括注射剂、片剂、脂质体、凝胶制剂、胶囊剂、颗粒剂、散剂、口服液、滴丸等中的一种。
进一步地,所述应用中的给药方式为皮下注射、静脉注射、肌肉注射、口服给药、舌下含服、腹腔注射、脑内注射、皮肤粘膜给药或植入的递送装置给药等。
优选地,所述应用中的给药方式为静脉给药。
基于同一发明构思,本发明还提供一种抗肿瘤药物,含有活性成分A和活性成分B,所述活性成分A为卡泊芬净和/或其可药用盐;所述活性成分B包括细胞毒类抗肿瘤药物、表观遗传修饰酶抑制剂、泛素蛋白酶体抑制剂、周期蛋白依赖性激酶抑制剂、免疫检查点抑制剂、抗凋亡蛋白抑制剂、代偿性通路抑制剂、抗新生血管生成药物、其他激酶抑制剂中的一种或几种。其他激酶抑制剂包括PI3K-AKT-mTOR通路抑制剂、MAPK信号通路抑制剂。
进一步地,所述细胞毒类抗肿瘤药物包括影响核酸生物合成的药物、影响DNA结构和功能的药物、干扰转录过程和阻止RNA合成的药物、抑制蛋白质合成与功能药物中的至少一种;优选地,所述影响DNA结构和功能的药物包括顺铂;所述干扰转录过程和阻止RNA合成的药物包括多柔比星;所述酪氨酸激酶抑制剂包括普纳替尼;所述抑制蛋白质合成与功能药物包括紫杉醇;表观遗传修饰酶抑制剂包括组蛋白去乙酰化酶抑制剂。。
申请人研究发现,卡泊芬净和/或其可药用盐联合其他抗肿瘤药物,可增强其他抗肿瘤药物的抗肿瘤作用,特别与普纳替尼、多柔比星、顺铂、紫杉醇等其他抗肿瘤药物联合应用时,可增强这些药物的抗肿瘤作用。联合用药时,活性成分A和活性成分B的质量比为1:(0.25~10),具体可根据药物对不同肿瘤的敏感性而定。
进一步地,活性成分A和活性成分B的质量比为1:(0.25~10),更进一步为1:(0.5~8)。
进一步地,所述肿瘤包括白血病、肺癌、肾细胞癌、乳腺癌、胰腺癌、脑肿瘤、黑色素瘤、卵巢癌、结直肠癌、甲状腺癌、胃肠道间质瘤、淋巴瘤、肝癌、骨肉瘤、食管癌、头颈癌、前列腺癌、宫颈癌中的一种或几种;进一步地,所述白血病包括慢性髓细胞白血病、Ph染色体阳性的急性淋巴细胞白血病中的至少一种;肺癌包括非小细胞肺癌;乳腺癌包括Her2阳性的乳腺癌。
进一步地,所述抗肿瘤药物是抑制人慢性髓细胞白血病细胞(K562)、人非小细胞肺癌细胞(NCI-H358)中的一种或几种生长的药物。
本发明人在离体细胞药物筛选过程中,偶然发现卡泊芬净具有抑制肿瘤细胞生长作用。肿瘤病人在抗肿瘤治疗过程中,往往因并发感染而使用抗生素,如果合用卡泊芬净则将会具有双重效果:达到抗感染和抗肿瘤的效果。
申请人在研究中,利用软件对卡泊芬净和ABL-1、PDGFR、VEGFR、FGFR、EGFR、ALK等蛋白晶体结构进行分子对接,发现卡泊芬净与上述分子具有较好相互作用,表明卡泊芬净有可能通过作用上述分子产生抑制肿瘤生长的作用。
本发明通过实验证实卡泊芬净具有明显抑制慢性髓细胞白血病细胞(K562细胞)作用,K562细胞是BCR-ABL1阳性的细胞,BCR-ABL1具有很强的酪氨酸激酶作活性,根据生物信息学分析和实验结果,可以推测卡泊芬净具有抑制酪氨酸激酶活性作用、继而抑制肿瘤细胞生长。目前,尚未有卡泊芬净抗肿瘤作用的报道。本发明首次证实卡泊芬净能抑制慢性髓细胞白血病细胞K562、人非小细胞肺癌细胞NCI-H358的生长,具有抗肿瘤作用。
目前,尚未发现卡泊芬净和/或其可药用盐在抗癌中应用的报道,本申请的发明人在经过不断的研究后意外发现,卡泊芬净及其可药用盐能够促进肿瘤细胞死亡,抑制肿瘤细胞生长,促进肿瘤细胞分化,具有抗肿瘤作用,可用作治疗和预防癌症。
本发明证实卡泊芬净及其可药用盐能促进肿瘤细胞死亡,抑制肿瘤细胞生长,促进肿瘤细胞分化,具有抗肿瘤作用,扩大其适应症范围。
卡泊芬净为抗真菌药,肿瘤病人在抗肿瘤治疗的过程中,往往因并发感染而使用抗生素;若将卡泊芬净和/或其可药用盐则可达到抗感染和抗肿瘤的双重效果,使病人受益。
本发明将卡泊芬净用于制备抗肿瘤药物,尤其是抗慢性髓细胞白血病、Ph染色体阳性的急性淋巴细胞白血病、肺癌、乳腺癌、肾细胞癌、胰腺癌、脑肿瘤、黑色素瘤、卵巢癌、甲状腺癌、结直肠癌等肿瘤,效果明显。卡泊芬净联合其他抗肿瘤药物,可增强抗瘤药物的抗肿瘤作用,特别与普纳替尼、多柔比星、顺铂、紫杉醇联合应用,可增强这些药物的抗肿瘤作用。
附图说明
图1:卡泊芬净处理慢性髓细胞白血病细胞K562、人非小细胞肺癌细胞NCI-H358细胞24小时和72小时抑制作用曲线。
具体实施方式
以下将参考附图并结合实施例来详细说明本发明。需要说明的是,在不冲突的情况下,本发明中的实施例及实施例中的特征可以相互组合。
实施例1
细胞实验:卡泊芬净对肿瘤细胞生长的抑制作用。
实施药品:将卡泊芬净购于试剂公司。
肿瘤细胞株:慢性髓细胞白血病细胞K562、人非小细胞肺癌细胞NCI-H358购于细胞库。
细胞培养方法:按常规进行,将以上细胞于DMEM培养基中培养(含10%胎牛血清,100U/mL青霉素和链霉素),细胞融合生长至90%时,采用胰酶消化,待细胞皱缩变圆,细胞间隙明显后,立即用培养基终止消化,将细胞打散吹匀为单个悬浮状态,分瓶传代,于37℃、含5%CO2的细胞培养箱中培养。悬浮细胞则无需胰酶消化,直接分瓶传代,于37℃、含5%CO2的细胞培养箱中培养。后续实验采用对数生长期细胞完成。
实验分组:
卡泊芬净对肿瘤细胞抑制作用检测:将卡泊芬净分为多个浓度组,在慢性髓细胞白血病细胞K562、人非小细胞肺癌细胞NCI-H358终浓度分别为0.5、1、2.5、5、10、20、40μmol/L(μM)不等,设置空白对照组,空白对照组仅加入相应容量的生理盐水,分别处理24小时或72小时。
MTS检测细胞活力,评价药物对肿瘤细胞生长的抑制作用
实验结果:
卡泊芬净对肿瘤细胞生长的抑制作用
结果:
1.如表1所示卡泊芬净对人体肿瘤细胞,如人慢性髓细胞白血病细胞K562、人非小细胞肺癌细胞NCI-H358具有抑制作用。
表1卡泊芬净对2种人肿瘤细胞生长的IC50
72小时 | K562 | NCI-H358 |
IC50值(μmol/L) | 2.36 | 10.7 |
2.如图1所示,卡泊芬净处理人慢性髓细胞白血病细胞K562、人非小细胞肺癌细胞NCI-H358细胞72小时,细胞活力明显降低,具有明显的抑制和杀灭肿瘤细胞作用,并呈现出剂量和时间依赖性。
上述实施例发现卡泊芬净可抑制肿瘤细胞生长,促进细胞分化,具有抗肿瘤作用,可用作治疗和预防癌症,为治疗癌症提供了新的药物。
但本发明不局限于上述癌症,故该药同样适用于治疗其他癌症。
上述实施例阐明的内容应当理解为这些实施例仅用于更清楚地说明本发明,而不用于限制本发明的范围,在阅读了本发明之后,本领域技术人员对本发明的各种等价形式的修改均落入本申请所附权利要求所限定的范围。
Claims (10)
1.卡泊芬净和/或其可药用盐在制备抗肿瘤药物中的应用。
2.根据权利要求1所述的应用,其特征在于,所述肿瘤包括白血病、肺癌、肾细胞癌、乳腺癌、胰腺癌、脑肿瘤、黑色素瘤、卵巢癌、结直肠癌、甲状腺癌、胃肠道间质瘤、淋巴瘤、肝癌、骨肉瘤、食管癌、头颈癌、前列腺癌、宫颈癌中的一种或几种。
3.根据权利要求2所述的应用,其特征在于,所述白血病包括慢性髓细胞白血病、Ph染色体阳性的急性淋巴细胞白血病中的至少一种。
4.根据权利要求2所述的应用,其特征在于,所述肺癌包括非小细胞肺癌。
5.根据权利要求2所述的应用,其特征在于,所述乳腺癌包括Her2阳性的乳腺癌。
6.根据权利要求1所述的应用,其特征在于,所述抗肿瘤药物是抑制人慢性髓细胞白血病细胞、人非小细胞肺癌细胞中的一种或几种生长的药物。
7.一种抗肿瘤药物,含有活性成分A和活性成分B,其特征在于,所述活性成分A为卡泊芬净和/或其可药用盐;所述活性成分B包括细胞毒类抗肿瘤药物、表观遗传修饰酶抑制剂、泛素蛋白酶体抑制剂、周期蛋白依赖性激酶抑制剂、免疫检查点抑制剂、抗凋亡蛋白抑制剂、代偿性通路抑制剂、抗新生血管生成药物、其他激酶抑制剂中的一种或几种;优选地,活性成分A和活性成分B的质量比为1:(0.25~10)。
8.根据权利要求7所述的抗肿瘤药物,其特征在于,所述细胞毒类抗肿瘤药物包括影响核酸生物合成的药物、影响DNA结构和功能的药物、干扰转录过程和阻止RNA合成的药物、抑制蛋白质合成与功能药物中的至少一种;优选地,所述影响DNA结构和功能的药物包括顺铂;所述干扰转录过程和阻止RNA合成的药物包括多柔比星;所述酪氨酸激酶抑制剂包括普纳替尼;所述抑制蛋白质合成与功能药物包括紫杉醇;表观遗传修饰酶抑制剂包括组蛋白去乙酰化酶抑制剂。
9.根据权利要求7或8所述的抗肿瘤药物,其特征在于,所述肿瘤包括白血病、肺癌、肾细胞癌、乳腺癌、胰腺癌、脑肿瘤、黑色素瘤、卵巢癌、结直肠癌、甲状腺癌、胃肠道间质瘤、淋巴瘤、肝癌、骨肉瘤、食管癌、头颈癌、前列腺癌、宫颈癌中的一种或几种;进一步地,所述白血病包括慢性髓细胞白血病、Ph染色体阳性的急性淋巴细胞白血病中的至少一种;所述肺癌包括非小细胞肺癌;所述乳腺癌包括Her2阳性的乳腺癌。
10.根据权利要求7或8所述的抗肿瘤药物,其特征在于,所述抗肿瘤药物是抑制人慢性髓细胞白血病细胞、人非小细胞肺癌细胞中的一种或几种生长的药物。
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