CN106236845A - 一种体现肿瘤多药耐药逆转作用的中药组合物 - Google Patents
一种体现肿瘤多药耐药逆转作用的中药组合物 Download PDFInfo
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Abstract
本发明公开了一种体现逆转肿瘤多药耐药作用的中药组合物及其制备方法，属中药领域；以中药破骨风、千屈草、荠菜花和番木瓜为原料组合制备成活性组分。
Description
技术领域
本发明涉及一种体现肿瘤多药耐药逆转作用的中药组合物，属中药领域。
技术背景
化疗、放疗和手术是目前恶性肿瘤三大常规治疗手段，其中化疗过程中常出现化疗不敏感或化疗达不到预期效果等问题，或者出现患者在开始化疗阶段尚敏感、而化疗进行过程中出现耐药现象，导致在手术后化疗常常出现肿瘤转移、复发等，最终导致死亡。肿瘤细胞对抗肿瘤药物的多药耐药(MDR)现象是导致肿瘤化学药物治疗失败常见因素，同时肿瘤多药耐药现象也包括肿瘤细胞不仅仅对原使用过的化学药物产生耐药，对未使用过、结构无关和机制各异的多种抗肿瘤药物也均有交叉耐药性。
目前国内多种肿瘤患病率呈上升趋势，90％以上肿瘤患者死亡均有不同程度上肿瘤耐药现象影响，如何逆转肿瘤多药耐药是当今肿瘤治疗亟待解决关键问题，由此也迫切需要寻求理想的肿瘤耐药逆转剂。当今研究表明多种机制参与肿瘤细胞多药耐药状态的形成，主要包括：细胞膜P-糖蛋白、多药耐药相关蛋白过度表达形成药物外输泵，使抗肿瘤药物在肿瘤细胞内蓄积下降；谷胱甘肽-S-转移酶单独或与谷胱甘肽一起参与多种细胞毒代谢及解毒过程；与细胞凋亡相关的因子及基因如bcl-2，P53等异常。国内外针对上述肿瘤多药耐药的发病机制研究较多，寻求拮抗和/或逆转肿瘤细胞多药耐药现象有效途径或方式，体外实验结果证明具有逆转肿瘤多药耐药活性的化合物或生物制剂很多，但真正能进入临床研究的只有异博定、环孢菌素A等极少数药物，且临床疗效不理想。
目前还没有一种药物或方法在临床被广泛接受原因在于：现有的肿瘤耐药逆转剂大多为“老药新用”，所体现的肿瘤逆转耐药作用往往不是其主要功能，临床使用禁忌症多，毒副作用大；生物制剂在机体内不稳定，难以作用到靶点且毒副反应多；临床耐药往往数种机制同时参与，只对单一机制起作用的耐药逆转剂往往不能发挥其显著效应。某些中药单体协同化疗起到很好的增效作用，能起到逆转肿瘤多药耐药，从而提高化疗效果，具有很好的应用和开发前景，对于这些中药单体成分的研究结果而言，大多体外实验疗效较好，真正能结合中医药理论及临床疗效研究甚少；在中医药理论指导下，结合肿瘤化疗多药耐药发病机制，采用中药组合物作为肿瘤多药耐药逆转剂，体现中医药临床疗效优势的报道基本未见。
中国发明专利CN200710143393.1公开了“青蒿素在制备抗肿瘤多药耐药药物中的应用”，中国发明专利CN200710070320.4公开了“姜黄素在制备肿瘤多药耐药预防剂中的用途”，中国发明专利CN1463701公开“联苯双酯作为肿瘤多药耐药逆转剂的新用途”；这类报道均为为中药单体成分作为耐药逆转剂。
中国发明专利CN102603692A公开了“一种抗肿瘤多药耐药抑制剂色满和色烯衍生物及其制备方法和应用”，中国发明专利CN101780068A公开了“片叶苔素D在制备抗肿瘤药物和抗肿瘤多药耐药逆转药物中的应用”，中国发明专利CN102274220A公开了“索拉菲尼在制备逆转肿瘤多药耐药性的药物中的应用”；这类报道为化学药物或拓展了原化学药物的新用途。目前有关制备肿瘤多药耐药逆转剂的发明专利报道基本集中在化学药物和中药单体成分。
发明内容
本发明的目的是提供一种逆转肿瘤多药耐药中药组合物。
本发明的另一个目的是提供一种逆转肿瘤多药耐药中药组合物的制备方法。
本发明上述具有逆转肿瘤多药耐药中药组合物的制备方法包括如下步骤：
1)称取各原料药破骨风、千屈草、荠菜花和番木瓜备用。
2)按上述重量配比的破骨风、千屈草、荠菜花和番木瓜，按照上述重量比混合，加3-5倍量水浸泡1-2小时，加热煎煮1.5小时，过滤，药渣再加2-3倍量水加热煎煮1小时，过滤，合并两次滤液，静置0.5小时，倒出上清液。
3)上清液浓缩至相对密度1.05-1.10，进喷雾干燥器，进风温度控制120-130℃，出风温度105-120℃，雾化器转速20-30转/分钟，进料速度为3-5ml/分钟，得喷雾干燥粉。
4)粉碎喷雾干燥粉，过筛后得细粉，即该中药组合物的活性组分。
与现有技术相比，本发明具有如下有益效果：
破骨风Jasminum lanceolarium Roxb.为木犀种植物清香藤的根及茎叶，味苦、辛，性平，具有清热解毒、祛湿凉血功效；千屈草为千屈草科千屈草属植物千屈菜Lythrumsalicaria L.全草，味苦、性凉，具有清热解毒、凉血止血功效；荠菜花为十字花科植物荠菜Capsellae bursa-pastoris(L.)Medic.的花序，味甘、性凉，具有清热利湿、凉血止血功效；番木瓜为番木瓜科植物番木瓜Papaya的果实，味甘、性平，具有清热解毒，利湿通络功效。在中医药理论指导下，上述中药材配伍，体现其清热解毒、利湿凉血功效；本发明中药组合物应用在肿瘤多药耐药治疗中起到逆转肿瘤多药耐药，且该中药组合物无毒副作用。
以下结合实施例对本发明作进一步的阐述
实施例1本发明中药组合物的制备
1.按下述重量配比称取各原料药
破骨风50克、千屈草50克、荠菜花100克和番木瓜100克备用。
2.按照上述重量比药材混合，加3倍量水浸泡1小时，加热煎煮1.5小时，过滤，药渣再加2倍量水加热煎煮1小时，过滤，合并两次滤液，静置0.5小时，倒出上清液；上清液 浓缩至相对密度1.05时，进喷雾干燥器，进风温度控制120℃，出风温度105℃，雾化器转速20转/分钟，进料速度为3ml/分钟，得喷雾干燥粉15克，粉碎过筛后可得细粉。
实施例2本发明中药组合物的制备
1.按下述重量配比称取各原料药
破骨风300克、千屈草300克、荠菜花200克和番木瓜200克备用。
2.按照上述重量比药材混合，加5倍量水浸泡2小时，加热煎煮1.5小时，过滤，药渣再加3倍量水加热煎煮1小时，过滤，合并两次滤液，静置0.5小时，倒出上清液；上清液浓缩至相对密度1.10时，进喷雾干燥器，进风温度控制130℃，出风温度120℃，雾化器转速30转/分钟，进料速度为5ml/分钟，得喷雾干燥粉50克，粉碎过筛后可得细粉。
实施例3本发明中药组合物的制备
1.按下述重量配比称取各原料药
破骨风150克、千屈草150克、荠菜花120克和番木瓜120克备用。
2.按照上述重量比药材混合，加3倍量水浸泡1小时，加热煎煮1.5小时，过滤，药渣再加2倍量水加热煎煮1小时，过滤，合并两次滤液，静置0.5小时，倒出上清液；上清液浓缩至相对密度1.09时，进喷雾干燥器，进风温度控制125℃，出风温度110℃，雾化器转速25转/分钟，进料速度为4ml/分钟，得喷雾干燥粉28克，粉碎过筛后可得细粉。
实验例1本发明中药组合物逆转多药耐药细胞株HL60/ADR耐药性研究
白血病细胞株HL60/S为敏感株，HL60/ADR为白血病细胞阿霉素耐药株；HL60/ADR是由HL60/S细胞接触递增浓度的ADR诱导而成，具有典型多药耐药性。细胞株均培养于含10％小牛血清的RPMI-1640培养液中。
含药血清制备：NIH小鼠适应性饲养3天后，称重，根据随机数目表随机分为高剂量组、中剂量组、低剂量组、空白对照组共4组，每组10只。
给药方法与剂量：中药组合物高剂量组按20g/kg灌胃给药，中剂量组按10g/kg灌胃给药，低剂量组按5g/kg灌胃给药，空白对照组以生理盐水灌胃。
上述给药组小鼠分别给药2h后取血离心分离血清，56℃灭活30min，用RPMI1640配制不同浓度的血清培养液。
取对数生长期HL60/ADR细胞以1×105/ml、HL60/S以0.5×105/ml分别接种于96孔培养板，100μl/孔。在37℃、5％CO2条件下培养过夜后，加不同浓度的受试含药血清和ADR共100μl，调零组和对照组加相应体积的培养液，每组设4个平行孔。培养72h后，每孔加5mg/mlMTT20μl(调零组除外)，再培养4h，倾去培养液，加DMSO100μl/孔，待完全溶解后，用酶联免疫仪在波长570nm处调零组调零后读取吸光度(A)值。
取4孔A值的均数按公式计算细胞抑制率，细胞抑制率(IR)＝[1-(试验孔A均值/对照孔A均值)]×100％；计算IR并求出半数抑制浓度(IC50)，以上实验重复3次；逆转倍数＝空白对照组IC50/用药组IC50。
表1 本发明中药组合物对HL60/ADR耐药株逆转作用
本发明组合物含药血清与ADR联合使用可致ADR对HL60/ADR的IC50明显下降，不同给药浓度对HL60/ADR逆转倍数为2.16-5.62，且呈浓度正相关，提示本发明中药组合物对HL60/ADR耐药株具有逆转作用。
实验例2本发明中药组合物逆转多药耐药细胞株K562/ADR耐药性研究
白血病细胞株K562/S为敏感株，K562/ADR为白血病细胞阿霉素耐药株；K562/ADR是由K562/S细胞接触递增浓度的ADR诱导而成，具有典型多药耐药性。细胞株均培养于含10％小牛血清的RPMI-1640培养液中。
含药血清制备：NIH小鼠适应性饲养3天后，称重，根据随机数目表随机分为高剂量组、中剂量组、低剂量组、空白对照组共4组，每组10只。
给药方法与剂量：中药组合物高剂量组按20g/kg灌胃给药，中剂量组按10g/kg灌胃给药，低剂量组按5g/kg灌胃给药，空白对照组以生理盐水灌胃。
上述给药组小鼠分别给药2h后取血离心分离血清，56℃灭活30min，用RPMI1640配制不同浓度的血清培养液。
取对数生长期K562/ADR细胞以1×105/ml、K562/S以0.5×105/ml分别接种于96孔培养板，100μl/孔。在37℃、5％CO2条件下培养过夜后，加不同浓度的受试含药血清和ADR共100μl，调零组和对照组加相应体积的培养液，每组设4个平行孔。培养72h后，每孔加5mg/mlMTT20μl(调零组除外)，再培养4h，倾去培养液，加DMSO100μl/孔，待完全溶解后，用酶联免疫仪在波长570nm处调零组调零后读取吸光度(A)值。
取4孔A值的均数按公式计算细胞抑制率，细胞抑制率(IR)＝[1-(试验孔A均值/对照孔A均值)]×100％；计算IR并求出半数抑制浓度(IC50)，以上实验重复3次；逆转倍数＝空白对照组IC50/用药组IC50。
表2 本发明中药组合物对K562/ADR耐药株逆转作用
本发明组合物含药血清与ADR联合使用可致ADR对K562/ADR的IC50明显下降，不同给药浓度对K562/ADR逆转倍数为2.18-3.71，且呈浓度正相关，提示本发明中药组合物对K562/ADR耐药株具有逆转作用。
Claims (4)
1.一种逆转肿瘤多药耐药的中药组合物，其特征在于它的活性组分是由下列重量份的原料药制成：破骨风5-30份、千屈草5-30份、荠菜花10-20份和番木瓜10-20份。
2.根据权利要求1的中药组合物，其中各原料药的用量为：破骨风15份、千屈草15份、荠菜花12份和番木瓜12份。
3.根据权利要求1或2所述的中药组合物的制备方法，包括如下步骤：
1)称取各原料药破骨风、千屈草、荠菜花和番木瓜备用。
2)按上述重量配比的破骨风、千屈草、荠菜花和番木瓜，按照上述重量比混合，加3-5倍量水浸泡1-2小时，加热煎煮1.5小时，过滤，药渣再加2-3倍量水加热煎煮1小时，过滤，合并两次滤液，静置0.5小时，倒出上清液。
3)上述2)上清液浓缩至相对密度1.05-1.10，进喷雾干燥器，进风温度控制120-130℃，出风温度110-120℃，雾化器转速20-30转/分钟，进料速度为3-5ml/分钟，得喷雾干燥粉。
4)粉碎上述3)喷雾干燥粉，过筛后得细粉，即该中药组合物的活性组分。
4.权利要求1所述中药组合物在制备逆转肿瘤多药耐药药物中的应用。
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