CN101940569A含有索拉非尼和青蒿素及青蒿素类衍生物的药物组合物及其在制备治疗癌症的药物中的应用|Medicament composition containing sorafenib, artemisinin and artemisinin derivative and application thereof in preparing medicament for treating cancer
The invention relates to a medicament composition containing sorafenib, artemisinin and an artemisinin derivative and application thereof in preparing a medicament for treating lung cancer, pancreas cancer, colon cancer, liver cancer, prostatic cancer, kidney cancer, stomach cancer, brain tumor, sarcoma, ovarian cancer or breast cancer. The medicament composition has remarkable synergistic effect, improves the curative effect of the medicament, reduces the administration dosage and reduces side effects.
本发明涉及一种含有索拉非尼与青蒿素及青蒿素类衍生物的药物组合物及其在制备治疗肺癌、胰腺癌、结肠癌、肝癌、前列腺癌、肾癌、胃癌、脑瘤、肉瘤、卵巢癌或乳腺癌的药物中的应用,本发明药物组合物具有显著的协同效应,提高了药物的疗效,降低了给药剂量,减少了副作用的发生。
含有索拉非尼和青蒿素及青蒿素类衍生物的药物组合物及其在制备治疗癌症的药物中的应用
技术领域
本发明涉及一种药物组合物及其在制备治疗癌症的药物中的应用,具体涉及含有索拉非尼和青蒿素及青蒿素类衍生物的药物组合物及其在制备治疗肺癌、胰腺癌、结肠癌、肝癌、前列腺癌、肾癌、胃癌、脑瘤、肉瘤、卵巢癌或乳腺癌的药物中的应用。
背景技术
世界卫生组织调查报告表明,全球癌症状况日益严重,今后20年新患者的人数将由目前的每年1000万增加到1500万,因癌症而死亡的人数也将由每年的600万增加至1000万。其中肺癌为常见的恶性肿瘤之一,源于各级支气管上皮,分为细胞肺癌和非小细胞肺癌;胰腺癌多发生于胰头部,90%来源于胰管上皮细胞,其余来自胰腺腺泡,为消化系统常见的恶性肿瘤,发病率呈逐年上升趋势。由于起病隐匿,缺乏有效的早期诊断方法,确诊时往往已到晚期或发生转移,晚期患者中位生存期不超过六个月;结肠癌的发病与环境、生活习惯,尤其是饮食方式有关。一般认为高脂肪饮食和纤维素不足是主要发病原因。随着生活水平的提高,饮食结构的改变,结肠癌的发病率呈逐年上升趋势;原发性肝癌为发生在肝细胞与肝内胆管上皮细胞的癌变,是人类最常见的恶性肿瘤之一;前列腺癌是男性泌尿生殖系统肿瘤中最重要的一种,是人类特有的疾病。前列腺癌为老年病,大多在50岁以后发病。随着人类平均寿命的延长、诊断技术的提高,生活方式的改变,前列腺癌的发病率在不断上升,因此研究前列腺癌的治疗药物迫在眉睫。
目前已上市的抗肿瘤药物较多,如烷化剂药物、抗代谢药物、抗肿瘤抗生素、免疫调节剂等,但是大多药物由于毒性较大,病人不耐受。随着对肿瘤的发生发展的分子机制研究越来越清楚,分子靶向治疗多种恶性肿瘤受到了广泛的关注和高度重视。分子靶向药物选择性高、广谱有效,其安全性优于细胞毒性化疗药物,是目前肿瘤治疗领域发展的新方向。
青蒿素是含有过氧桥的新型倍半萜内酯,其衍生物有青蒿琥酯、蒿甲醚和双氢青蒿素等。青蒿素及其衍生物是一类高效、低毒的抗疟药物,随着研究的深入,人们发现青蒿素及青蒿素类化合物还具有其它很多重要的药理活性,如抗血吸虫、免疫调节、抗心律失常、抗肿瘤等,尤其是其抗肿瘤作用,越来越引起研究者们的重视。很多实验研究表明,青蒿素及青蒿素类化合物对多种肿瘤细胞的生长具有显著的抑制作用,而且对正常组织细胞的毒性很低,作用机制可能与肿瘤细胞内自由基的产生及氧化应激,延迟细胞周期,诱导细胞凋亡和抗肿瘤血管生成有关。双氢青蒿素是青蒿素类药物中活性较强的衍生物,青蒿琥酯是青蒿素最重要的衍生物之一,具有水溶性好,青蒿琥酯抗肿瘤机理与其对肿瘤细胞株有直接杀伤作用、或与诱导细胞凋亡有关,还可能与其抑制肿瘤组织血管生成等有关。青蒿素及青蒿素类药物可以选择性杀伤肿瘤细胞,并且与传统化疗药不存在交叉耐药,能够逆转肿瘤细胞的多药耐药现象。
索拉非尼为由拜耳和ONYX共同研制的一种多靶点激酶抑制剂,靶向作用于肿瘤细胞以及肿瘤血管内丝氨酸/苏氨酸激酶受体和酪氨酸激酶受体,通过抑制Raf/MEK/ERK信号传导途径抑制肿瘤生长,同时还通过抑制与新生血管生成有关的酪氨酸激酶受体的活性,阻断肿瘤新生血管的生成,间接抑制肿瘤细胞的生长。索拉非尼目前在临床使用的剂量为成人为800mg/天。然而索拉非尼有较多的不良反应,如,“索拉非尼的毒副作用及其处理”,《癌症进展杂志》2007年7月第5卷第4期第370-373页所记载的,不良反应包括手足综合症、疲乏、腹泻、皮肤毒性和胃肠道反应等,并经常导致药物服用的中断或减少药物服用剂量。因此寻找治疗效果更好、副作用低的抗癌药物为目前研究的热点。
随着肿瘤分子生物学的研究进展,肿瘤分子靶向治疗已成为肿瘤研究的热点,在多种肿瘤的治疗中发挥了重要的作用。然而,大部分肿瘤的生物学行为并非由单一信号传导通路所支配,而是多个信号传导通路共同起作用的,因此联合用药针对多靶点进行靶向治疗将不仅旨在减少或延缓耐药性的出现、降低毒性,而且通过多种药物对癌细胞杀伤的协同作用取得更好的疗效。
发明内容
针对以上技术缺陷,本发明提供一种药物组合物及其在制备治疗肺癌、胰腺癌、结肠癌、肝癌、前列腺癌、肾癌、胃癌、脑瘤、肉瘤、卵巢癌或乳腺癌的药物中的应用,具体为含有索拉非尼和青蒿素及青蒿素类衍生物的药物组合物在制备治疗肺癌、胰腺癌、结肠癌、肝癌、前列腺癌、肾癌、胃癌、脑瘤、肉瘤、卵巢癌或乳腺癌的药物中的应用。
本发明含有索拉非尼和青蒿素及青蒿素类衍生物的药物组合物中,所述青蒿素及青蒿素类衍生物可以为青蒿素、青蒿琥酯、双氢青蒿素、蒿甲醚或蒿乙醚,或它们的相应衍生物。
本发明药物组合物中的青蒿素及青蒿素类衍生物优选为:青蒿琥酯、双氢青蒿素或蒿甲醚,其相应的结构式分别为式I、式II和式III。
本发明药物组合物中,所述组分不限于青蒿琥酯、双氢青蒿素和蒿甲醚药物本身,还可以是其可药用的盐、水合物或衍生物等。
本发明中,所述索拉非尼(英文名:Sorafenib)为4-{4-[3-(4-氯-3-三氟甲基-苯基)-酰脲]苯氧基}-吡啶-2-羧酸甲胺,其结构式为式IV。
本发明中,索拉非尼不限于该药物本身,还可以是其可药用的盐,索拉非尼的衍生物或如WO2000041698专利申请中所披露的各种索拉非尼的类似物;同时本发明应用中还可以将索拉非尼替换为多靶点激酶抑制剂的其它药物。
本发明含有索拉非尼和青蒿素及青蒿素类衍生物的药物组合物中,索拉非尼与青蒿素及青蒿素类衍生物的摩尔比为1.0-15.0∶1.0-25.0;进一步优选所述索拉非尼与青蒿素及青蒿素类衍生物的摩尔比为2.0-7.5∶2.5-12.5。
本发明含有索拉非尼和青蒿素及青蒿素类衍生物的药物组合物可以用于治疗各种肿瘤,所述肿瘤包括但不限于肺癌、胰腺癌、结肠癌、肝癌、前列腺癌、肾癌、胃癌、脑瘤、肉瘤、卵巢癌或乳腺癌。
本发明优选索拉非尼和青蒿素及青蒿素类衍生物的药物组合物用于制备治疗肺癌、胰腺癌、结肠癌、肝癌及前列腺癌的药物中的应用。
在本发明药物组合物用于制备治疗肺癌的药物中的应用中,所述索拉非尼和青蒿素及青蒿素类衍生物的摩尔比为2.0-4.0∶3.0-10.0;优选为索拉非尼和青蒿素及青蒿素类衍生物的摩尔比为3.0-4.0∶5.0-10.0;更进一步优选为索拉非尼和青蒿素及青蒿素类衍生物的摩尔比为4.0∶10.0。
在本发明药物组合物用于制备治疗胰腺癌的药物中的应用中,所述索拉非尼和青蒿素及青蒿素类衍生物的摩尔比为2.5-7.5∶2.5-10.0;优选为索拉非尼和青蒿素及青蒿素类衍生物的摩尔比为5.0-7.5∶5.0-10.0;更进一步优选为索拉非尼和青蒿素及青蒿素类衍生物的摩尔比为7.5∶10.0。
在本发明药物组合物用于制备治疗结肠癌的药物中的应用中,所述索拉非尼和青蒿素及青蒿素类衍生物的摩尔比为2.5-6.0∶2.5-7.5;优选为索拉非尼和青蒿素及青蒿素类衍生物的摩尔比为4.0-6.0∶5.0-7.5;更进一步优选为索拉非尼和青蒿素及青蒿素类衍生物的摩尔比为6.0∶7.5。
在本发明药物组合物用于制备治疗肝癌的药物中的应用中,所述索拉非尼和青蒿素及青蒿素类衍生物的摩尔比为2.0-4.0∶3.0-10.0;优选为索拉非尼和青蒿素及青蒿素类衍生物的摩尔比为3.0-4.0∶6.0-10.0;更进一步优选为索拉非尼和青蒿素及青蒿素类衍生物的摩尔比为4.0∶10.0。
在本发明药物组合物用于制备治疗前列腺癌的药物中的应用中,所述索拉非尼和青蒿素及青蒿素类衍生物的摩尔比为2.5-5.0∶5.0-12.5;优选为索拉非尼和青蒿素及青蒿素类衍生物的摩尔比为3.5-5.0∶7.5-12.5;更进一步优选为索拉非尼和青蒿素及青蒿素类衍生物的摩尔比为5.0∶12.5。
含有索拉非尼和青蒿素及青蒿素类衍生物的药物组合物在制备治疗肺癌、胰腺癌、结肠癌、肝癌、前列腺癌、肾癌、胃癌、脑瘤、肉瘤、卵巢癌或乳腺癌的药物的应用中,在将本发明组合物制成同时给药的药剂的方案中,青蒿素及青蒿素类衍生物和索拉非尼可以含在同一种药物制剂如片剂或胶囊中,也可以将青蒿素及青蒿素类衍生物和索拉非尼分别做成制剂,如分别做成片剂或胶囊,并采用本领域常规的方式将它们包装或结合在一起,患者然后按照药品说明书的指示同时服用;在将本发明组合物制成先后给药的药剂的方案中,可以将青蒿素及青蒿素类衍生物和索拉非尼分别做成不同的制剂,并采用本领域常规的方式将它们包装或结合在一起,患者然后按照药品说明书指示的先后顺序进行服用,或将上述组合物中的两种成分制成一种控释的制剂,先释放组合物中的一种成分、然后再释放组合物中的另一种成分,患者只需要服用该控释组合物制剂;在将本发明组合物制备成交叉给药的药剂的方案中,可以将青蒿素及青蒿素类衍生物和索拉非尼分别做成不同的制剂,并采用本领域常规的方式将它们包装或结合在一起,患者然后按照药品说明书指示的交叉顺序服用,或者将该药物组合物制备成青蒿素及青蒿素类衍生物和索拉非尼交叉释放的控释制剂。
索拉非尼和青蒿素及青蒿素类衍生物的药物组合物在制备治疗肺癌、胰腺癌、结肠癌、肝癌、前列腺癌、肾癌、胃癌、脑瘤、肉瘤、卵巢癌或乳腺癌的药物中的应用中,所述组合物中的青蒿素及青蒿素类衍生物和索拉非尼可以同时使用或以任何先后的顺序使用,如可以将青蒿素及青蒿素类衍生物和索拉非尼同时给患者服用;也可以先将青蒿素及青蒿素类衍生物药物给患者服用、然后服用索拉非尼,或先服用索拉非尼、然后服用青蒿素及青蒿素类衍生物药物,对于两者服用的时间间隔没有特别要求,但优选服用两种药物的时间间隔不超过一天;或者两种药物交替给药。
本发明中,可将本发明青蒿素及青蒿素类衍生物和索拉非尼采用本领域常规的方法制备成适于胃肠道给药或非胃肠道给药的药物制剂,本发明优选将青蒿素及青蒿素类衍生物和索拉非尼制成胃肠道给药的药物制剂,其制剂形式可以为常规片剂或胶囊、或控释、缓释制剂。在本发明青蒿素及青蒿素类衍生物和索拉非尼组合物的药物制剂中,根据不同的制剂形式和制剂规格,所述组合物在制剂中的含量可以为质量计为1-99%,优选为10%-90%;制剂使用的辅料可采用本领域常规的辅料,以不和本发明组合物发生反应或不影响本发明药物的疗效为前提;所述制剂的制备方法可采用本领域常规的制备方法进行制备。
本发明中,组合物的制备方法没有什么限制,青蒿素及青蒿素类衍生物和索拉非尼两者可以进行直接混合然后做成制剂,或分别和/或相应的辅料混合分别做成制剂,然后再按照本领域常规的方式包装在一起,或分别和相应的辅料混合然后再混合做成制剂。
本发明中的药物组合物的给药剂量根据给药对象、给药途径或药物的制剂形式不同可以进行适当的变化,但以保证该药物组合物在哺乳动物体内能够达到有效的血药浓度为前提。
本发明分别进行了索拉非尼和青蒿素及青蒿素类衍生物组合杀死H460(肺癌细胞株)、Panc1(胰腺癌细胞株)、HCT-116(结肠癌细胞株)、HepG2(肝癌细胞株)和22RV1(前列腺癌细胞株)的试验,结果提示,本发明索拉非尼和青蒿素及青蒿素类衍生物组合治疗肺癌、胰腺癌、结肠癌、肝癌及前列腺癌具有显著的协同效应,提高了药物的疗效,降低了用药剂量,减少了副作用的发生。
具体实施方式
结合以下实施例对本发明作进一步的阐述,但本发明并不受限于此。
实施例
试剂和方法:
细胞:H460(肺癌细胞株)、Panc 1(胰腺癌细胞株)、HCT-116(结肠癌细胞株)、HepG2(肝癌细胞株)和22RV1(前列腺癌细胞株),均购自American Type Culture Collection(ATCC),Rockville,MD,USA。药品:以下实施例中所用药物组合物均按下列方法1或方法2所述来制备;青蒿素类衍生物青蒿琥酯、双氢青蒿素和蒿甲醚均购自Sigma;索拉非尼参考专利US2003207872合成而得。
方法1:准确称量相应的药物组合物的各组分,以二甲基亚砜分别溶解,各自配成10mM的贮存液,在-20℃下保存,使用时用新鲜的培养基稀释到合适的浓度,然后各自取1微升的各组分的溶液,混合在一起备用。所有的试验中,二甲基亚砜的最终浓度应≤5g/L,以便不影响细胞的活性。
将所有的细胞于含10%小牛血清、100kU/L青霉素、100mg/L链霉素的RPMI 1640培养基中,37℃、5%CO2的湿度条件下培养,在加药的前一天,在六孔板上进行细胞接种2×105/孔,然后向细胞中加入按上述方法制备的药物组合物溶液,使各组分达到其工作浓度,具体见表中第1-15。
药物处理后,通过台盼蓝(Trypan Blue)测定细胞死亡,细胞通过在37℃用胰蛋白酶钠/EDTA进行胰酶化作用10分钟。因为死亡的细胞从培养器上脱落进入培养基中,通过在1200转/分钟下离心收集所有的细胞,然后再用培养基重新悬浮沉淀物,与台盼蓝染料混合。染色之后,用光学显微镜和血细胞计数器进行计数。被染料染成蓝色的计为死亡细胞。随机选取500个细胞进行计数,死亡的细胞以占总计数细胞的百分比来表达。
方法2:准确称量相应的药物组合物的各组分,以二甲基亚砜分别溶解,各自配成10mM的贮存液,在-20℃下保存。使用时用新鲜的培养基稀释到合适的浓度,然后各自取1微升的各组分的溶液备用。所有的试验中,二甲基亚砜的最终浓度应≤5g/L,以便不影响细胞的活性。
将所有的细胞于含10%小牛血清、100kU/L青霉素、100mg/L链霉素的RPMI 1640培养基中,37℃、5%CO2的湿度条件下培养,在加药的前一天,在六孔板上进行细胞接种2×105/孔,然后以任意次序向细胞中加入按上述方法制备的药物组合物的各组分溶液,使各组分达到其工作浓度,具体见表中第16-27。
药物处理后,通过台盼蓝(Trypan Blue)测定细胞死亡,细胞通过在37℃用胰蛋白酶钠/EDTA进行胰酶化作用10分钟。因为死亡的细胞从培养器上脱落进入培养基中,通过在1200转/分钟下离心收集所有的细胞,然后再用培养基重新悬浮沉淀物,与台盼蓝染料混合。染色之后,用光学显微镜和血细胞计数器进行计数。被染料染成蓝色的计为死亡细胞。随机选取500个细胞进行计数,死亡的细胞以占总计数细胞的百分比来表达。
下列表1所示的药物组合中,第1-15的组合按方法1,第16-27的组合按方法2制备。
表1
实施例1不同比例的青蒿琥酯与索拉非尼的组合协同增效促进H460细胞死亡试验,见表2。
表2
在考察相关化合物导致肺癌细胞株H460细胞死亡的试验中,发现当单独使用10.0μM青蒿琥酯只有约20%细胞死亡、单独使用4.0μM索拉非尼只有约15%细胞死亡;而当两者在较低浓度下合用时(5.0μM青蒿琥酯+3.0μM索拉非尼)则产生明显的协同作用,导致约80%的癌细胞死亡;当两者以10.0μM青蒿琥酯+4.0μM索拉非尼的比例合用时,则产生更加显著的协同作用,导致99%的癌细胞死亡。
实施例2不同比例的双氢青蒿素与索拉非尼的组合协同增效促进H460细胞死亡试验,见表3。
表3
在考察相关化合物导致肺癌细胞株H460细胞死亡的试验中,发现当单独使用10.0μM双氢青蒿素只有约20%细胞死亡、单独使用4.0μM索拉非尼只有约15%细胞死亡;而当两者在较低浓度下合用时(5.0μM双氢青蒿素+3.0μM索拉非尼)则产生明显的协同作用,导致约65%的癌细胞死亡;当两者以10.0μM双氢青蒿素+4.0μM索拉非尼的比例合用时,则产生更加显著的协同作用,导致99%的癌细胞死亡。
实施例3不同比例的蒿甲醚与索拉非尼的组合协同增效促进H460细胞死亡试验,见表4。
表4
在考察相关化合物导致肺癌细胞株H460细胞死亡的试验中,发现当单独使用10.0μM蒿甲醚、4.0μM索拉非尼只有约15%细胞死亡;而当两者在较低浓度下合用时(5.0μM蒿甲醚+3.0μM索拉非尼)则产生明显的协同作用,导致约50%的癌细胞死亡;当两者以10.0μM蒿甲醚+4.0μM索拉非尼的比例合用时,则产生更加显著的协同作用,导致约88%的癌细胞死亡。
实施例4不同比例的青蒿琥酯与索拉非尼的组合协同增效促进Panc1细胞死亡试验,见表5。
表5
在考察相关化合物导致胰腺癌细胞株Panc1细胞死亡的试验中,发现当单独使用10.0μM青蒿琥酯或更低浓度时只有很少量的细胞死亡,即使单独使用7.5μM索拉非尼也只有约20%细胞死亡;而当两者在较低浓度下合用时(5.0μM青蒿琥酯+5.0μM索拉非尼)则产生明显的协同作用,导致68%的癌细胞死亡;当两者以10.0μM青蒿琥酯+7.5μM索拉非尼的比例合用时,则产生更加显著的协同作用,导致92%的癌细胞死亡。
实施例5不同比例的双氢青蒿素与索拉非尼的组合协同增效促进Panc1细胞死亡试验,见表6。
表6
在考察相关化合物导致胰腺癌细胞株Panc1细胞死亡的试验中,发现当单独使用10.0μM双氢青蒿素或更低浓度时只有很少量的细胞死亡,即使单独使用7.5μM索拉非尼也只有约20%细胞死亡;而当两者在较低浓度下合用时(5.0μM双氢青蒿素+5.0μM索拉非尼)则产生明显的协同作用,导致51%的癌细胞死亡;当两者以10.0μM双氢青蒿素+7.5μM索拉非尼的比例合用时,则产生更加显著的协同作用,导致81%的癌细胞死亡。
实施例6不同比例的青蒿琥酯与索拉非尼的组合协同增效促进HCT116细胞死亡试验,见表7。
表7
在考察相关化合物导致结肠癌细胞株HCT116细胞死亡的试验中,发现当单独使用7.5μM青蒿琥酯或6.0μM索拉非尼时只有约20%细胞死亡;而当两者在较低浓度下合用时(5.0μM青蒿琥酯+4.0μM索拉非尼)则产生明显的协同作用,导致76%的癌细胞死亡;当两者以7.5μM青蒿琥酯+6.0μM索拉非尼的比例合用时,则产生更加显著的协同作用,导致约95%的癌细胞死亡。
实施例7不同比例的双氢青蒿素与索拉非尼的组合协同增效促进HCT116细胞死亡试验,见表8。
表8
在考察相关化合物导致结肠癌细胞株HCT116细胞死亡的试验中,发现当单独使用7.5μM双氢青蒿素或6.0μM索拉非尼时只有约20%细胞死亡;而当两者在较低浓度下合用时(5.0μM双氢青蒿素+4.0μM索拉非尼)则产生明显的协同作用,导致67%的癌细胞死亡;当两者以7.5μM双氢青蒿素+6.0μM索拉非尼的比例合用时,则产生更加显著的协同作用,导致约90%的癌细胞死亡。
实施例8不同比例的青蒿琥酯与索拉非尼的组合协同增效促进HepG2细胞死亡试验,见表9。
表9
在考察相关化合物导致肝癌细胞株HepG2细胞死亡的试验中,发现当单独使用10.0μM青蒿琥酯或4.0μM索拉非尼时只有约15%细胞死亡;而当两者在较低浓度下合用时(6.0μM青蒿琥酯+3.0μM索拉非尼)则产生明显的协同作用,导致42%的癌细胞死亡;当两者以10.0μM青蒿琥酯+4.0μM索拉非尼的比例合用时,则产生更加显著的协同作用,导致约91%的癌细胞死亡。
实施例9不同比例的双氢青蒿素与索拉非尼的组合协同增效促进22RV1细胞死亡试验,见表10。
表10
在考察相关化合物导致前列腺癌细胞株22RV1细胞死亡的试验中,发现当单独使用7.5μM双氢青蒿素、3.5μM索拉非尼或更低浓度时只有约10%细胞死亡;即使增加单药的浓度至12.5μM双氢青蒿素、5.0μM索拉非尼时也只有约20%细胞死亡;而当两者在较低浓度下合用时(7.5μM双氢青蒿素+3.5μM索拉非尼)则产生明显的协同作用,导致44%的癌细胞死亡;当两者以12.5μM双氢青蒿素+5.0μM索拉非尼的比例合用时,则产生更加显著的协同作用,导致81%的癌细胞死亡。
1.一种药物组合物,其特征在于含有索拉非尼与青蒿素及青蒿素类衍生物。
2.根据权利要求1所述的药物组合物,其特征在于,所述索拉非尼与青蒿素及青蒿素类衍生物的摩尔比为1.0-15.0∶1.0-25.0。
3.根据权利要求2所述的药物组合物,其特征在于,所述索拉非尼与青蒿素及青蒿素类衍生物的摩尔比为2.0-7.5∶2.5-12.5。
4.根据权利要求3所述的药物组合物,其特征在于,所述青蒿素及青蒿素类衍生物为青蒿素、青蒿琥酯、双氢青蒿素、蒿甲醚或蒿乙醚。
5.权利要求1-4任一所述的药物组合物在制备治疗肺癌、胰腺癌、结肠癌、肝癌、前列腺癌、肾癌、胃癌、脑瘤、肉瘤、卵巢癌或乳腺癌的药物中的应用。
6.根据权利要求5所述的应用,其特征在于,在制备治疗肺癌的药物中的应用中,所述索拉非尼与青蒿素及青蒿素类衍生物的摩尔比为2.0-4.0∶3.0-10.0。
7.根据权利要求6所述的应用,其特征在于,在制备治疗肺癌的药物中的应用中,所述索拉非尼与青蒿素及青蒿素类衍生物的摩尔比为3.0-4.0∶5.0-10.0。
8.根据权利要求5所述的应用,其特征在于,在制备治疗胰腺癌的药物中的应用中,所述索拉非尼与青蒿素及青蒿素类衍生物的摩尔比为2.5-7.5∶2.5-10.0。
9.根据权利要求8所述的应用,其特征在于,在制备治疗胰腺癌的药物中的应用中,所述索拉非尼与青蒿素及青蒿素类衍生物的摩尔比为5.0-7.5∶5.0-10.0。
10.根据权利要求5所述的应用,其特征在于,在制备治疗结肠癌的药物中的应用中,所述索拉非尼与青蒿素及青蒿素类衍生物的摩尔比为2.5-6.0∶2.5-7.5。
11.根据权利要求10所述的应用,其特征在于,在制备治疗结肠癌的药物中的应用中,所述索拉非尼与青蒿素及青蒿素类衍生物的摩尔比为4.0-6.0∶5.0-7.5。
12.根据权利要求5所述的应用,其特征在于,在制备肝癌的药物中的应用中,所述索拉非尼与青蒿素及青蒿素类衍生物的摩尔比为2.0-4.0∶3.0-10.0。
13.根据权利要求12所述的应用,其特征在于,在制备肝癌的药物中的应用中,所述索拉非尼与青蒿素及青蒿素类衍生物的摩尔比为3.0-4.0∶6.0-10.0。
14.根据权利要求5所述的应用,其特征在于,在制备前列腺癌的药物中的应用中,所述索拉非尼与青蒿素及青蒿素类衍生物的摩尔比为2.5-5.0∶5.0-12.5。
15.根据权利要求14所述的应用,其特征在于,在制备前列腺癌的药物中的应用中,所述索拉非尼与青蒿素及青蒿素类衍生物的摩尔比为3.5-5.0∶7.5-12.5。
16.根据权利要求5所述的应用,其特征在于,所述药物组合物中的索拉非尼与青蒿素及青蒿素类衍生物可以同时使用或以任何先后的顺序使用。
Contain the pharmaceutical composition and the application in the medicine of preparation treatment cancer thereof of Sorafenib and arteannuin and artemisinin derivatives
Technical field
The present invention relates to a kind of pharmaceutical composition and the application in the medicine of preparation treatment cancer thereof, be specifically related to contain the pharmaceutical composition and the application in the medicine of preparation treatment pulmonary carcinoma, cancer of pancreas, colon cancer, hepatocarcinoma, carcinoma of prostate, renal carcinoma, gastric cancer, cerebroma, sarcoma, ovarian cancer or breast carcinoma thereof of Sorafenib and arteannuin and artemisinin derivatives.
Background technology
World Health Organization's investigation report shows that global cancer condition is serious day by day, and 20 years from now on new patients' number will be increased to 1,500 ten thousand by present every year 1000 ten thousand, because of the number that cancer is dead also will be by increasing to 1,000 ten thousand 6,000,000 of every year.Wherein pulmonary carcinoma is one of common malignancy, comes from bronchiolar epitheliums at different levels, is divided into cell lung cancer and nonsmall-cell lung cancer; The cancer of pancreas pilosity is born in head of pancreas portion, and 90% derives from the ductus pancreaticus epithelial cell, and all the other are the digestive system common malignancy from pancreatic acini, and sickness rate is ascendant trend year by year.Because onset concealment lacks effective method of early diagnosis, often reach an advanced stage when making a definite diagnosis or shift, the patients with terminal median survival interval is no more than six months; The morbidity of colon cancer and environment, living habit, especially diet style is relevant.It is generally acknowledged that high fat diet and cellulose deficiency are main pathogenic factors.Along with growth in the living standard, the change of dietary structure, the sickness rate of colon cancer is ascendant trend year by year; Primary hepatocarcinoma is one of human modal malignant tumor for occurring in the epithelial canceration of hepatocyte and stones in intrahepatic bile duct; Carcinoma of prostate is most important a kind of in the male genitourinary system tumor, is human distinctive disease.Carcinoma of prostate is a senile disease, mostly at 50 years old with sequela.Along with the prolongation of human average life, the raising of diagnostic techniques, the change of life style, the sickness rate of carcinoma of prostate is in continuous rising, and it is extremely urgent therefore to study the treatment of prostate cancer medicine.
The antitumor drug that has gone on the market at present is more, and as alkylating agent medicine, antimetabolite, antitumor antibiotics, immunomodulator etc., but medicine is because toxicity is bigger mostly, and patient does not tolerate.The Study on Molecular Mechanism that develops along with the generation to tumor is more and more clearer, and the multiple malignant tumor of molecular targeted treatment has been subjected to paying close attention to widely and paying much attention to.Molecular targeted agents selectivity height, wide spectrum are effective, and its safety is better than the cytotoxicity chemotherapeutics, are the new directions of present oncotherapy field development.
Arteannuin is the sesquiterpene lactone that contains peroxide bridge, and its derivant has artesunate, Artemether and dihydroarteannuin etc.Arteannuin and derivant thereof are that a class is efficient, the antimalarial agent of low toxicity, along with going deep into of research, it is found that arteannuin and artemisine compounds also have other a lot of important pharmacologically actives, as schistosomicide, immunomodulating, arrhythmia, antitumor etc., especially its antitumor action more and more causes the attention of researcheres.A lot of experimentatioies show, arteannuin and artemisine compounds have significant inhibitory effect to the growth of kinds of tumor cells, and it is very low to normal histiocytic toxicity, mechanism of action may with the generation and the oxidative stress of free radical in the tumor cell, postpone cell cycle, cell death inducing generates relevant with antineoplastic vascular.Dihydroarteannuin is an active stronger derivant in the artemisinin-based drug, artesunate is one of most important derivant of arteannuin, has good water solubility, artesunate antitumor mechanism has direct killing effect or relevant with cell death inducing with it to tumor cell line, also may be relevant with its inhibition tumor tissues angiogenesis etc.Arteannuin and artemisinin-based drug can the selective killing tumor cells, and do not have crossing drug resistant with traditional chemotherapeutic, multidrug resistance phenomenon that can the reversing tumor cell.
Sorafenib is a kind of many target spots inhibitors of kinases by Bayer and the common development of ONYX, targeting is serine/threonine kinase receptor and tyrosine kinase receptor in tumor cell and tumor vessel, suppress tumor growth by suppressing the Raf/MEK/ERK signal transduction path, simultaneously also by suppressing to generate the activity of relevant tyrosine kinase receptor with new vessels, block tumor neovasculature generation, suppress the growth of tumor cell indirectly.Sorafenib is 800mg/ days at the clinical dosage that uses for the adult at present.Yet Sorafenib has more untoward reaction, as, " toxic and side effects of Sorafenib and processing thereof ", what " cancer progression magazine " July in 2007, the 5th volume the 4th phase 370-373 page or leaf was put down in writing, untoward reaction comprises brothers' syndrome, tired, diarrhoea, dermal toxicity and gastrointestinal reaction etc., and often causes the interruption of drug administration or reduce drug dose.Therefore seek the focus of cancer therapy drug that therapeutic effect is better, side effect is low for studying at present.
Along with the progress of oncomolecularbiology, the molecular targeted treatment of tumor has become the focus of tumor research, has brought into play important effect in the treatment of kinds of tumors.Yet, the biological behaviour of most of tumor is arranged by single signal transduction pathway, but a plurality of signal transduction pathway concur, therefore drug combination carries out targeted therapy at many target spots and will not only be intended to reduce or delay chemical sproof appearance, reduce toxicity, and by multiple medicine the synergism that cancerous cell kills and wounds is obtained better therapeutic.
Summary of the invention
At above technological deficiency, the invention provides a kind of pharmaceutical composition and the application in the medicine of preparation treatment pulmonary carcinoma, cancer of pancreas, colon cancer, hepatocarcinoma, carcinoma of prostate, renal carcinoma, gastric cancer, cerebroma, sarcoma, ovarian cancer or breast carcinoma thereof, be specially the application of pharmaceutical composition in the medicine of preparation treatment pulmonary carcinoma, cancer of pancreas, colon cancer, hepatocarcinoma, carcinoma of prostate, renal carcinoma, gastric cancer, cerebroma, sarcoma, ovarian cancer or breast carcinoma that contains Sorafenib and arteannuin and artemisinin derivatives.
The present invention contains in the pharmaceutical composition of Sorafenib and arteannuin and artemisinin derivatives, and described arteannuin and artemisinin derivatives can be arteannuin, artesunate, dihydroarteannuin, Artemether or arteether, or their corresponding derivative.
Arteannuin and artemisinin derivatives in the pharmaceutical composition of the present invention are preferably: artesunate, dihydroarteannuin or Artemether, its corresponding structure formula is respectively formula I, formula II and formula III.
In the pharmaceutical composition of the present invention, described component is not limited to artesunate, dihydroarteannuin and Artemether medicine itself, can also be its pharmaceutically useful salt, hydrate or derivant etc.
Among the present invention, described Sorafenib (English name: Sorafenib) be 4-{4-[3-(4-chloro-3-trifluoromethyl-phenyl)-uride] phenoxy group }-the pyridine-2-carboxylic acids methylamine, its structural formula is formula IV.
Among the present invention, Sorafenib is not limited to this medicine itself, can also be its pharmaceutically useful salt, the analog of the derivant of Sorafenib or the various Sorafenibs disclosed in the WO2000041698 patent application; During using, the present invention simultaneously Sorafenib can also be replaced with the other medicines of many target spots inhibitors of kinases.
The present invention contains in the pharmaceutical composition of Sorafenib and arteannuin and artemisinin derivatives, and the mol ratio of Sorafenib and arteannuin and artemisinin derivatives is 1.0-15.0: 1.0-25.0; Further the mol ratio of preferred described Sorafenib and arteannuin and artemisinin derivatives is 2.0-7.5: 2.5-12.5.
The pharmaceutical composition that the present invention contains Sorafenib and arteannuin and artemisinin derivatives can be used for the treatment of various tumors, and described tumor includes but not limited to pulmonary carcinoma, cancer of pancreas, colon cancer, hepatocarcinoma, carcinoma of prostate, renal carcinoma, gastric cancer, cerebroma, sarcoma, ovarian cancer or breast carcinoma.
The pharmaceutical composition of the preferred Sorafenib of the present invention and arteannuin and artemisinin derivatives is used for preparing the application of the medicine for the treatment of pulmonary carcinoma, cancer of pancreas, colon cancer, hepatocarcinoma and carcinoma of prostate.
Be used for preparing in the application for the treatment of lung cancer drugs at pharmaceutical composition of the present invention, the mol ratio of described Sorafenib and arteannuin and artemisinin derivatives is 2.0-4.0: 3.0-10.0; The mol ratio that is preferably Sorafenib and arteannuin and artemisinin derivatives is 3.0-4.0: 5.0-10.0; The mol ratio that further is preferably Sorafenib and arteannuin and artemisinin derivatives is 4.0: 10.0.
Be used for preparing in the application of the medicine for the treatment of cancer of pancreas at pharmaceutical composition of the present invention, the mol ratio of described Sorafenib and arteannuin and artemisinin derivatives is 2.5-7.5: 2.5-10.0; The mol ratio that is preferably Sorafenib and arteannuin and artemisinin derivatives is 5.0-7.5: 5.0-10.0; The mol ratio that further is preferably Sorafenib and arteannuin and artemisinin derivatives is 7.5: 10.0.
Be used for preparing in the application of the medicine for the treatment of colon cancer at pharmaceutical composition of the present invention, the mol ratio of described Sorafenib and arteannuin and artemisinin derivatives is 2.5-6.0: 2.5-7.5; The mol ratio that is preferably Sorafenib and arteannuin and artemisinin derivatives is 4.0-6.0: 5.0-7.5; The mol ratio that further is preferably Sorafenib and arteannuin and artemisinin derivatives is 6.0: 7.5.
Be used for preparing in the application of the medicine for the treatment of hepatocarcinoma at pharmaceutical composition of the present invention, the mol ratio of described Sorafenib and arteannuin and artemisinin derivatives is 2.0-4.0: 3.0-10.0; The mol ratio that is preferably Sorafenib and arteannuin and artemisinin derivatives is 3.0-4.0: 6.0-10.0; The mol ratio that further is preferably Sorafenib and arteannuin and artemisinin derivatives is 4.0: 10.0.
Be used for preparing in the application of the medicine for the treatment of carcinoma of prostate at pharmaceutical composition of the present invention, the mol ratio of described Sorafenib and arteannuin and artemisinin derivatives is 2.5-5.0: 5.0-12.5; The mol ratio that is preferably Sorafenib and arteannuin and artemisinin derivatives is 3.5-5.0: 7.5-12.5; The mol ratio that further is preferably Sorafenib and arteannuin and artemisinin derivatives is 5.0: 12.5.
The pharmaceutical composition that contains Sorafenib and arteannuin and artemisinin derivatives is in preparation treatment pulmonary carcinoma, cancer of pancreas, colon cancer, hepatocarcinoma, carcinoma of prostate, renal carcinoma, gastric cancer, cerebroma, sarcoma, in the application of the medicine of ovarian cancer or breast carcinoma, in the scheme of the medicament of the present composition being made administration simultaneously, arteannuin and artemisinin derivatives and Sorafenib can be contained in in a kind of pharmaceutical preparation such as tablet or the capsule, also arteannuin and artemisinin derivatives and Sorafenib can be made preparation respectively, as making tablet or capsule respectively, and the mode that adopts this area routine is with their packings or combine, and the patient takes simultaneously according to the indication of package insert then; In the scheme of the medicament of the present composition being made administration successively, arteannuin and artemisinin derivatives can be made different preparations respectively with Sorafenib, and the mode that adopts this area routine is with their packings or combine, the patient takes according to the sequencing of package insert indication then, or two kinds of compositions in the above-mentioned composition are made a kind of preparation of controlled release, a kind of composition in elder generation's release composition and then the another kind of composition in the release composition, the patient only need take this controlled release composition preparation; In the scheme of the medicament that the present composition is prepared into the intersection administration, arteannuin and artemisinin derivatives can be made different preparations respectively with Sorafenib, and the mode that adopts this area routine is with their packings or combine, the patient takes according to the chi sequence of package insert indication then, the controlled release preparation that perhaps this preparation of pharmaceutical compositions is become arteannuin and artemisinin derivatives and Sorafenib intersection to discharge.
In the application of the pharmaceutical composition of Sorafenib and arteannuin and artemisinin derivatives in the medicine of preparation treatment pulmonary carcinoma, cancer of pancreas, colon cancer, hepatocarcinoma, carcinoma of prostate, renal carcinoma, gastric cancer, cerebroma, sarcoma, ovarian cancer or breast carcinoma, arteannuin in the described compositions and artemisinin derivatives and Sorafenib can use or simultaneously with the using in order of any priority, as arteannuin and artemisinin derivatives and Sorafenib being taken to the patient simultaneously; Also can earlier Sorafenib be taken, be taken then to arteannuin and artemisinin derivatives medicine to the patient, or take Sorafenib earlier, take arteannuin and artemisinin derivatives medicine then, the interval of taking for both does not have special requirement, but the interval of preferably taking two kinds of medicines is no more than one day; Perhaps two kinds of medicines replace administration.
Among the present invention, the method of arteannuin of the present invention and artemisinin derivatives and Sorafenib employing this area routine can be prepared into the pharmaceutical preparation that is suitable for gastrointestinal administration or parenteral administration, the pharmaceutical preparation that the present invention preferably makes gastrointestinal administration with arteannuin and artemisinin derivatives and Sorafenib, its dosage form can be conventional tablet or capsule or controlled release, slow releasing preparation.In the pharmaceutical preparation of arteannuin of the present invention and artemisinin derivatives and Sorafenib compositions, according to different dosage forms and preparation specification, the content of described compositions in preparation can be counted 1-99% for quality, is preferably 10%-90%; The adjuvant that preparation uses can adopt the adjuvant of this area routine, reacts or the curative effect that do not influence medicine of the present invention is a prerequisite with the discord present composition; The preparation method of described preparation can adopt the preparation method of this area routine to be prepared.
Among the present invention, the preparation of compositions method does not have any restriction, arteannuin and artemisinin derivatives and Sorafenib can directly mix makes preparation then, or respectively and/or corresponding auxiliary material mix and to make preparation respectively, and then be packaging together, or mix and then mix and make preparation with corresponding auxiliary material respectively according to the mode of this area routine.
The dosage of the pharmaceutical composition among the present invention can carry out suitable variation according to the dosage form difference of administration object, route of administration or medicine, but is prerequisite to guarantee that this pharmaceutical composition can reach effective blood drug level in mammalian body.
The present invention has carried out the test that H460 (lung cancer cell line), Panc1 (pancreas cancer cell strain), HCT-116 (colon cancer cell line), HepG2 (hepatoma cell strain) and 22RV1 (prostate gland cancer cell strain) are killed in the combination of Sorafenib and arteannuin and artemisinin derivatives respectively, results suggest, Sorafenib of the present invention and arteannuin and artemisinin derivatives combined therapy pulmonary carcinoma, cancer of pancreas, colon cancer, hepatocarcinoma and carcinoma of prostate have significant cooperative effect, improved the curative effect of medicine, reduce dosage, reduced the generation of side effect.
The specific embodiment
The invention will be further elaborated with the following Examples, but the present invention is not limited to this.
Embodiment
Reagent and method:
Cell: H460 (lung cancer cell line), Panc 1 (pancreas cancer cell strain), HCT-116 (colon cancer cell line), HepG2 (hepatoma cell strain) and 22RV1 (prostate gland cancer cell strain), all available from American Type Culture Collection (ATCC), Rockville, MD, USA.Medicine: institute's pharmaceutical composition is all by following method 1 or 2 described preparations of method in following examples; Artemisinin derivatives artesunate, dihydroarteannuin and Artemether are all available from Sigma; Sorafenib referenced patent US2003207872 is synthesized into.
Method 1: each component of accurate weighing corresponding pharmaceutical compositions, dissolve respectively with dimethyl sulfoxide, be made into the stock solution of 10mM separately, preserve down at-20 ℃, be diluted to suitable concentration with fresh culture medium during use, the solution of each component of 1 microlitre of respectively asking for then mixes standby.In all tests, the ultimate density of dimethyl sulfoxide is answered≤5g/L, so that do not influence cell activity.
With all cells in RPMI 1640 culture medium that contain 10% calf serum, 100kU/L penicillin, 100mg/L streptomycin, 37 ℃, 5%CO 2Damp condition cultivate down, in the previous day of dosing, on six orifice plates, carry out cell inoculation 2 * 10 5/ hole adds the pharmaceutical composition solution of preparation as stated above then in cell, make each component reach its working concentration, 1-15 in specifically seeing Table.
After the drug treating, measure cell death by trypan blue (Trypan Blue), cell turns into 10 minutes by carrying out pancreatin at 37 ℃ with trypsin sodium/EDTA.Because dead cell comes off from incubator enter the culture medium,, and then, mix with the trypan blue dyestuff with culture medium suspended sediment again by all cells of centrifugal collection under 1200 rev/mins.After the dyeing, count with optical microscope and hematimeter.Dyed the blue dead cell of counting by dyestuff.500 cells of picked at random are counted, and dead cell is recently expressed with the percentage that accounts for the grand total cell.
Method 2: each component of accurate weighing corresponding pharmaceutical compositions, dissolve respectively with dimethyl sulfoxide, be made into the stock solution of 10mM separately, preserve down at-20 ℃.Be diluted to suitable concentration with fresh culture medium during use, the solution for standby of each component of 1 microlitre of respectively asking for then.In all tests, the ultimate density of dimethyl sulfoxide is answered≤5g/L, so that do not influence cell activity.
With all cells in RPMI 1640 culture medium that contain 10% calf serum, 100kU/L penicillin, 100mg/L streptomycin, 37 ℃, 5%CO 2Damp condition cultivate down, in the previous day of dosing, on six orifice plates, carry out cell inoculation 2 * 10 5/ hole adds each component solution of the pharmaceutical composition of preparation as stated above with any order then in cell, make each component reach its working concentration, 16-27 in specifically seeing Table.
After the drug treating, measure cell death by trypan blue (Trypan Blue), cell turns into 10 minutes by carrying out pancreatin at 37 ℃ with trypsin sodium/EDTA.Because dead cell comes off from incubator enter the culture medium,, and then, mix with the trypan blue dyestuff with culture medium suspended sediment again by all cells of centrifugal collection under 1200 rev/mins.After the dyeing, count with optical microscope and hematimeter.Dyed the blue dead cell of counting by dyestuff.500 cells of picked at random are counted, and dead cell is recently expressed with the percentage that accounts for the grand total cell.
Tabulate down in the drug regimen shown in 1, the combination of 1-15 prepares by method 2 by the combination of method 1, the 16-27.
Table 1
The artesunate of embodiment 1 different proportion and the combination Synergistic of Sorafenib promote the test of H460 cell death, see Table 2.
Table 2
Cause in the test of lung cancer cell line H460 cell death investigating related compound, find when use separately 10.0 μ M artesunate only have an appointment 20% cell death, use 4.0 μ M Sorafenibs, 15% cell death of only having an appointment separately; (5.0 μ M artesunate+3.0 μ M Sorafenibs) then produce the obvious synergistic effect when both share under low concentration, cause about 80% cancer cell death; When both share with the ratio of 10.0 μ M artesunate+4.0 μ M Sorafenibs, then produce significant more synergism, cause 99% cancer cell death.
The dihydroarteannuin of embodiment 2 different proportions and the combination Synergistic of Sorafenib promote the test of H460 cell death, see Table 3.
Table 3
Cause in the test of lung cancer cell line H460 cell death investigating related compound, find when use separately 10.0 μ M dihydroarteannuins only have an appointment 20% cell death, use 4.0 μ M Sorafenibs, 15% cell death of only having an appointment separately; (5.0 μ M dihydroarteannuins+3.0 μ M Sorafenibs) then produce the obvious synergistic effect when both share under low concentration, cause about 65% cancer cell death; When both share with the ratio of 10.0 μ M dihydroarteannuins+4.0 μ M Sorafenibs, then produce significant more synergism, cause 99% cancer cell death.
The Artemether of embodiment 3 different proportions and the combination Synergistic of Sorafenib promote the test of H460 cell death, see Table 4.
Table 4
Cause in the test of lung cancer cell line H460 cell death investigating related compound, find when using 10.0 μ M Artemether, 4.0 μ M Sorafenibs 15% cell death of only having an appointment separately; (5.0 μ M Artemether+3.0 μ M Sorafenibs) then produce the obvious synergistic effect when both share under low concentration, cause about 50% cancer cell death; When both share with the ratio of 10.0 μ M Artemether+4.0 μ M Sorafenibs, then produce significant more synergism, cause about 88% cancer cell death.
The artesunate of embodiment 4 different proportions and the combination Synergistic of Sorafenib promote the test of Panc1 cell death, see Table 5.
Table 5
Cause in the test of pancreas cancer cell strain Panc1 cell death at the investigation related compound, find when use 10.0 μ M artesunate or lower concentration separately, to have only very a spot of cell death, even use 7.5 μ M Sorafenibs, 20% cell death of also only having an appointment separately; (5.0 μ M artesunate+5.0 μ M Sorafenibs) then produce the obvious synergistic effect when both share under low concentration, cause 68% cancer cell death; When both share with the ratio of 10.0 μ M artesunate+7.5 μ M Sorafenibs, then produce significant more synergism, cause 92% cancer cell death.
The dihydroarteannuin of embodiment 5 different proportions and the combination Synergistic of Sorafenib promote the test of Panc1 cell death, see Table 6.
Table 6
Cause in the test of pancreas cancer cell strain Panc1 cell death at the investigation related compound, find when use 10.0 μ M dihydroarteannuins or lower concentration separately, to have only very a spot of cell death, even use 7.5 μ M Sorafenibs, 20% cell death of also only having an appointment separately; (5.0 μ M dihydroarteannuins+5.0 μ M Sorafenibs) then produce the obvious synergistic effect when both share under low concentration, cause 51% cancer cell death; When both share with the ratio of 10.0 μ M dihydroarteannuins+7.5 μ M Sorafenibs, then produce significant more synergism, cause 81% cancer cell death.
The artesunate of embodiment 6 different proportions and the combination Synergistic of Sorafenib promote the test of HCT116 cell death, see Table 7.
Table 7
Cause in the test of colon cancer cell line HCT116 cell death at the investigation related compound, find 20% cell death of when using 7.5 μ M artesunate or 6.0 μ M Sorafenibs separately, only having an appointment; (5.0 μ M artesunate+4.0 μ M Sorafenibs) then produce the obvious synergistic effect when both share under low concentration, cause 76% cancer cell death; When both share with the ratio of 7.5 μ M artesunate+6.0 μ M Sorafenibs, then produce significant more synergism, cause about 95% cancer cell death.
The dihydroarteannuin of embodiment 7 different proportions and the combination Synergistic of Sorafenib promote the test of HCT116 cell death, see Table 8.
Table 8
Cause in the test of colon cancer cell line HCT116 cell death at the investigation related compound, find 20% cell death of when using 7.5 μ M dihydroarteannuins or 6.0 μ M Sorafenibs separately, only having an appointment; (5.0 μ M dihydroarteannuins+4.0 μ M Sorafenibs) then produce the obvious synergistic effect when both share under low concentration, cause 67% cancer cell death; When both share with the ratio of 7.5 μ M dihydroarteannuins+6.0 μ M Sorafenibs, then produce significant more synergism, cause about 90% cancer cell death.
The artesunate of embodiment 8 different proportions and the combination Synergistic of Sorafenib promote the test of HepG2 cell death, see Table 9.
Table 9
Cause in the test of hepatoma cell strain HepG2 cell death at the investigation related compound, find 15% cell death of when using 10.0 μ M artesunate or 4.0 μ M Sorafenibs separately, only having an appointment; (6.0 μ M artesunate+3.0 μ M Sorafenibs) then produce the obvious synergistic effect when both share under low concentration, cause 42% cancer cell death; When both share with the ratio of 10.0 μ M artesunate+4.0 μ M Sorafenibs, then produce significant more synergism, cause about 91% cancer cell death.
The dihydroarteannuin of embodiment 9 different proportions and the combination Synergistic of Sorafenib promote the test of 22RV1 cell death, see Table 10.
Table 10
Cause in the test of prostate gland cancer cell strain 22RV1 cell death at the investigation related compound, find 10% cell death of when using 7.5 μ M dihydroarteannuins, 3.5 μ M Sorafenibs or lower concentration separately, only having an appointment; Even also only have an appointment 20% cell death when increasing concentration to 12.5 μ M dihydroarteannuin, the 5.0 μ M Sorafenibs of single medicine; (7.5 μ M dihydroarteannuins+3.5 μ M Sorafenibs) then produce the obvious synergistic effect when both share under low concentration, cause 44% cancer cell death; When both share with the ratio of 12.5 μ M dihydroarteannuins+5.0 μ M Sorafenibs, then produce significant more synergism, cause 81% cancer cell death.
1. a pharmaceutical composition is characterized in that containing Sorafenib and arteannuin and artemisinin derivatives.
2. pharmaceutical composition according to claim 1 is characterized in that, the mol ratio of described Sorafenib and arteannuin and artemisinin derivatives is 1.0-15.0: 1.0-25.0.
3. pharmaceutical composition according to claim 2 is characterized in that, the mol ratio of described Sorafenib and arteannuin and artemisinin derivatives is 2.0-7.5: 2.5-12.5.
4. pharmaceutical composition according to claim 3 is characterized in that, described arteannuin and artemisinin derivatives are arteannuin, artesunate, dihydroarteannuin, Artemether or arteether.
5. the application of the arbitrary described pharmaceutical composition of claim 1-4 in the medicine of preparation treatment pulmonary carcinoma, cancer of pancreas, colon cancer, hepatocarcinoma, carcinoma of prostate, renal carcinoma, gastric cancer, cerebroma, sarcoma, ovarian cancer or breast carcinoma.
6. application according to claim 5 is characterized in that, in the application in preparation treatment lung cancer drugs, the mol ratio of described Sorafenib and arteannuin and artemisinin derivatives is 2.0-4.0: 3.0-10.0.
7. application according to claim 6 is characterized in that, in the application in preparation treatment lung cancer drugs, the mol ratio of described Sorafenib and arteannuin and artemisinin derivatives is 3.0-4.0: 5.0-10.0.
8. application according to claim 5 is characterized in that, in the application in the medicine of preparation treatment cancer of pancreas, the mol ratio of described Sorafenib and arteannuin and artemisinin derivatives is 2.5-7.5: 2.5-10.0.
9. application according to claim 8 is characterized in that, in the application in the medicine of preparation treatment cancer of pancreas, the mol ratio of described Sorafenib and arteannuin and artemisinin derivatives is 5.0-7.5: 5.0-10.0.
10. application according to claim 5 is characterized in that, in the application in the medicine of preparation treatment colon cancer, the mol ratio of described Sorafenib and arteannuin and artemisinin derivatives is 2.5-6.0: 2.5-7.5.
11. application according to claim 10 is characterized in that, in the application in the medicine of preparation treatment colon cancer, the mol ratio of described Sorafenib and arteannuin and artemisinin derivatives is 4.0-6.0: 5.0-7.5.
12. application according to claim 5 is characterized in that, in the application in the medicine of preparation hepatocarcinoma, the mol ratio of described Sorafenib and arteannuin and artemisinin derivatives is 2.0-4.0: 3.0-10.0.
13. application according to claim 12 is characterized in that, in the application in the medicine of preparation hepatocarcinoma, the mol ratio of described Sorafenib and arteannuin and artemisinin derivatives is 3.0-4.0: 6.0-10.0.
14. application according to claim 5 is characterized in that, in the application in the medicine of preparation carcinoma of prostate, the mol ratio of described Sorafenib and arteannuin and artemisinin derivatives is 2.5-5.0: 5.0-12.5.
15. application according to claim 14 is characterized in that, in the application in the medicine of preparation carcinoma of prostate, the mol ratio of described Sorafenib and arteannuin and artemisinin derivatives is 3.5-5.0: 7.5-12.5.
16. application according to claim 5 is characterized in that, Sorafenib in the described pharmaceutical composition and arteannuin and artemisinin derivatives can use or using in order with any priority simultaneously.
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