CN112274645A - 一种抗结直肠癌的联合用药物组合物及其应用 - Google Patents
一种抗结直肠癌的联合用药物组合物及其应用 Download PDFInfo
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- CN112274645A CN112274645A CN202011364832.3A CN202011364832A CN112274645A CN 112274645 A CN112274645 A CN 112274645A CN 202011364832 A CN202011364832 A CN 202011364832A CN 112274645 A CN112274645 A CN 112274645A
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- Prior art keywords
- colorectal cancer
- fluvoxamine
- combination
- glucuronidase
- erlotinib
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Abstract
本发明涉及一种抗结直肠癌的联合用药物组合物及其应用。所述联合用药物组合物包括β‑葡萄糖醛酸苷酶抑制剂和抗肿瘤药物。本发明所涉及的联合用药物组合物创造性地将β‑葡萄糖醛酸苷酶抑制剂和抗肿瘤药物联合使用,具有比单独抗肿瘤药物更强的抗结直肠癌活性,为结直肠癌的治疗提供了新的策略和思路。
Description
技术领域
本发明属于生物医药领域,具体涉及一种抗结直肠癌的联合用药物组合物及其应用。
背景技术
结直肠癌是常见的消化系统恶性肿瘤,其发病隐匿,死亡率较高。伊利替康是治疗结直肠癌的临床一线用药。伊利替康是在肝脏中完成代谢,会对肝脏造成非常大的负担,大部分服用伊利替康患者,会出现恶心、食欲下降、反胃、消化不良等症状,还会有延迟性腹泻,这样会导致患者出现腹部异常蠕动的情况,严重的还有可能导致患者死亡;或引起患者出现中性粒细胞减少的现象,导致免疫力下降。
氟伏沙明(Fluoxamine maleate,FM)作为抗抑郁临床药物,通过选择性抑制中枢神经突触前膜对5-羟色胺的再摄取,增加突触前膜间隙5-羟色胺的浓度,进而起到对抗抑郁和焦虑的效用。
现有技术中也有对结直肠癌治疗相关策略的报道,CN107158367A公开了结直肠癌干细胞疫苗制备方法及应用,通过使用来源于结直肠癌患者术后瘤组织细胞、人结直肠癌细胞系Lovo或小鼠结直肠癌细胞系CT26经过反复冻融法制备得到CD133+结直肠癌干细胞疫苗。所得CD133+结直肠癌干细胞疫苗能够减低免疫鼠血清TGF-β水平,提高IFN-γ水平,增强脾NK细胞杀伤活性和CDC活性,使免疫鼠抵抗结直肠癌细胞攻击,诱导免疫细胞靶向杀伤CD133+结直肠癌干细胞进而抑制肿瘤的生长。
CN105816886A公开了AMPKα1基因及其表达产物在治疗结直肠癌中的应用。在此基础上,本发明还提供了一种靶向AMPKα1基因的新型基因载体及其对干扰基因片段的包裹方法,所得产物可特异性的沉默抑制AMPKα1基因的表达,实现抑制结直肠癌复发转移、治疗结直肠癌的目的。相比传统的结直肠癌的治疗方法,使用基因技术来预防结直肠癌的复发转移具有特异性和灵敏性,从而使患者在疾病早、中期就能得到有效的复发转移风险预测,针对风险高低,采取相应的预防和治疗措施。
CN109589407A公开了一种用于结直肠癌靶向治疗的介孔钌纳米粒子及其制备方法和应用。包括(1)将三氯化钌溶解到高氯酸溶液中,加入非离子表面活性剂,混合得到混合溶液I;(2)将氨基修饰的胶体二氧化硅纳米粒子加入到混合溶液I中,混合得到混合溶液II;(3)将硼氢化钠溶液加入到混合溶液II中,超声进行反应,待反应结束后水洗、离心,得到中间产物;(4)将中间产物分散到氢氟酸溶液中,然后水洗、干燥,得到用于结直肠癌靶向治疗的介孔钌纳米粒子。本发明制备的钌纳米粒子比表面积大,可负载钌配合物和偶联双特异性抗体,用于靶向抗结直肠癌联合光热和免疫治疗。
但现有技术中对于结直肠癌治疗策略的报道还很有限,且大部分的治疗效果并不显著,因此,开发出一种新的结直肠癌治疗策略是非常有意义的。
发明内容
针对现有技术的不足,本发明的目的在于提供一种抗结直肠癌的联合用药物组合物及其应用,该联合用药物组合物具有比单独的抗肿瘤药物更强的抗结直肠癌活性,为结直肠癌的治疗提供了新的策略和思路。
为达到此发明目的,本发明采用以下技术方案:
第一方面,本发明提供一种抗结直肠癌的联合用药物组合物,所述联合用药物组合物包括β-葡萄糖醛酸苷酶抑制剂和抗肿瘤药物。
本发明所涉及的联合用药物组合物创造性地将抗肿瘤药物和β-葡萄糖醛酸苷酶抑制剂结合起来,具有比单独的抗肿瘤药物更强的抗结直肠癌活性,为结直肠癌的治疗提供了新的策略和思路。
优选地,所述β-葡萄糖醛酸苷酶抑制剂包括氟伏沙明或氟伏沙明盐。
优选地,所述氟伏沙明盐包括氟伏沙明柠檬酸盐、氟伏沙明琥珀酸盐、氟伏沙明磷酸盐、氟伏沙明对甲苯磺酸盐、氟伏沙明氢溴酸盐、氟伏沙明硫酸盐、氟伏沙明乙酸盐或氟伏沙明甲磺酸盐中的任意一种或至少两种的组合。
所述至少两种的组合例如氟伏沙明磷酸盐和氟伏沙明柠檬酸盐的组合、氟伏沙明柠檬酸盐和氟伏沙明琥珀酸盐的组合、氟伏沙明磷酸盐和氟伏沙明对甲苯磺酸盐的组合等,其他任意的组合方式均可选择,在此便不再一一赘述。
优选地,所述抗肿瘤药物包括伊立替康、紫杉醇、多西他赛、卡巴他赛,阿霉素、长春新碱、苯达莫司汀、硼替佐米、环磷酰胺、地塞米松、依托泊什、氛达拉滨、胫基道诺红菌素、异环磷酰胺、来那度胺、美沙拉呤、喷司他汀、泼尼松、吉非替尼、厄洛替尼、奥西替尼、埃克替尼、阿法替尼、达克替尼、劳拉替尼、克唑替尼、布加替尼、艾乐替尼、色瑞替尼、恩曲替尼、达拉非尼、维莫非尼、曲美替尼、卡马替尼、塞尔帕替尼、安罗替尼、拉罗替尼、恩曲替尼、帕博西林、瑞博西林、玻马西林、图卡替尼、拉帕替尼、来那替尼、吡咯替尼、依维莫司、奥拉帕尼、阿培利司、瑞戈非尼、呋喹替尼、阿柏西普、康奈菲尼、伊马替尼、舒尼替尼、瑞普替尼、舒尼替尼、奥拉帕尼、索拉菲尼、乐伐替尼、尼拉帕尼、厄达替尼、帕唑替尼、阿昔替尼、卡博替尼、尼拉帕尼、厄诺替尼、博舒替尼、普纳替尼、依鲁替尼、贝利司他、罗米地辛、卡菲司米托、维莫非尼、达拉非尼、曲美替尼、卡比替尼、维莫德吉、索尼德吉、凡德他尼、依维莫司、帕唑帕尼、他泽司他、泊马度胺、阿仑珠单抗、利妥昔单抗、托西莫单抗、阿特珠单抗、得鲁瓦单抗、纳武单抗、帕姆单抗、特瑞普利单抗、信迪利单抗、卡瑞丽珠单抗、替雷利珠单抗、耐昔妥珠单抗、雷莫芦单抗、贝伐珠单抗、帕妥珠单抗、曲妥珠单抗、西妥昔单抗、帕尼单抗、雷莫芦单抗、伊匹单抗、派姆单抗、奥法木单抗、替伊莫单抗、托西莫单抗、本妥昔单抗、达雷木单抗或埃罗妥珠单抗中的任意一种或至少两种的组合。
所述至少两种的组合例如伊立替康和紫杉醇的组合、紫杉醇和多西他赛的组合、卡巴他赛和阿霉素的组合等,其他任意的组合方式均可选择,在此便不再一一赘述。
作为本发明的最优选技术方案,本发明所涉及的联合用药物组合物将结直肠癌临床一线用药伊立替康和抗抑郁临床药物氟伏沙明结合起来,具有较高的生物安全性,具有比单独的伊立替康更强的抗结直肠癌活性,为结直肠癌的治疗提供了新的策略和思路。其中,氟伏沙明通过抑制β-葡萄糖醛酸苷酶的活性进而使得原本促进β-葡萄糖醛酸苷酶活性的伊立替康对β-葡萄糖醛酸苷酶的作用逆转,因为β-葡萄糖醛酸苷酶可能会降低伊立替康的药效,同时引发一些副作用,本发明所涉及的组合物通过这种逆转作用最终促进联合用药物组合物在治疗结直肠癌中的效果。
优选地,所述联合用药物组合物为单一的复方制剂。
优选地,所述联合用药物组合物为β-葡萄糖醛酸苷酶抑制剂制剂和抗肿瘤药物制剂两种单独的制剂的组合。
优选地,所述两种单独的制剂同时施用。
优选地,所述两种单独的制剂依次施用。
所述联合用药物组合物可以为单一的复方制剂形式,也可以为两种单独的制剂的组合;当为两种单独的制剂的组合时,其用药方式可以为同时施用,也可以为依次施用,例如可以先施用抗肿瘤药物,间隔一段时间再施用β-葡萄糖醛酸苷酶抑制剂,也可以先施用β-葡萄糖醛酸苷酶抑制剂,间隔一段时间再施用抗肿瘤药物,或者抗肿瘤药物和β-葡萄糖醛酸苷酶抑制剂交替施用。
在本发明中,所述制剂的剂型包括药剂学上可接受的任意一种剂型。例如片剂、散剂、混悬剂、颗粒剂、胶囊剂、注射剂、喷雾剂、溶液剂、灌肠剂、乳剂、膜剂、栓剂、贴剂、滴鼻剂或滴丸剂等。
优选地,所述联合用药物组合物还包括药剂学上可接受药用辅料中的任意一种或至少两种的组合。
本发明所述联合用药物组合物可单独给药也可以与辅料搭配做成适当的剂型进行给药,所述辅料包括稀释剂、赋形剂、填充剂、粘合剂、润湿剂、崩解剂、乳化剂、助溶剂、增溶剂、渗透压调节剂、表面活性剂、pH调节剂、抗氧剂、抑菌剂或缓冲剂中的任意一种或至少两种的组合。所述至少两种的组合例如稀释剂和赋形剂的组合、乳化剂和助溶剂的组合、填充剂和粘合剂和润湿剂的组合等。
在本发明中,所述联合用药物组合物的给药途径包括静脉注射、腹腔注射、肌肉注射、皮下注射、口服给药、舌下给药、鼻腔给药或经皮给药,优选腹腔注射。
优选地,所述联合用药物组合物为负载于药用载体上的联合用药物组合物。
优选地,所述药用载体包括脂质体、胶束、树枝状大分子、微球或微囊。
第二方面,本发明提供一种如上所述的抗结直肠癌的联合用药物组合物在制备抗结直肠癌药物中的应用。
第三方面,本发明提供一种氟伏沙明或其盐在制备β-葡萄糖醛酸苷酶活性抑制剂中的应用。
第四方面,本发明还提供一种新型的抗结直肠癌联合疗法,所述抗结直肠癌联合疗法为β-葡萄糖醛酸苷酶抑制剂和抗肿瘤药物的联合使用疗法。将β-葡萄糖醛酸苷酶抑制剂和抗肿瘤药物结合起来,比单一使用常规抗肿瘤药物具有更强的抗结直肠癌活性,能够更有效地延长荷瘤小鼠的生存期,为结直肠癌的治疗提供了新的策略和思路;另外该联合疗法能够显著抑制β-葡萄糖醛酸苷酶的活性,发挥更有效的抗结直肠癌活性。
优选地,所述β-葡萄糖醛酸苷酶抑制剂的给药途径包括静脉注射、腹腔注射、肌肉注射、皮下注射、口服给药、舌下给药、鼻腔给药或经皮给药,优选腹腔注射。
优选地,所述抗肿瘤药物的给药途径包括静脉注射、腹腔注射、肌肉注射、皮下注射、口服给药、舌下给药、鼻腔给药或经皮给药,优选腹腔注射。
相对于现有技术,本发明具有以下有益效果:
本发明所涉及的联合用药物组合物创造性地将抗肿瘤药物和β-葡萄糖醛酸苷酶抑制剂结合起来,具有比单独的抗肿瘤药物更强的抗结直肠癌活性,为结直肠癌的治疗提供了新的策略和思路。β-葡萄糖醛酸苷酶抑制剂通过抑制β-葡萄糖醛酸苷酶的活性进而使得原本促进β-葡萄糖醛酸苷酶活性的抗肿瘤药物对β-葡萄糖醛酸苷酶的作用逆转,最终促进联合用药物组合物在治疗结直肠癌中的效果。
附图说明
图1是实施例1中的标准曲线图;
图2是实施例1中β-葡萄糖醛酸苷酶的相对活性随氟伏沙明浓度变化的曲线图;
图3是实施例2中各组盲肠部位β-葡萄糖醛酸苷酶活性比较结果图;
图4是实施例2中各组回肠部位β-葡萄糖醛酸苷酶活性比较结果图;
图5是实施例3中各组小鼠结肠病理切片图(a为正常组,b为模型组,c为氟伏沙明组,d为伊立替康组,e为联合用药组)。
具体实施方式
下面通过具体实施方式来进一步说明本发明的技术方案。本领域技术人员应该明了,所述实施例仅仅是帮助理解本发明,不应视为对本发明的具体限制。
下面通过具体实施方式来进一步说明本发明的技术方案。本领域技术人员应该明了,所述实施例仅仅是帮助理解本发明,不应视为对本发明的具体限制。
实施例1和实施例2所需的实验材料和试剂如下:
试验动物:雄性C57BL/6小鼠,体重18-22g,合格证号:(京)scxk20060008,购自北京大学医学部实验动物中心。
化学药品和试剂:β-葡萄糖醛酸苷酶粉末(美国Sigma公司);4-硝基苯基β-D-葡糖苷酸(PNPG)(美国Sigma公司);偶氮甲烷(AOM)/硫酸葡聚糖(DSS)(美国Sigma公司)。
化学治疗药物:氟伏沙明,购自丽珠集团丽珠制药厂;伊立替康,购自美国SelleckChemicals。
实施例1
氟伏沙明对β-葡萄糖醛酸苷酶活性抑制作用的评价试验
具体方法为:将β-葡萄糖醛酸苷酶粉末(美国Sigma公司)配制成5U/μL溶液,取33μL加入到1.617mL磷酸盐缓冲液(PBS)中混合均匀,取100μL上述混合液加入到96孔板的33孔中。使用PBS将氟伏沙明配制成一下浓度范围0.0005-10μM,取不同浓度的氟伏沙明各100μL加入到含有β-葡萄糖醛酸苷酶的96孔板中,每个浓度做3个复孔。每孔加入2μL(25mM)反应底物4-硝基苯基β-D-葡糖苷酸(PNPG)(美国Sigma公司),37℃避光反应1h。使用1×PBS对4-硝基苯酚(PNP)进行稀释,稀释后浓度为1-200μM,作为标准溶液,上述不同浓度的标准溶液100μL,各加入150μL 0.2M的Na2CO3,混匀1min后,405nm测定其吸光度,得到标准曲线,如图1所示。得到的标准曲线方程式为y=0.0042x+0.069,R2=0.9948。并计算出IC50,如图2所示,氟伏沙明的IC50=0.3023μM。证明氟伏沙明β-葡萄糖醛酸苷酶的活性有显著的抑制作用。
实施例2
体内试验Ⅰ
具体方法为:氟伏沙明使用时以生理盐水配制成所需浓度。将试验动物笼养,每笼8只,每三日清扫笼舍一次,并适应性饲养1周,实验室室温20-22℃,相对湿度40%-60%,换气扇通气,自然光源12h/日。
将90只小鼠采用偶氮甲烷(AOM)/硫酸葡聚糖(DSS)模型诱导方法建立结直肠癌模型:用12.5mg/kg的AOM腹腔注射后,并用3%DSS饮水7天,之后改为正常饮水14天为1个循环,共循环2次;第3周开始有2/5的小鼠出现结肠管状腺瘤,第4周有3/5小鼠发生腺癌,第6周100%小鼠发生腺癌。选取30只结肠癌模型小鼠,随机分成3组,每组10只。第一组腹腔注射生理盐水,第二组腹腔注射伊利替康(36.8mg/kg),第三组腹腔注射伊利替康(36.8mg/kg)+氟伏沙明(2mg/kg)(同时注射),注射量为20mL/kg,每天注射一次,连续注射7天。
小鼠处死解剖,取等量盲肠和回肠内容物,用5mL 1×PBS溶液匀浆,4000rpm离心10min,将上清液置于无菌EP管中,取2mL待测上清液,检测β-葡萄糖醛酸苷酶的活性。检测采用PNPG法进行。
结果如图3和图4所示(图3为各组盲肠β-葡萄糖醛酸苷酶活性比较结果图,图4为各组回肠β-葡萄糖醛酸苷酶活性比较结果图)。
由图3和图4可知:相对于对照组,单独注射伊利替康会使β-葡萄糖醛酸苷酶的活性有所提高,伊利替康与氟伏沙明联合使用会使β-葡萄糖醛酸苷酶的活性显著下降。
实施例3
体内试验Ⅱ
1、实验材料
1.1实验仪器
离心机(SiGMA)、分析天平(ME204梅特勒-托利多仪器(上海)有限公司)、PH计、眼科镊、小鼠灌胃针、电泳槽(BIO-RAD公司)。
1.2实验试剂
AOM(SiGMA)、生理盐水、DSS(SiGMA)、伊立替康(辉瑞中国公司)、氟伏沙明(丽珠集团丽珠制药厂)、小鼠TNF-ɑ试剂盒(南京建成生物工程研究所)、小鼠IL-6试剂盒(南京建成生物工程研究所)。
1.3实验动物
SPF级雄性C57BL/6小鼠,体重18-22g,购自赣南医学院实验动物中心。
2、实验方法
2.1小鼠分组及给药
小鼠饲养于SPF环境中,光照12h。适应性饲养1周后,随机分组5组,每组12只,共60只,分别为正常组(a组):腹腔注射0.9%生理盐水。模型组(b组):腹腔注射0.9%生理盐水;氟伏沙明组(c组):腹腔注射氟伏沙明2mg/kg;伊立替康组(d组):腹腔注射伊立替康80mg/kg;伊利替康联合氟伏沙明组(e组):腹腔注射伊立替康80mg/kg+氟伏沙明10mg/kg;灌胃量为20mL/kg,造模后1周开始给药,每天注射一次,连续注射7天。
2.2小鼠结直肠癌模型的建立
采用偶氮甲烷(AOM)/硫酸葡聚糖(DSS)模型诱导方法:用10.0mg/kg的AOM腹腔注射后,并用3%DSS饮水7天,之后改为正常饮水14天为1个循环,共循环2次,造模共6周。其中DSS溶液制备:溶解10g DSS于500mL无菌饮用水中,保存在4℃,现配现用。其中AOM溶液制备:将AOM溶解在无菌生理盐水中,放-80℃保存,避免反复冻融,再用无菌生理盐水稀释。
2.3测定小室血清中TNF-ɑ、IL-6含量
连续造模6周,末次给药1h后,摘眼球取血,将血液静止一段时间后,离心(3000rpm,4℃,10min)。离心后取上清液,采用elisa法检测TNF-ɑ、IL-6含量变化(根据南京建成生物工程研究所试剂盒说明书)。
2.4小鼠结肠组织重量的称量
摘眼球取血后将小鼠处死,并放置于冰上解剖,取小鼠结肠组织,用PBS溶液冲洗结直肠,称重。用肠重/体重来表示肠道重量(CW/BW),同时测定肿瘤的体积。
2.5小鼠结肠组织病理切片
将称重后的小鼠结肠组织,放于10%的甲醛中进行固定24h,用PBS清洗之后,用乙醇进行脱水,置于二甲苯I和二甲苯II重静置,再用石蜡进行包埋,后进行切片;再进行HE染色,将切片进行苏木素染色5min,盐酸分化10s,水洗两次后,再用伊红染色3min,用乙醇脱水处理,再用二甲苯I和二甲苯II分别处理3min、5min后,于显微镜下观察。
2.6统计学分析
采用SPSS24.0进行分析,处理实验数据。
3、实验结果
3.1各组小鼠的血清中TNF-ɑ、IL-6检测结果
炎症因子在结肠癌的发生过程中起着重要的作用,通过检测炎症因子能够评价小鼠结肠癌发病情况。用试剂盒检测了各组血清中TNF-ɑ、IL-6的含量,如表1所示,得到以下结论:联合给药组的TNF-ɑ、IL-6含量明显低于伊利替康组、氟伏沙明组和模型组,且和模型组之间存在显著性差异。说明伊利替康与氟伏沙明的联合使用相较于单独使用伊利替康具有更好的降低炎症因子的效果。
表1
注:*表示与模型组比较,P<0.05;**表示与模型组比较,P<0.01。
3.2各组小鼠结肠组织重量、肿瘤体积的结果
表2数据可以反映出各个组别对肿瘤的抑制情况,结肠的重量是结肠癌严重程度的指标,而肿瘤的体积能够很清晰的反映出各个给药组对肿瘤的抑制作用。结果显示联合给药组肿瘤体积、重量明显低于伊利替康组、氟伏沙明组和模型组肿瘤体积和重量,且与模型组之间存在显著性差异。说明伊利替康与氟伏沙明的联合使用相较于单独使用伊利替康具有更好的降低肠重/体重(CW/BW)指数和肿瘤体积的效果。
表2
注:*表示与模型组比较,P<0.05;**表示与模型组比较,P<0.01。
3.3各组小鼠结肠病理切片图结果
结果如图5所示:正常组结构完整,而模型组有纤维化的表现,且遭到破坏,肿瘤恶性程度较高,联合给药组、伊利替康组和氟伏沙明组的纤维化均有缓解,肿瘤恶性程度较模型组低,但是联合给药组的肿瘤恶性程度低于伊利替康组和氟伏沙明组。
综上实验结果,说明伊利替康与氟伏沙明的联合使用相较于单独使用伊利替康具有更好的抗结直肠癌效果。
申请人声明,本发明通过上述实施例来说明本发明的一种抗结直肠癌的联合用药物组合物及其应用,但本发明并不局限于上述实施例,即不意味着本发明必须依赖上述实施例才能实施。所属技术领域的技术人员应该明了,对本发明的任何改进,对本发明产品各原料的等效替换及辅助成分的添加、具体方式的选择等,均落在本发明的保护范围和公开范围之内。
以上详细描述了本发明的优选实施方式,但是,本发明并不限于上述实施方式中的具体细节,在本发明的技术构思范围内,可以对本发明的技术方案进行多种简单变型,这些简单变型均属于本发明的保护范围。
另外需要说明的是,在上述具体实施方式中所描述的各个具体技术特征,在不矛盾的情况下,可以通过任何合适的方式进行组合,为了避免不必要的重复,本发明对各种可能的组合方式不再另行说明。
Claims (10)
1.一种抗结直肠癌的联合用药物组合物,其特征在于,所述联合用药物组合物包括β-葡萄糖醛酸苷酶抑制剂和抗肿瘤药物。
2.如权利要求1所述的抗结直肠癌的联合用药物组合物,其特征在于,所述β-葡萄糖醛酸苷酶抑制剂包括氟伏沙明或氟伏沙明盐;
优选地,所述氟伏沙明盐包括氟伏沙明柠檬酸盐、氟伏沙明琥珀酸盐、氟伏沙明磷酸盐、氟伏沙明对甲苯磺酸盐、氟伏沙明氢溴酸盐、氟伏沙明硫酸盐、氟伏沙明乙酸盐或氟伏沙明甲磺酸盐中的任意一种或至少两种的组合;
优选地,所述抗肿瘤药物包括伊立替康、紫杉醇、多西他赛、卡巴他赛,阿霉素、长春新碱、苯达莫司汀、硼替佐米、环磷酰胺、地塞米松、依托泊什、氛达拉滨、胫基道诺红菌素、异环磷酰胺、来那度胺、美沙拉呤、喷司他汀、泼尼松、吉非替尼、厄洛替尼、奥西替尼、埃克替尼、阿法替尼、达克替尼、劳拉替尼、克唑替尼、布加替尼、艾乐替尼、色瑞替尼、恩曲替尼、达拉非尼、维莫非尼、曲美替尼、卡马替尼、塞尔帕替尼、安罗替尼、拉罗替尼、恩曲替尼、帕博西林、瑞博西林、玻马西林、图卡替尼、拉帕替尼、来那替尼、吡咯替尼、依维莫司、奥拉帕尼、阿培利司、瑞戈非尼、呋喹替尼、阿柏西普、康奈菲尼、伊马替尼、舒尼替尼、瑞普替尼、舒尼替尼、奥拉帕尼、索拉菲尼、乐伐替尼、尼拉帕尼、厄达替尼、帕唑替尼、阿昔替尼、卡博替尼、尼拉帕尼、厄诺替尼、博舒替尼、普纳替尼、依鲁替尼、贝利司他、罗米地辛、卡菲司米托、维莫非尼、达拉非尼、曲美替尼、卡比替尼、维莫德吉、索尼德吉、凡德他尼、依维莫司、帕唑帕尼、他泽司他、泊马度胺、阿仑珠单抗、利妥昔单抗、托西莫单抗、阿特珠单抗、得鲁瓦单抗、纳武单抗、帕姆单抗、特瑞普利单抗、信迪利单抗、卡瑞丽珠单抗、替雷利珠单抗、耐昔妥珠单抗、雷莫芦单抗、贝伐珠单抗、帕妥珠单抗、曲妥珠单抗、西妥昔单抗、帕尼单抗、雷莫芦单抗、伊匹单抗、派姆单抗、奥法木单抗、替伊莫单抗、托西莫单抗、本妥昔单抗、达雷木单抗或埃罗妥珠单抗中的任意一种或至少两种的组合。
3.如权利要求1所述的抗结直肠癌的联合用药物组合物,其特征在于,所述联合用药物组合物为单一的复方制剂。
4.如权利要求1所述的抗结直肠癌的联合用药物组合物,其特征在于,所述联合用药物组合物为β-葡萄糖醛酸苷酶抑制剂制剂和抗肿瘤药物制剂两种单独的制剂的组合。
5.如权利要求4所述的抗结直肠癌的联合用药物组合物,其特征在于,所述两种单独的制剂同时施用。
6.如权利要求4所述的抗结直肠癌的联合用药物组合物,其特征在于,所述两种单独的制剂依次施用。
7.如权利要求1所述的抗结直肠癌的联合用药物组合物,其特征在于,所述联合用药物组合物还包括药剂学上可接受药用辅料中的任意一种或至少两种的组合。
8.如权利要求1所述的抗结直肠癌的联合用药物组合物,其特征在于,所述联合用药物组合物为负载于药用载体上的联合用药物组合物。
9.如权利要求1所述的抗结直肠癌的联合用药物组合物在制备抗结直肠癌药物中的应用。
10.氟伏沙明或其盐在制备β-葡萄糖醛酸苷酶活性抑制剂中的应用。
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