CN107519494B - 一种含有短葶山麦冬皂苷c的药物组合物 - Google Patents
一种含有短葶山麦冬皂苷c的药物组合物 Download PDFInfo
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Abstract
本发明涉及一种含有短葶山麦冬皂苷C的药物组合物,所述组合物包括短葶山麦冬皂苷C和其他抗肿瘤药物,所述其他抗肿瘤药物选自烷化剂类、抗代谢药类、抗肿瘤抗生素类、植物碱及其衍生物类、抗肿瘤激素类、铂类或其他抗肿瘤药物等。将短葶山麦冬皂苷C与其他抗肿瘤药物合用,降低了药物的用量,减少了毒性,同时,还增加了抗肿瘤效果。
Description
技术领域:
本发明涉及一种药物组合物,所述药物组合物为一种复方药物,所述药物组合物由短葶山麦冬皂苷C和抗肿瘤药物组成。
背景技术:
短葶山麦冬皂苷C(以下简称DT-13)是以鲁斯可皂苷元为母核的甾体皂苷类成分,为短亭山麦冬须根中含量最高的活性成分,具有较明确的抗肿瘤转移、抗炎、增强免疫等多种药理活性,其中抗肿瘤主要是肝癌、宫颈癌、肺癌、乳腺癌、艾氏腹水瘤、肉瘤(张媛媛等,短葶山麦冬皂苷DT-13研究进展,中国药科大学学报,2014,45(5):593-598),肿瘤转移(包括乳腺癌、黑色素瘤,CN10352448B,中国药科大学)。
DT-13的结构如式Ⅰ所示,其为难溶于水的白色无定形固体,分子式为C44H70O17,相对分子量为871.4676,化学名称为25(R,S)Ruscogenin-1-O-[β-D-glucopyranosyl-(1→2)]-[β-D-xylopyranosyl-(1→3)]-β-D-fucopyranoside。
本发明人在研究了DT-13的效果的基础上,意外的发现,将DT-13和其他抗肿瘤药物合用具有意想不到的协同增效作用,为此本发明提供一种DT-13和其他抗肿瘤药物合用组合发明。
发明内容:
本发明提供了一种含有DT-13的药物组合物,该组合物由DT-13和一种或几种抗肿瘤药物制备而成。
其中所述的抗肿瘤药物为不是DT-13的任何一种抗肿瘤药物,选自烷化剂类、抗代谢药类、抗肿瘤抗生素类、植物碱及其衍生物类、抗肿瘤激素类、铂类或其他抗肿瘤药物等。
所述烷化剂选自环磷酰胺、异环磷酰胺、卡莫司汀等;
所述抗代谢药类选自吉西他滨、卡培他滨、培美曲塞、氟尿嘧啶、甲氨蝶呤、阿糖胞苷、巯嘌呤、羟基脲等;
所述抗肿瘤抗生素类选自表柔比星、多柔比星、柔红霉素、丝裂霉素、更生霉素、阿霉素等;
所述植物碱及其衍生物类选自紫杉醇、多西他赛、伊立替康、羟基喜树碱、长春地辛、长春瑞滨、替尼泊苷、伊立替康、鲁比替康、贝洛替康等;
所述抗肿瘤激素类选自戈舍瑞林、亮丙瑞林、来曲唑、他莫西芬、甲羟孕酮、甲地孕酮、氟他胺等;
所述铂类选自卡铂、顺铂、奥沙利铂等;
所述其它抗肿瘤药选自伊马替尼、吉非替尼、厄洛替尼等替尼类,以及曲妥珠单抗、利妥昔单抗、贝伐单抗等。
优选地,本发明所述的药物组合物中,抗肿瘤药物选自紫杉醇、卡铂、顺铂、5-氟尿嘧啶、长春瑞滨。
本发明的药物组合物,优选的是DT-13与一种抗肿瘤药物制备而成,两者的重量比为 0.1-30:0.01-30,优选地,两者重量比为0.5-30:0.01-10。
本发明的药物组合物,其中一种优选的方案是DT-13与紫杉醇的组合,两者的重量比为3-30:0.01,优选重量比为3-10:0.01或10-30:0.01;
本发明的药物组合物,其中一种优选的方案是DT-13与卡铂的组合,两者的重量比为 3-30:0.01-1,优选重量比为3-30:0.01或3-10:0.01或10-30:0.01或10:0.1-1;
本发明的药物组合物,其中一种优选的方案是DT-13与顺铂的组合,两者的重量比为 1-10:0.1-10,优选重量比为10:0.1-10或10:0.1-1;
本发明的药物组合物,其中一种优选的方案是DT-13与5-氟尿嘧啶的组合,两者的重量比为1-10:0.1-100,优选重量比为10:1-10或10:1-100;
本发明的药物组合物,其中一种优选的方案是DT-13与长春瑞滨的组合,两者的重量比为0.5-20:0.01-1,优选重量比为5:1或10-20:0.01-0.1或5:0.01-1或20:1,或优选重量比为0.625-1.25:0.5-1,进一步优选为1.25:1;
本发明还提供了一种含上述药物组合物的组合物,所述组合物为药物制剂,由药物组合物和药学上可接受的载体。
所述组合物可以是DT-13与抗肿瘤药物可以组合在一个制剂中,也可以分别独立包装,在服用时同时服用。
优选的是,本发明的组合物为口服制剂或注射剂。
其中,所述口服制剂选自胶囊剂、片剂、滴丸剂、颗粒剂、浓缩丸、口服液和合剂中的一种。
其中,所述注射剂选自注射液、冻干粉针剂和水针剂中的一种。
对于本发明的组合物而言,其口服给药的制剂可含有常用的赋形剂,诸如粘合剂、填充剂、稀释剂、压片剂、润滑剂、崩解剂、着色剂、调味剂和湿润剂,必要时可对片剂进行包衣。
适用的填充剂包括纤维素、甘露糖醇、乳糖和其它类似的填充剂。适宜的崩解剂包括淀粉、聚乙烯吡咯烷酮和淀粉衍生物(例如羟基乙酸淀粉钠)。适宜的润滑剂例如,硬脂酸镁等。适宜的药学上可接受的湿润剂包括十二烷基硫酸钠等。
本发明的组合物可通过混合、填充、压片等本领域常用的方法制备成固体口服组合物。反复进行混合可使活性物质均匀分布在整体上使用大量填充剂的组合物中。
口服液体制剂的形式例如可以是水性或油性悬浮液、溶液剂、乳剂、糖浆剂或酏剂,或者还可以是一种在使用前可用水或其它适宜的载体复配的干燥产品。这种液体制剂可含有常规的添加剂,诸如悬浮剂,例如山梨醇、糖浆、甲基纤维素、明胶、羟乙基纤维素、羧甲基纤维素、硬脂酸铝凝胶或氢化食用脂肪;乳化剂,例如卵磷脂、脱水山梨醇一油酸酯或阿拉伯胶;非水性载体(可包括食用油),例如杏仁油、分馏椰子油、诸如甘油酯的油性酯、丙二醇或乙醇;防腐剂,例如对羟基苯甲酯或对羟基苯甲酸丙酯或山梨酸,并且如果需要,还可进一步含有常规的香味剂或着色剂。
对于注射剂,制备的液体单位剂型含有本发明的活性物质和无菌载体。根据载体和浓度,可将活性物质悬浮或者溶解。溶液剂的制备通常是通过将活性物质溶解在一种载体中,并在将其装入一种适宜的小瓶或安瓿前过滤消毒,然后密封。辅料例如局部麻醉剂、防腐剂和缓冲剂也可溶解在所述载体中。为了提高液体单位剂型的稳定性,可在装入小瓶以后将这种组合物冰冻,并在真空下将水除去。
在将本发明的组合物制备成药剂时,可选择性地向其中加入一种或多种适合的药学上可接受的载体,所述药学上可接受的载体选自:糖醇,例如甘露醇、山梨醇、木糖醇;氨基酸,例如盐酸半胱氨酸、蛋氨酸、甘氨酸;无机盐,例如一价碱金属的碳酸盐、磷酸盐或其水溶液,氯化钠、氯化钾,焦亚硫酸钠、亚硫酸氢钠、硫代硫酸钠,碳酸钙、碳酸氢钙;无机酸,例如盐酸、硫酸、磷酸;有机酸,例如醋酸、维生素C、巯基乙酸;有机酸盐,例如醋酸盐、藻酸盐、乳酸钠、EDTA二钠、EDTA钙钠,硬脂酸盐,例如硬脂酸钙、硬脂酸镁;寡糖、多糖、纤维素及其衍生物,例如麦芽糖、葡萄糖、果糖、右旋糖苷、蔗糖、乳糖、环糊精(例如β-环糊精)、淀粉;硅衍生物;明胶;聚乙烯吡咯烷酮;甘油;琼脂;表面活性剂(例如吐温80);聚乙二醇;磷脂类材料;高岭土;滑石粉等。
本发明还提供了上述药物组合物或含药物组合物的组合物在制备抗肿瘤的药物中的应用。
所述肿瘤包括但不限于胃癌、肺癌、乳腺癌、脑瘤、非小细胞肺癌等。
实验例1、药物联合体外实验
1、细胞株与方法
细胞株见表1
表1:细胞名称及细胞来源
序号 | 细胞名称 | 细胞来源 |
1 | 人肺癌细胞A549(MTT) | 中科院上海细胞库 |
2 | 人胃癌细胞BGC-823(MTT) | 中科院上海细胞库 |
3 | 人肺癌细胞95D(MTT) | 中科院上海细胞库 |
4 | 人乳腺癌细胞SKBR-3(MTT) | 中科院上海细胞库 |
5 | 人胃癌细胞HGC-27(MTT) | 中科院上海细胞库 |
6 | 人肺癌细胞NCI-H1975(MTT) | 中科院上海细胞库 |
7 | 人乳腺癌细胞MCF-7(MTT) | 中科院上海细胞库 |
8 | 人肺癌细胞NCI-H1299(MTT) | 中科院上海细胞库 |
9 | 人脑瘤细胞SF-763(MTT) | 中科院上海细胞库 |
[MTT方法(MTT全称为3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide,汉语化学名为3-(4,5-二甲基噻唑-2)-2,5-二苯基四氮唑溴盐,商品名:噻唑蓝)]
1)取处于指数生长期状态良好的细胞一瓶,加入0.25%胰蛋白酶消化液,消化使贴壁细胞脱落,计数2~4×104个/ml,制成细胞悬液。
2)取细胞悬液接种于96孔板上,180μl/孔,置恒温CO2培养箱中培养24小时。
3)换液,加入受试药物,20μl/孔,培养72小时。
4)将MTT试剂加入96孔板中,20μl/孔,培养箱中反应4小时(培养温度为37℃,5%CO2)。
5)MTT法,吸去上清液,加入DMSO,150μl/孔,平板摇床上振摇5分钟。
6)用酶联免疫检测仪在波长为570nm处测定每孔的吸光值,并计算细胞抑制。
7)药物联合作用评价采用药物相互作用指数Q评价两药相互作用性质,Q值按下列公式计算:
Q=EAB/(EA+EB-EA×EB)
AB为两药联合组的抑制率;A或B是各药物单独使用组的抑制率。当Q>1.15时,表示两药联合有协同作用;当Q<0.85时,表示两药联合无效;当0.85<Q<1.15时,表示两药联合有相加作用。
2、实验
2.1DT-13与紫杉醇(taxol,简写成TAX)联合应用对肿瘤细胞的生长抑制作用:结果见表2、表3
表2:DT-13与TAX联合应用对人胃癌BGC-823细胞的影响
药物 | 浓度(μM) | 抑制率% | 联合指数Q值 |
DT-13 | 10 | 30.1 | |
DT-13 | 3 | 17.1 | |
TAX | 0.01 | 8.2 | |
DT-13+TAX | 10+0.01 | 47.3 | 1.32 |
DT-13+TAX | 3+0.01 | 24.4 | 1.02 |
表3:DT-13与TAX联合应用对人肺癌95D细胞的影响
药物 | 浓度(μM) | 抑制率% | 联合指数Q值 |
DT-13 | 30 | 48.0 | |
DT-13 | 10 | 23.6 | |
TAX | 0.01 | 9.6 | |
DT-13+TAX | 30+0.01 | 68.1 | 1.29 |
DT-13+TAX | 10+0.01 | 42.0 | 1.36 |
实验结果:表2、3结果显示,当DT-13与TAX按照3-30:0.01配伍时,其联合指数 Q值不低于1.02。
结论:对胃癌和肺癌,DT-13和紫杉醇合用起到协同作用。
讨论:紫杉醇主要适用于卵巢癌和乳腺癌,对肺癌、大肠癌、黑色素瘤、头颈部癌、淋巴瘤、脑瘤也都有一定疗效,DT-13也可以治疗肝癌、宫颈癌、肺癌、乳腺癌、艾氏腹水瘤、肉瘤等,但是现有技术没有公开DT-13与紫杉醇合用后,具有了新的抗胃癌效果,且具有协同效果;在肺癌方面,紫杉醇与DT-13可以增加抗肺癌效果。同时可以降低紫杉醇在治疗肺癌中的用量。
2.2DT-13与卡铂联合应用对肿瘤细胞的生长抑制作用:实验结果见表4-8
表4:DT-13与卡铂联合应用对人肺癌A549细胞的影响
表5:DT-13与卡铂联合应用对人胃癌BGC-823细胞的影响
药物 | 浓度(μM) | 抑制率% | 联合指数Q值 |
DT-13 | 10 | 30.1 | |
DT-13 | 3 | 17.1 | |
卡铂 | 0.01 | 11.8 | |
DT-13+卡铂 | 10+0.01 | 36.1 | 0.94 |
DT-13+卡铂 | 3+0.01 | 24.0 | 0.90 |
表6:DT-13与卡铂联合应用对人乳腺癌SKBR-3细胞的影响
药物浓度 | 浓度(μM) | 抑制率% | 联合指数Q值 |
DT-13 | 30 | 26.6 | |
DT-13 | 10 | 18.3 | |
卡铂 | 0.01 | 14.9 | |
DT-13+卡铂 | 30+0.01 | 39.1 | 1.04 |
DT-13+卡铂 | 10+0.01 | 31.6 | 1.04 |
表7:DT-13与卡铂联合应用对人肺癌NCI-H1975细胞的影响
药物 | 浓度(μM) | 抑制率% | 联合指数Q值 |
DT-13 | 10 | 29.3 | |
DT-13 | 3 | 11.3 | |
卡铂 | 0.01 | 23.0 | |
DT-13+卡铂 | 10+0.01 | 42.0 | 0.92 |
DT-13+卡铂 | 3+0.01 | 34.2 | 1.08 |
表8:DT-13与卡铂联合应用对人乳腺癌细胞MCF-7的影响
药物 | 浓度(μM) | 抑制率% | 联合指数Q值 |
DT-13 | 10 | 29.1 | |
卡铂 | 0.1 | 13.3 | |
卡铂 | 1 | 16.9 | |
DT-13+卡铂 | 10+0.1 | 31.6 | 0.82 |
DT-13+卡铂 | 10+1 | 48.4 | 1.18 |
表4-8结果显示:对A549、BGC-823、SKBR-3、NCI-H1975和MCF-7细胞,DT-13和卡铂联合应用起到相加的作用。
结果表明:对肺癌、胃癌、乳腺癌,DT-13与卡铂合用具有协同效果。
讨论:
卡铂Carboplatin 1980年由Clear等发现,1986年首先在英国上市,美国FDA 1989年批准上市,应用逐渐推广。我国1990年批准生产卡铂粉、针剂。卡铂与其他抗肿瘤药无交叉耐药性,与DDP有交叉耐药性,该药易于溶解,不需水化、利水化、利尿,使用方便。主要用于小细胞肺癌、卵巢癌、睾丸肿瘤、头颈部鳞癌、卵巢上皮癌、头颈产鳞癌、非小细胞肺癌、膀胱癌、子宫颈癌、胸膜间皮瘤、黑色素瘤及子宫内膜癌等。也可用于消化系统肿瘤、肝癌等及放射增效治疗。
DT-13也可以治疗肝癌、宫颈癌、肺癌、乳腺癌、艾氏腹水瘤、肉瘤等。
现有技术没有报道卡铂可以与DT-13合用的信息,发明人发现,将二者按照3-30:0.01-1的配比关系进行组合后,没有抗胃癌效果的DT-13可以有效的增加卡铂治疗胃癌的效果,没有抗乳腺癌效果的卡铂可以有效的增加DT-13治疗乳腺癌的效果。
总之,DT-13可以降低卡铂在治疗人乳腺癌、肺癌时的常规用量,降低用量的同时预示可以降低化疗药物的毒副作用。
(3)DT-13与顺铂联合应用对肿瘤细胞的生长抑制作用:见表9、10
表9:DT-13与顺铂联合应用对人胃癌BGC-823细胞的影响
药物 | 浓度(μM) | 抑制率% | 联合指数Q值 |
DT-13 | 10 | 18.4 | |
顺铂 | 0.1 | 39.8 | |
顺铂 | 1 | 46.5 | |
顺铂 | 10 | 84.4 | |
DT-13+顺铂 | 10+0.1 | 74.0 | |
DT-13+顺铂 | 10+1 | 59.9 | 2.26 |
DT-13+顺铂 | 10+10 | 83.5 | 1.06 |
表10:DT-13与顺铂联合应用对人乳腺癌MCF-7细胞的影响
药物 | 浓度(μM) | 抑制率% | 联合指数Q值 |
DT-13 | 10 | 29.1 | |
顺铂 | 0.1 | 11.7 | |
顺铂 | 1 | 37.4 | |
DT-13+顺铂 | 10+0.1 | 28.2 | 0.76 |
DT-13+顺铂 | 10+1 | 76.5 | 1.38 |
表9、10结果显示:对BGC-823和MCF-7细胞,DT-13和顺铂联合应用起到相加的作用。
结果表明:对于胃癌和乳腺癌来说,DT-13和顺铂具有协同效果。
讨论:20世纪60年代,Rosenberg等偶然发现顺铂能够抑制细胞分裂,引起了人们的强烈兴趣,由此拉开了铂类抗肿瘤药物研究的序幕。时至今日,顺铂仍是用于癌症治疗的最常用的药物之一,它对睾丸癌和子宫癌有显著疗效,是治疗这两种癌症的首选药物;
同时,它也可用于治疗咽喉癌、支气管癌、宫颈癌、淋巴癌、骨肉瘤、黑色素瘤、膀胱癌以及神经母细胞瘤等。但是,顺铂具有严重的肾毒性、神经毒性、胃肠道毒性及耳毒性,
从而限制了其给药剂量;此外,一些肿瘤组织对顺铂具有先天耐药性,还有些肿瘤在初次给药时对顺铂敏感,长期使用则会产生耐药性。顺铂的所有这些缺陷尤其是它的毒副作用使人们迫切需要寻找更加低毒、高效、水溶性好、又无交叉耐药性的新一代铂类金属抗肿瘤药物。
现有技术没有报道顺铂可以与DT-13合用的信息,发明人发现,将二者按照10:0.1-10 的配比关系进行组合后,没有抗胃癌和乳腺癌效果的DT-13可以有效的增加顺铂治疗乳腺癌和胃癌的效果,没有抗乳腺癌效果的顺铂可以有效的增加DT-13治疗乳腺癌的效果。
故可以总之,DT-13可以降低顺铂在治疗人乳腺癌、胃癌时的常规用量。,降低用量的同时预示可以降低化疗药物的毒副作用。
(4)DT-13与5-FU(5-氟尿嘧啶)联合应用对肿瘤细胞的生长抑制作用:见表11-14
表11:DT-13与5-FU联合应用对人乳腺癌MCF-7细胞的影响
药物 | 浓度(μM) | 抑制率% | 联合指数Q值 |
DT-13 | 10 | 46.1 | |
5-氟尿嘧啶 | 1 | 16.1 | |
5-氟尿嘧啶 | 10 | 25.1 | |
DT-13+氟尿嘧啶 | 10+1 | 61.8 | 1.13 |
DT-13+氟尿嘧啶 | 10+10 | 65.4 | 1.10 |
表12:DT-13与5-FU联合应用对人肺癌NCI-H1299细胞的影响
药物 | 浓度(μM) | 抑制率% | 联合指数Q值 |
DT-13 | 10 | 23.4 | |
5-FU | 1 | 1.4 | |
5-FU | 10 | 32.1 | |
5-FU | 100 | 37.1 | |
DT-13+5-FU | 10+1 | 30.3 | 1.24 |
DT-13+5-FU | 10+10 | 45.7 | 0.95 |
DT-13+5-FU | 10+100 | 60.3 | 1.16 |
表13:DT-13与5-FU联合应用对人胃癌BGC-823细胞的影响
表14:DT-13与5-FU联合应用对人脑瘤SF763细胞的影响
药物浓度 | 浓度(μM) | 抑制率% | 联合指数Q值 |
DT-13 | 10 | 34.2 | |
5-FU | 1 | 19.3 | |
5-FU | 10 | 20.6 | |
5-FU | 100 | 58.6 | |
DT-13+5-FU | 10+1 | 39.6 | 1.04 |
DT-13+5-FU | 10+10 | 46.6 | 1.18 |
DT-13+5-FU | 10+100 | 63.1 | 1.87 |
表11-14实验结果显示:对MCF-7、NCI-H1299、BGC-823和SF763,DT-13和5-FU联合应用起到协同的作用。
结果表明:针对乳腺癌、肺癌、胃癌和脑癌,DT-13和5-FU具有协同效果。
讨论:
5-氟尿嘧啶类抗肿瘤药物是一类广谱抗肿瘤药物,通过多种途径、多种代谢产物来干扰肿瘤细胞的核酸代谢,主要途径:5-氟尿嘧啶在肿瘤细胞内转化为5-氟尿嘧啶脱氧核苷酸(5F-dUMP),可与还原型四氢叶酸及胸腺嘧啶核苷酸合成酶(TS)以共价结合形成三元复合物,使TS酸失活,进而抑制DNA的合成,从而达到抑制肿瘤细胞增殖的目的。该药主要为S期特异性药物,但其在体内转化为5-氟尿嘧啶核苷(5-FUR)后,也能掺入 RNA中干扰蛋白合成,故对其他各期细胞也有作用。5-氟尿嘧啶作为一种抗癌药物,它对多种肿瘤有抑制作用,但缺点是服药有效剂量与中毒量相近,在杀死癌细胞的同时也使正常细胞严重受损。
5-氟尿嘧啶类抗肿瘤药物安全窗口非常小,故限制了该药的广泛应用,DT-13与5-氟尿嘧啶联用后,起到明显的协同作用,可以降低5-氟尿嘧啶的使用量,故而降低该药所产生的副作用。
3、对表或结果的说明
3.1抗肿瘤活性判断标准:见表15
表15:抗肿瘤活性判断标准
3.2抗肿瘤药物初筛样本数n=3。
实验例2:药物联合体外实验-DT-13协同增强长春瑞滨(NVB)抗非小细胞肺癌(NSCLC) 作用研究
1、DT-13联合NVB对三种NSCLC细胞增殖的影响
为了检测DT-13能否增强三种NSCLC细胞(A549、NCI-H460和NCI-H1299)对NVB 的敏感性,分别以三种浓度DT-13(5μM、10μM和20μM)与三种浓度NVB(0.01μM、0.1μM 和1μM)进行联合作用48h,所得MTT结果采用calcusyn法分别计算其联合指数(CI)。其中CI<0.9,则提示两药联合发挥协同作用,数值越小,协同作用越强;0.9<CI<1.1,则表示相加作用。CI>1.1,则表示拮抗作用,实验结果见表16-1~16-3。
表16-1:DT-13与NVB联合应用对非小细胞肺癌A549细胞的影响
表16-2:DT-13与NVB联合应用对非小细胞肺癌NCI-H460细胞的影响
表16-3:DT-13与NVB联合应用对非小细胞肺癌NCI-H1299细胞的影响
实验统计中显著性差异采用student t方法评估,将10μM DT-13分别与不同浓度NVB 进行联合用药,并采用MTT法[1]考察联合用药对细胞增殖的影响。结果显示与单NVB用药相比,联合用药对三种细胞的抑制作用均显著提高(p<0.05)。同时采用calcusyn法对联合用药情况进行分析,并根据计算所得联合指数(CI),发现实验中DT-13联合NVB所得CI几乎均小于1,且数值较低。
结果说明:联合用药对非小细胞肺癌产生了强效的协同抑制作用。
2、DT-13联合NVB对三种NSCLC细胞克隆形成的影响
为了进一步考察DT-13联合NVB对三种NSCLC细胞(A549、NCI-H460和NCI-H1299)的克隆形成的影响,采用了结晶紫染色法[2]对联合用药作用进行考察。
结果如图1(图1与表17-1、17-2、17-3的关系:表的内容是图1的计算结果),其中A.选择10μMDT-13联合0.01μM NVB分别作用于A549和NCI-H460细胞;10μMDT-13联合0.1μNVB作用于NCI-H1299细胞。药物作用12h后,采用不含药的完全培养基继续培养8天。固定后采用结晶紫染色,并进行拍照。B.根据拍照结果,进行克隆形成数的统计分析。实验统计中显著性差异采用student t方法评估,其中*代表p<0.05,**代表p<0.01, ***代表p<0.001。
表17-1:DT-13与NVB联合应用对A549细胞克隆的影响
表17-2:DT-13与NVB联合应用对NCH-H460细胞克隆的影响
表17-3:DT-13与NVB联合应用对NCH-H1299细胞克隆的影响
表17-1、17-2和17-3结果显示:DT-13和NVB单药组产生了较弱的克隆抑制作用,而联合用药后,三种肿瘤细胞的克隆数均显著减少(p<0.05)。这些结果说明,DT-13与NVB 联合用药对于非小细胞肺癌具有协同抑制作用。
3、DT-13联合NVB对三种NSCLC细胞凋亡的影响
细胞凋亡是细胞毒类抗肿瘤药物发挥药效的作用之一。为了检测DT-13联合NVB对细胞凋亡作用的影响,采用AnnexinⅤ-PI双染法[3]对联合用药所诱导的凋亡作用进行考察。(图 2与表18-1、18-2、18-3的关系:表的内容是图2的计算结果)
表18-1:DT-13与NVB联合应用对A549细胞凋亡率的影响
表18-2:DT-13与NVB联合应用对NCH-H460细胞凋亡率的影响
表18-3:DT-13与NVB联合应用对NCH-H1299细胞凋亡率的影响
结果见表18-1、18-2、18-3,在A549及NCI-H460细胞中,DT-13能显著增强NVB 所诱导的凋亡作用(p<0.05)。而在NCI-H1299细胞中,虽然NVB单药组产生了一定的凋亡诱导作用,但联合用药后细胞凋亡作用并未显著增强(p>0.05)。
结果表明:DT-13与NVB联合用药对于非小细胞肺癌具有协同抑制作用
4、DT-13联合NVB对A549及NCI-H460细胞凋亡相关蛋白的影响
根据结果3.3中联合用药对A549及NCI-H460细胞的凋亡诱导作用,进一步采用western blot法[4、5]对于凋亡相关蛋白进行了检测。选择10μMDT-13联合0.01μM NVB分别作用于 A549和NCI-H460细胞48h,并采用western blot法检测凋亡相关蛋白Parp、caspase-3、 cleaved caspase-3、caspase-9和cleaved caspase-9的表达。
结果如图3,在A549细胞中,发现,与单药作用相比,DT-13与NVB联合用药组可显著增加Parp、cleaved caspase-3和cleaved caspase-9的剪切形式的表达,同时显著降低caspase-3和caspase-9的总蛋白表达水平。此外,在NCI-H460细胞中得到了类似的结果。这些研究表明,联合用药可通过诱导凋亡相关蛋白的变化而发挥诱导凋亡的作用。
5、DT-13联合NVB对三种NSCLC细胞周期相关蛋白的影响
为了进一步考察细胞周期的阻滞作用,采用了western blot法对周期相关蛋白进行分析。选择10μMDT-13联合0.01μM NVB分别作用于A549和NCI-H460细胞12h;10μMDT-13联合0.1μNVB作用于NCI-H1299细胞48h。采用western blot法检测cyclinB1、cdc2、 p-cdc2(Tyr15)和MPM-2的表达情况。
结果如图4,在A549细胞中,联合用药组可显著提高cyclinB1的蛋白表达水平,并降低p-cdc2(Tyr15)的表达,同时M期标志物MPM2的表达也发生显著的提高。这提示联合用药可显著增强有丝分裂促进因子(MPF)的活性,进而促使细胞由G2期转换到M期。此外,在NCI-H460和NCI-H1299细胞中也得到了类似的作用。这些研究表明DT-13联合NVB 可显著诱导细胞发生M期阻滞。
实验例3:DT-13联合长春瑞滨对人肺癌NCI-H460裸小鼠移植瘤的实验治疗作用
1、实验目的
考察DT-13联合长春瑞滨(NVB)对人肺癌NCI-H460裸小鼠移植瘤的联合抑制作用及作用强度。
2材料与方法
2.1受试物与药物配置方法
受试物:DT-13自制,纯度95%,批次编号20130801;NVB购于百灵威科技有限公司,纯度98%,产品编号522690。
药物配置方法:
DT-13药物配置:称取DT-13粉末,置于灭菌的0.5%CMC-Na溶液中,超声过夜溶解,得到最高浓度0.125mg/ml(即给药浓度1.25mg/Kg)。其他浓度按比例进行稀释。
NVB药物配置:称取NVB粉末,溶解于生理盐水溶液,混匀,配置最高浓度1mg/ml(即给药浓度10mg/Kg)。其他浓度按比例进行稀释。
2.2实验动物
雌性BALB/c裸小鼠,5周龄,体重15-22g,由南京大学南京生物医药研究院提供,动物合格证编号201602888。许可证号为SCXK(苏)2015-0001。每组动物数为阴性对照组 12只,给药组6只。
2.3实验方法
取生长旺盛期的瘤组织剪切成1.5mm3左右,在无菌条件下,接种于裸小鼠右侧腋窝皮下。裸小鼠移植瘤用游标卡尺测量移植瘤直径,待肿瘤生长至100-300mm3后将动物随机分组。使用测量瘤径的方法,动态观察被试药物抗肿瘤效应。肿瘤直接的测量次数为每周3次,每次测量同时还需称鼠重。DT-13 1.25mg/Kg、0.625mg/Kg灌胃给药,每日一次,每周共六次,共三周;NVB 10mg/Kg尾静脉给药,每周一次,共三周;NVB 1mg/Kg、 0.5mg/Kg尾静脉给药,每周三次,共三周;阴性对照组同时给予等量的CMC-Na。
2.4检测指标及计算方法
肿瘤体积(Tumor volume,TV),计算公式为:TV=1/2×a×b2,其中a、b分别表示长宽。
相对肿瘤体积(Relative tumor volume,RTV),计算公式为:RTV=TVt/TV0。
其中TV0为分笼给药时(即d0)肿瘤体积,TVt为每一次测量时的肿瘤体积。
相对肿瘤增殖率T/C(%),计算公式为:
其中:
TRTV:治疗组RTV;CRTV:阴性对照组RTV。
试验结果以相对肿瘤增殖率T/C(%)作为抗肿瘤活性的评价指标。
3、统计方法:实验数据以平均值和标准差表示,统计方法采用t-检验。
4、实验结果
4.1治疗效果:见表19-1、19-2、19-3、19-4、19-5
表19-1:对人肺癌NCI-H460裸小鼠移植瘤的实验治疗作用
注:给药组与Control组的显著性差异以P表示,其中*代表P<0.05,**代表P<0.01。
表19-2:对人肺癌NCI-H460裸小鼠移植瘤瘤体积的影响
表19-3:对人肺癌NCI-H460裸小鼠模型动物体重的影响
表19-4:对人肺癌NCI-H460裸小鼠移植瘤RTV的影响
表19-5:对人肺癌NCI-H460裸小鼠移植瘤瘤重的影响
表19-1、19-2、19-3、19-4、19-5结果显示:DT-13 0.625mg/Kg灌胃给药对人肺癌NCI-H460裸小鼠移植瘤的生长有较强的生长抑制作用,T/C(%)为77.34;DT-13 1.25mg/Kg灌胃给药对人肺癌NCI-H460裸小鼠移植瘤的生长有较弱生长抑制作用,T/C(%)为88.23。
NVB 10mg/Kg尾静脉给药对人肺癌NCI-H460裸小鼠移植瘤的生长有很强生长抑制作用,T/C(%)为43.15。但毒性较大,小鼠死亡一只。NVB 0.5mg/Kg、1mg/Kg尾静脉给药对人肺癌NCI-H460裸小鼠移植瘤的生长有较弱的生长抑制作用,T/C(%)分别为75.56 和75.08。
DT-13 0.625mg/Kg灌胃和NVB 0.5mg/Kg尾静脉联合给药对人肺癌NCI-H460裸小鼠移植瘤的生长有生长抑制作用,T/C(%)为66.29;DT-13 0.625mg/Kg灌胃和NVB 1mg/Kg尾静脉联合给药对人肺癌NCI-H460裸小鼠移植瘤的生长有生长抑制作用,T/C(%)为66.45; DT-13 1.25mg/Kg灌胃和NVB 0.5mg/Kg尾静脉联合给药对人肺癌NCI-H460裸小鼠移植瘤的生长有生长抑制作用,T/C(%)为73.79;DT-13 1.25mg/Kg灌胃和NVB 1mg/Kg尾静脉联合给药对人肺癌NCI-H460裸小鼠移植瘤的生长有生长抑制作用,T/C(%)为53.15。
实验发现,NVB 10mg/Kg组裸小鼠体重降低明显,并且有一只裸鼠提前死亡,此现象与NVB毒性较大有关。此外实验发现,联合治疗组体重与单药组体重相比,未见明显降低。说明联合用药对裸小鼠并无显著的毒性。
4.2DT-13与NVB抗人肺癌NCI-H460裸小鼠移植瘤联合用药指数:见表20-1、20-2、20-3、20-4
表20-1:DT-13与NVB抗人肺癌NCI-H460裸小鼠移植瘤联合用药指数
表20-2:DT-13与NVB抗人肺癌NCI-H460裸小鼠移植瘤联合用药指数
表20-3:DT-13与NVB抗人肺癌NCI-H460裸小鼠移植瘤联合用药指数
表20-4:DT-13与NVB抗人肺癌NCI-H460裸小鼠移植瘤联合用药指数
注:
a.FTV,fractional tumor volume=肿瘤体积分数;
b.Expected FTV(FTV的预期值)=(mean FTV of A)×(mean FTV of B);
c.Observed FTV(FTV的观察值)=final tumor volume of combinationtherapy/final tumor volume of control;
d.Combination Ratio(组合比例)=Expected FTV/Observed FTV.
e.当该指数大于1,表示具有协同作用;若小于1,则两药联合无协同作用。
表20-1、20-2、20-3和20-4结果表明:DT-13 0.625mg/Kg联合NVB 0.5mg/Kg、NVB1mg/Kg的联合指数分别为0.80和1.09,DT-13 1.25mg/Kg联合NVB 0.5mg/Kg、NVB 1 mg/Kg的联合指数分别为0.80和1.55。
结果提示:DT-13 1.25mg/Kg联合NVB 1mg/Kg具有较强的协同作用。
实验小结:体外实验证实DT-13和NVB具有协同抑制人肺癌细胞生长作用,进一步通过小鼠原位移植瘤模型考察其协同抗肿瘤体内作用效果。实验证实,DT-13能显著增强NVB 抑制肺癌的生长。
本发明提供的药物组合物具有以下优点:
与单独使用短葶山麦冬皂苷C或抗肿瘤药相比,将短葶山麦冬皂苷C与其他抗肿瘤药物联合使用,不仅降低了药物的用量,减少了毒性,同时,还增加了抗肿瘤效果,这是本领域技术人员不能通过现有技术得知的。
附图说明:
图1:DT-13与NVB联合用药对于三种NSCLC细胞的克隆增殖的影响;
图2:DT-13联合NVB对三种NSCLC细胞凋亡的影响;
图3:DT-13联合NVB对A549和NCI-H460细胞凋亡相关蛋白表达的影响;
图4:DT-13联合NVB对三种NSCLC细胞周期相关蛋白表达的影响。
具体实施方式:
以下通过实施例进一步说明本发明,但不作为对本发明的限制。
实施例1
本发明的药物组合物,是DT-13与紫杉醇的组合,两者的重量比为3:0.01,根需要加入药物可接受的载体,用制剂学常规技术制备成药物制剂,如片剂或注射剂。
或者
是DT-13与紫杉醇的组合,两者的重量比为30:0.01,根需要加入药物可接受的载体,用制剂学常规技术制备成药物制剂,如片剂或注射剂。
或者
是DT-13与紫杉醇的组合,两者的重量比为10:0.01,根需要加入药物可接受的载体,用制剂学常规技术制备成药物制剂,如片剂或注射剂。
实施例2
本发明的药物组合物,是DT-13与卡铂的组合,两者的重量比为3:0.01,根需要加入药物可接受的载体,用制剂学常规技术制备成药物制剂,如片剂或注射剂。
或者
是DT-13与卡铂的组合,两者的重量比为30:1,根需要加入药物可接受的载体,用制剂学常规技术制备成药物制剂,如片剂或注射剂。
或者
是DT-13与卡铂的组合,两者的重量比为10:0.1,根需要加入药物可接受的载体,用制剂学常规技术制备成药物制剂,如片剂或注射剂。
实施例3
本发明的药物组合物,是DT-13与顺铂的组合,两者的重量比为1:0.1,根需要加入药物可接受的载体,用制剂学常规技术制备成药物制剂,如片剂或注射剂。
或者
是DT-13与顺铂的组合,两者的重量比为10:10,根需要加入药物可接受的载体,用制剂学常规技术制备成药物制剂,如片剂或注射剂。
或者
是DT-13与顺铂的组合,两者的重量比为5:1,根需要加入药物可接受的载体,用制剂学常规技术制备成药物制剂,如片剂或注射剂。
实施例4
本发明的药物组合物,是DT-13与5-氟尿嘧啶的组合,两者的重量比为1:0.1,根需要加入药物可接受的载体,用制剂学常规技术制备成药物制剂,如片剂或注射剂。
或者
是DT-13与5-氟尿嘧啶的组合,两者的重量比为1:10,根需要加入药物可接受的载体,用制剂学常规技术制备成药物制剂,如片剂或注射剂。
或者
是DT-13与5-氟尿嘧啶的组合,两者的重量比为1:1,根需要加入药物可接受的载体,用制剂学常规技术制备成药物制剂,如片剂或注射剂。
实施例5
本发明的药物组合物,是DT-13与长春瑞滨的组合,两者的重量比为1:0.1,根需要加入药物可接受的载体,用制剂学常规技术制备成药物制剂,如片剂或注射剂。
或者
是DT-13与长春瑞滨的组合,两者的重量比为1:10,根需要加入药物可接受的载体,用制剂学常规技术制备成药物制剂,如片剂或注射剂。
或者
是DT-13与长春瑞滨的组合,两者的重量比为1:1,根需要加入药物可接受的载体,用制剂学常规技术制备成药物制剂,如片剂或注射剂。
参考文献:
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[4]Tian SS,Lamb P,King AG,et al.A small,nonpeptidyl mimic ofgranunocyt e-colony-st imulating factors[J].Science,1998,281:257.
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Claims (10)
1.一种含有短葶山麦冬皂苷C的药物组合物,其特征在于,所述药物组合物由短葶山麦冬皂苷C与紫杉醇组成,两者的摩尔比为10-30:0.01。
2.一种含有短葶山麦冬皂苷C的药物组合物,其特征在于,所述药物组合物由短葶山麦冬皂苷C与卡铂组成,两者的摩尔比为3:0.01,或10:1。
3.一种含有短葶山麦冬皂苷C的药物组合物,其特征在于,所述药物组合物由短葶山麦冬皂苷C与顺铂组成,两者的摩尔比为10:0.1,或10:1。
4.一种含有短葶山麦冬皂苷C的药物组合物,其特征在于,所述药物组合物由短葶山麦冬皂苷C与5-氟尿嘧啶组成,两者的摩尔比为10:1或10:100。
5.一种含有短葶山麦冬皂苷C的药物组合物,其特征在于,所述药物组合物由短葶山麦冬皂苷C与长春瑞滨组成,两者的摩尔比为5-20:0.01-1。
6.根据权利要求5所述的药物组合物,其特征在于,所述药物组合物由短葶山麦冬皂苷C与长春瑞滨组成,两者的摩尔比为10-20:0.01-0.1或5:0.01-1。
7.根据权利要求6所述的药物组合物,其特征在于,所述药物组合物由短葶山麦冬皂苷C与长春瑞滨组成,两者的重量比为0.625-1.25:0.5-1。
8.根据权利要求7所述的药物组合物,其特征在于,所述药物组合物由短葶山麦冬皂苷C与长春瑞滨组成,两者的重量比为1.25:1。
9.一种含药物组合物的药物制剂,其特征在于,该药物制剂,由权利要求1-8任一项所述的药物组合物和药学上可接受的载体组成。
10.权利要求1-8任一项所述的药物组合物或权利要求9所述的药物制剂在制备抗肿瘤的药物中的应用,其中所述肿瘤为:胃癌、肺癌、乳腺癌、肺癌。
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