WO2016062279A1 - 苹果酸丙氯陪拉辛锭用于制备治疗癌症药物的用途 - Google Patents
苹果酸丙氯陪拉辛锭用于制备治疗癌症药物的用途 Download PDFInfo
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Definitions
- the cancer is one or more of a chest-related cancer, an abdominal cavity-related cancer, an endocrine-related cancer, and a digestive tract-related cancer.
- Fig. 1 shows the results of analyzing the cancer cells of the present invention using a propionate of malic acid.
- Figure 3 is a graph showing the inhibitory effect of high-dose and low-dose malic acid on a tumor growth in the present invention.
- the analysis of the inhibitory effect of malic acid galic acid on the pleural cavity-related cancer cells was mainly tested on two kinds of lung cancer cells.
- the cancer cell lines were A549 and H1650, respectively, and the cancer cells were inhibited four times.
- the experimental results, and the average value is calculated, and the results are shown in Table 2.
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Abstract
本发明提供苹果酸丙氯陪拉辛锭在制备治疗癌症药物中的用途。
Description
本发明涉及一种苹果酸丙氯陪拉辛锭药物的新适应症的应用,尤其该苹果酸丙氯陪拉辛锭药物具有抑制多种癌症的用途
癌症长期高居全球死因之首,且罹患癌症人数更是逐年攀升,因此治疗癌症俨然成为重要的课题。癌症的治疗可区分为手术治疗、放射线治疗、化学治疗及标靶治疗。
一般来说,癌症药物治疗无论是化学治疗或标靶治疗,目的多是让癌细胞无法复制、分裂,来阻断肿瘤的蔓延扩张。
在癌症药物的设计上也是均朝向高专一性的药物分子开发或标靶型的抗体设计,根据统计,平均每一万个新药约只有五个能够进入第一期临床试验。
此外,除了药物本身是否能大量制造的难题外,还需克服药物安全性、病人筛选、试用剂量等问题,即便药物已经通过FDA的核准并上市,还是常遇到患者对于治疗药物的反应不佳。进一步,许多癌细胞相继产生抗药性,使药物的使用成效大幅降低,最终导致癌症治疗失败。由此可见药物开发具有一定的困难程度。
苹果酸丙氯陪拉辛锭(PROCHLORPERAZINE MALEATE,马来酸甲哌氯丙嗪、丙氯拉嗪)在临床上常用于精神病状态、恶心、呕吐时的用药。主要是透过抑制骨髓的化学接收器引发区而产生止吐作用的药物。苹果酸丙氯陪拉辛锭
是早已被FDA所认可的用药,具有大量药物机转及人体研究成果资料。
由于临床应用上的差异,因此从来没有人认为苹果酸丙氯陪拉辛锭具有抑制癌症细胞的可能性。
发明内容
为解决上述的问题,本发明针对苹果酸丙氯陪拉辛锭(马来酸甲哌氯丙嗪、丙氯拉嗪)药物进行新适应症的研发,而达到老药新用的目标。
经过实验设计结果显示苹果酸丙氯陪拉辛锭药物对正常细胞没有或仅有微小的毒性,但至于苹果酸丙氯陪拉辛锭在正常细胞与肿瘤细胞之间是否具有选择性的影响。
本发明提供一种苹果酸丙氯陪拉辛锭用于制备治疗癌症药物的用途,其中所述药物由有效剂量的苹果酸丙氯陪拉辛锭及药学上可接受的盐类所组成。
本发明一实施例中,其中所述癌症为胸腔相关癌症、腹腔相关癌症、内分泌相关癌症、消化道相关癌症中的一种或多种。
本发明一实施例中,其中所述癌症为骨肉瘤相关癌症、皮肤癌相关癌症、血癌相关癌症中的一种或多种。
本发明一实施例中,其中所述胸腔相关癌症指的是肺癌。
本发明一实施例中,其中所述腹腔相关癌症为膀胱癌或/和子宫颈癌。
本发明一实施例中,其中所述内分泌相关癌症为前列腺癌、乳癌、卵巢癌中的一种或多种。
本发明一实施例中,其中所述内分泌相关癌症系选自由胃癌、肝癌、大肠癌、胰脏癌、舌癌中的一种或多种。
本发明一实施例中,其中所述苹果酸丙氯陪拉辛锭药物的有效剂量浓度为
20~500mg/kg/天。
图1为本发明苹果酸丙氯陪拉辛锭用药应用于抑制癌细胞分析结果。
图2为本发明苹果酸丙氯陪拉辛锭可对肿瘤体积的效果
图3为本发明高剂量及低剂量苹果酸丙氯陪拉辛锭肿瘤生长的抑制效果
各种癌症细胞株建立
将不同癌症类型的细胞株进行继代培养,癌症细胞种类包含肺癌、胃癌、肝癌、直肠癌、皮肤癌、子宫颈癌、前列腺癌、膀胱癌、乳癌、血癌、胰腺癌、卵巢癌、舌癌、骨肉瘤、肾脏癌,并且对照组亦使用肾脏(HEK293(Kidney))、纤维母细胞HFW(fibroblast)、肺部上皮细胞BEAS-2B(Lung Epithelial)的正常细胞做测试(表一)。
先将各细胞于培养液培养后,由于各细胞的属性不同,因此针对不同种的细胞也要用相对应的培养液(表一),计算细胞数目,回种2×106个细胞数,然后加入培养该细胞株的培养液补至体积为10ml,继续培养2-3天。之后将细胞计数,并分装至96孔盘,其中每孔的细胞数目固定为3000颗,且体积为100ul。
表一、癌症测试细胞株及其培养所用的培养液
细胞存活分析方法
将96孔盘中原有的培养液吸掉,每孔加入浓度10uM、体积100ul的市售药物,放置72小时后,每孔再加入100ul已稀释的WST-1试剂,该稀释比例为培养液与WST-1原液的体积比为9:1,最后每个孔盘的总体积为200ul,然后将96孔盘放置于37℃,30~90分钟,利用Elisa Reader(酶联免疫检测仪)于OD450侦测吸光值,并计算各癌症细胞株的存活率。
IC50即半抑制浓度(或称半抑制率)。在间接竞争ELISA标准曲线中是一个非常重要的数据,标准曲线是一个S型曲线。ICELISA中,不添加药物的对照组的OD值定为B0,添加了药物的实验组的OD值为B,B/B0%就叫做结合率,在结合率为50%时所对应的药物的浓度就叫做IC50。一般IC50的数值越小表示药物的抑制效果越强。
苹果酸丙氯陪拉辛锭对胸腔相关癌症细胞抑制效果的测试
本分析苹果酸丙氯陪拉辛锭对胸腔相关癌症细胞抑制效果的测试,主要针对两种肺癌细胞进行测试,癌细胞株分别为A549和H1650两个细胞株,各做4次的癌细胞抑制实验结果,并且计算其平均值,结果如表二所示。
表二、苹果酸丙氯陪拉辛锭对肺癌相关癌症细胞抑制测试
0524-10min | 0526-10min | 0529-10min | 0531-10min | 平均 | |
A549 | 55.1 | 55.3 | 50.1 | 55.4 | 54.0 |
1-10min | 2-20min | 3-20min | 4-20min | 平均 | |
H1650 | 71.9 | 67.6 | 100.7 | 119.6 | 90.0 |
苹果酸丙氯陪拉辛锭对腹腔相关癌症细胞抑制效果的测试
本分析苹果酸丙氯陪拉辛锭对腹腔相关癌症细胞抑制效果的测试,主要针对两种腹腔相关癌症种类细胞进行测试,膀胱癌细胞株分别为TSGH和T24两个细胞株(表三),子宫颈癌细胞株分别为HeLa和C-33A兩個細胞株细胞株(表四),各做4次的癌细胞抑制实验结果,并且计算其平均值。
表三、苹果酸丙氯陪拉辛锭对膀胱癌相关癌症细胞抑制测试
0510-10min | 0512-10min | 0515-10min | 0517-10min | 平均 | |
TSGH | 88.0 | 77.0 | 74.3 | 47.9 | 71.8 |
1-30min | 2-20min | 3-20min | 4-20min | 平均 | |
T24 | 94.3 | 76.1 | 111.4 | 96.1 | 94.5 |
表四、苹果酸丙氯陪拉辛锭对子宫颈癌相关癌症细胞抑制测试
0524-10min | 0526-10min | 0529-10min | 0531-10min | 平均 | |
HeLa | 83.6 | 87.0 | 78.7 | 82.5 | 82.9 |
C-33A | 102.5 | 86.8 | 107.8 | 110.0 | 101.8 |
表五、苹果酸丙氯陪拉辛锭对肾脏癌相关癌症细胞抑制测试
0524-10min | 0526-10min | 0529-10min | 0531-10min | 平均 | |
786-O | 30.0 | 52.9 | 31.3 | 22.7 | 34.2 |
苹果酸丙氯陪拉辛锭对内分泌相关癌症细胞抑制效果的测试
本分析苹果酸丙氯陪拉辛锭对腹腔相关癌症细胞抑制效果的测试,主要针对三种内分泌相关癌症种类细胞进行测试,前列腺癌细胞株分别为PC-3和LNCap两个细胞株(表六),乳癌细胞株分别为MCF7和MDA-MB-231两个细胞株(表七),卵巢癌细胞株分别为NIH-OVCAR-3细胞株和TOV-21G(表八),各做4次的癌细胞抑制实验结果,并且计算其平均值。
表六、苹果酸丙氯陪拉辛锭对前列腺癌相关癌症细胞抑制测试
PC-3-0524-10min | PC-3-0526-10min | PC-3-0529-10min | PC-3-0531-10min | 平均 | |
PC-3 | 60.7 | 75.2 | 59.6 | 46.3 | 60.5 |
LNCap-1-10min | LNCap-2-20min | LNCap-3-20min | LNCap-4-20min | 平均 | |
LNCap | 40.4 | 51.0 | 76.5 | 63.1 | 57.7 |
表七、苹果酸丙氯陪拉辛锭对乳癌相关癌症细胞抑制测试
表八、苹果酸丙氯陪拉辛锭对卵巢癌相关癌症细胞抑制测试
7-3-30min | 7-4-30min | 7-7-30min | 7-4-30min | 平均 |
NIH-OVCAR-3 | 63.1 | 65.7 | 70.3 | 72.6 | 67.9 |
7-3-30min | 7-4-30min | 7-7-30min | 7-4-30min | 平均 | |
TOV-21G | 67.8 | 54.2 | 72.2 | 53.5 | 61.9 |
苹果酸丙氯陪拉辛锭对消化道相关癌症细胞抑制效果的测试
分析苹果酸丙氯陪拉辛锭对消化道相关癌症细胞抑制效果的测试,主要针对五种消化道相关癌症种类细胞进行测试,胃癌细胞株分别为AGS和MKN-45两个细胞株(表九),肝癌细胞株分别为HepG2和Hep3B两个细胞株(表十),大肠癌细胞株分别为HCT116-wt和LoVo细胞株(表十一),胰脏癌细胞株分别为AsPC和BxPC细胞株(表十二),舌癌细胞株为SAS细胞株(表十三),各做4次的癌细胞抑制实验结果,并且计算其平均值。
表九、苹果酸丙氯陪拉辛锭对胃癌相关癌症细胞抑制测试
0510-10min | 0512-10min | 0515-10min | 0517-10min | 平均 | |
AGS | 50.0 | 87.0 | 57.4 | 78.1 | 68.1 |
0510-10min | 0512-10min | 0515-10min | 0517-10min | 平均 | |
MKN-45 | 71.9 | 91.9 | 69.0 | 88.5 | 80.4 |
表十、苹果酸丙氯陪拉辛锭对肝癌相关癌症细胞抑制测试
0524-20min | 0526-20min | 0529-20min | 0531-20min | 平均 | |
HepG2 | 78.9 | 70.2 | 49.8 | 66.7 | 66.4 |
0612-20min | 0614-20min | 0616-20min | 0619-20min | 平均 | |
Hep3B | 137.9 | 97.2 | 82.6 | 102.0 | 104.9 |
表十一、苹果酸丙氯陪拉辛锭对大肠癌相关癌症细胞抑制测试
0602-30min | 0605-10min | 0607-10min | 0609-10min | 平均 | |
HCT116-wt | 77.2 | 112.3 | 94.6 | 68.9 | 88.3 |
0616-10min | 0619-10min | 0621-10min | 0623-10min | 平均 | |
LoVo | 83.4 | 66.2 | 77.9 | 82.8 | 77.55 |
表十二、苹果酸丙氯陪拉辛锭对胰脏癌相关癌症细胞抑制测试
1-7-3-30min | 1-7-4-30min | 1-7-7-30min | 1-4-30min | 平均 | |
AsPC | 61.6 | 65.3 | 53.9 | 72.8 | 63.4 |
3-7-3-30min | 3-7-4-30min | 3-7-7-30min | 3-4-30min | 平均 | |
BxPC | 43.5 | 74.5 | 59.5 | 66.1 | 60.9 |
表十三、苹果酸丙氯陪拉辛锭对舌癌相关癌症细胞抑制测试
6-26-10min | 6-28-10min | 6-30-10min | 7-3-10min | 平均 | |
SAS | 47.9 | 56.7 | 52.5 | 45.2 | 50.56 |
苹果酸丙氯陪拉辛锭对其他癌症细胞抑制效果的测试
分析苹果酸丙氯陪拉辛锭对其他类型癌正进行测试,骨肉癌细胞株为U2OS细胞株(表十四),皮肤癌细胞株分别为A375和BCC两个细胞株(表十五),各做4次的癌细胞抑制实验结果,并且计算其平均值。
表十四、苹果酸丙氯陪拉辛锭对骨肉瘤相关癌症细胞抑制测试
6-26-10min | 6-28-10min | 6-30-10min | 7-3-10min | 平均 | |
U2OS | 69.6 | 67.4 | 76.2 | 53.1 | 66.58 |
表十五、苹果酸丙氯陪拉辛锭对皮肤癌相关癌症细胞抑制测试
0602-30min | 0605-10min | 0607-10min | 0609-10min | 平均 | |
A375 | 108.3 | 81.0 | 64.2 | 78.1 | 82.9 |
0602-30min | 0605-10min | 0607-10min | 0609-10min | 平均 | |
BCC | 85.8 | 81.9 | 82.0 | 83.2 |
对照组实验设计
苹果酸丙氯陪拉辛锭对正常细胞抑制效果的测试
分析苹果酸丙氯陪拉辛锭对多种正常细胞进行测试,正常肾脏细胞株为HEK293细胞株(表十六),正常肺部上皮细胞细胞株为BEAS-2B细胞株(表十七),各做4次的癌细胞抑制实验结果,并且计算其平均值,结果如表16-18所
示。
表十六、苹果酸丙氯陪拉辛锭对正常肾脏细胞抑制测试
平均 | |
HEK293 | 109.7 |
表十七、苹果酸丙氯陪拉辛锭对正常肺部上皮细胞抑制测试
0510-10min | 0512-10min | 0515-10min | 0517-10min | 平均 | |
BEAS-2B | 52.8 | 76.5 | 87.5 | 73.4 | 72.5 |
针对苹果酸丙氯陪拉辛锭对各种癌症细胞抑制效果汇整于表十九中,清楚看出苹果酸丙氯陪拉辛锭对于多项癌症有明显的抑制效果。经过发明人实验结果,苹果酸丙氯陪拉辛锭药物对于不同的癌症细胞有明显的抑制效果。(图一)
表十九、苹果酸丙氯陪拉辛锭对各种癌症细胞抑制效果的汇整
癌症細胞 | 抑制效果 |
肺癌 | 71.97116867 |
膀胱癌 | 83.1 |
子宮頸癌 | 82.95 |
前列腺癌 | 60.46 |
乳癌 | 61.73 |
卵巢癌 | 64.9 |
胃癌 | 74.2 |
肝癌 | 85.66 |
大腸癌 | 82.90 |
胰臟癌 | 62.1 |
舌癌 | 50.56 |
骨肉癌 | 66.58 |
皮膚癌 | 83.08 |
腎臟癌 | 72.5 |
腎臟 | 109.74 |
肺部上皮細胞 | 72.54 |
动物实验分析
本实验使用雌性BALB/cAnN.Cg-Foxn1nu/CrlNarl小鼠为样本(购自国家实验动物中心),体重为21±1g,皮下注射胃癌细胞(AGS)后随机分笼,测试药物分
成三组:正常对照组、低剂量(100mg/kg/day)、高剂量(200mg/kg/day)。肿瘤形成超过100mm3后,每天采取腹腔注射方式给予药物;每周测量肿瘤大小两次,肿瘤体积测量公式如下:(L×W2);L代表肿瘤最长直径;W代表肿瘤最短直径。
表二十、苹果酸丙氯陪拉辛锭于动物实验对癌症对癌症的抑制效果
依据第2图的结果,低剂量与高剂量的苹果酸丙氯陪拉辛锭均对肿瘤具有良好的抑制效果,且于实验过程中各组小鼠的重量均未出现明显降低的现象,因此表示苹果酸丙氯陪拉辛锭不论高低剂量在治疗过程均能使受测小鼠具有良好的健康状态而不死亡。
依据第3图的结果,高低剂量的苹果酸丙氯陪拉辛锭可有效减缓肿瘤体积增长,并可同时减少肿瘤体积,其中以高剂量的苹果酸丙氯陪拉辛锭具有较佳的效果。
上列详细说明是针对本发明的可行实施例的具体说明,惟该实施例并非用以限制本发明的专利范围,凡未脱离本发明技艺精神所为的等效实施或变更,均应包含于本发明的专利范围中。
Claims (8)
- 一种苹果酸丙氯陪拉辛锭用于制备治疗癌症药物的用途,其特征是,所述药物由有效剂量的苹果酸丙氯陪拉辛锭及药学上可接受的盐类所组成。
- 如权利要求1所述的用途,其特征是,所述癌症为胸腔相关癌症、腹腔相关癌症、内分泌相关癌症、消化道相关癌症中的一种或多种。
- 如权利要求1所述的用途,其特征是,所述癌症为骨肉瘤相关癌症、皮肤癌相关癌症、血癌相关癌症中的一种或多种。
- 如权利要求2所述的用途,其特征是,所述胸腔相关癌症为肺癌。
- 如权利要求2所述的用途,其特征是,所述腹腔相关癌症为膀胱癌或/和子宫颈癌。
- 如权利要求2所述的用途,其特征是,所述内分泌相关癌症为前列腺癌、乳癌、卵巢癌中的一种或多种。
- 如权利要求2所述的用途,其特征是,所述消化道相关癌症为胃癌、肝癌、大肠癌、胰脏癌、舌癌中的一种或多种。
- 如权利要求1所述的用途,其特征是,所述苹果酸丙氯陪拉辛锭的有效剂量浓度为20mg/kg/天~500mg/kg/天。
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