CN112336746A - 一种膀胱癌灌注化疗药物及其应用 - Google Patents
一种膀胱癌灌注化疗药物及其应用 Download PDFInfo
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- CN112336746A CN112336746A CN202011145940.1A CN202011145940A CN112336746A CN 112336746 A CN112336746 A CN 112336746A CN 202011145940 A CN202011145940 A CN 202011145940A CN 112336746 A CN112336746 A CN 112336746A
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- bladder cancer
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- arsenic trioxide
- chemotherapeutic
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种膀胱癌灌注化疗药物及其应用,属于药物领域;其组成中含有三氧化二砷或三氧化二砷的水溶产物亚砷酸或亚砷酸根;所述的三氧化二砷的水溶产物亚砷酸为H3AsO3;所述的亚砷酸根指含有AsO3 3‑;所述对膀胱癌具有明显的增殖抑制作用,且可见明显的剂量依赖效应;效果显著,成本低廉。
Description
技术领域
本发明属于医药领域,具体地说,涉及到一种膀胱癌灌注化疗药物及其应用。
背景技术
膀胱癌是泌尿生殖系统最常见的恶性肿瘤。全球范围内,膀胱癌年新增病例38.63万,死亡病例15.02万,列恶性肿瘤发病率的第九位,男性恶性肿瘤发病率的第七位,致死率的第九位。膀胱癌在我国也是泌尿系统发病率最高的恶性肿瘤,2009年全国肿瘤登记地区膀胱癌发病率为6.61/10万,标准化发病率为3.03/10万。膀胱癌致病原因尚不完全清楚,经流行病学调查可能与长期工业染料接触、吸烟等危险因素有关,并与年龄、性别及家族史有相关性。临床上根据肿瘤累及膀胱壁的深度将膀胱癌分为非肌层浸润性膀胱癌(nonmuscleinvasive bladder cancer,NMIBC)和肌层浸润性膀胱癌(muscle invasive bladdercancer,MIBC),其中75%-85%的患者在初次就诊时为NMIBC。NMIBC的主要治疗方法为经尿道膀胱肿瘤电切术(transurethral resection of bladder tumor,TUR-Bt),但术后复发率高是导致手术治疗失败的主要原因。研究表明,TUR-Bt术后5年肿瘤复发率高达60%-70%,且有25%左右的患者会进展为MIBC。目前预防NMIBC患者术后复发最有效的办法是在TUR-Bt术后辅以膀胱灌注化疗,可使一年内复发率降低44%。膀胱灌注化疗使用药物主要有免疫制剂和细胞毒性化疗药物两类,卡介苗(Bacillus Calmette-Guérin,BCG)是临床最常用的免疫制剂类药物,抗有丝分裂类制剂如丝裂霉素、阿霉素、吡柔比星等是常用的细胞毒性化疗药物,其中疗效最好的是BCG。尽管使用现行药物进行膀胱灌注化疗在近期(一年内)具有一定的疗效,但长期使用并不能有效抑制肿瘤复发和进展,仍有20%左右的患者虽经膀胱灌注化疗肿瘤仍会复发,其中中危NMIBC患者术后5年复发率高达42%-65%。患者进展到MIBC后,5年生存率仅有50%。如发生转移,患者的5年生存率低至5-10%。鉴于目前膀胱癌治疗药物疗效的不稳定性,寻找一种安全有效药物已经成为膀胱癌治疗领域研究的热点和难点。
经检索,现有关于膀胱癌灌注的专利不少,但是其中所提供的技术方案还是存在治疗药物疗效的不稳定性的问题。例如,公开号CN 101904892A,公开时间为:2010-12-08,公开的中国专利文件,其提供了苏木提取物制备灌注液制备工艺及其在治疗膀胱癌上的用途,具体为一种苏木提取物灌注液制备工艺及其在治疗膀胱癌上的用途。主要是解决苏木提取物在治疗膀胱癌肿瘤方面的应用。步骤包括,取苏木粉碎,三次水提,合并三次得到的提取液,减压浓缩;静置过夜,除去沉淀;再加入石油醚,萃取,保留水相;再加入乙酸乙酯,萃取,去掉水相;减压挥发尽乙酸乙酯;干燥物称重,加纯化水,使干物质含量为2%,加热溶解,室温静置过夜,过滤除去沉淀物;冻干,分装,即可。但是效果依然不太理想。再如公开号CN109675023A,公开日为:2019年04月26日的专利申请文件,发明公开了一种卡介苗促进表阿霉素治疗膀胱癌的方法,具体涉及临床医学中的抗膀胱癌的联合治疗领域,包括细胞水平研究BCG对表柔比星的增效作用的方法以及体内BCG对表柔比星的增效作用的方法。本发明通过使用细胞水平研究BCG对表柔比星的增效作用的方法以及体内BCG对表柔比星的增效作用的方法,提供了一种联合用药的方案,以提高治疗效率,降低药物灌注时的毒副作用,该本发明灌注药物浓度不高,但是膀胱内保持时间长,从而抗肿瘤效果越好,但是该发明长期使用并不能有效抑制肿瘤复发和进展。
发明内容
1、要解决的问题
针对现有膀胱癌治疗药物疗效不稳定的问题,本发明提供一种膀胱癌灌注化疗药物及其应用,其能通过药物灌注,解决膀胱癌的治疗稳定性问题。
2、技术方案
为解决上述问题,本发明采用如下的技术方案。
一种膀胱癌灌注化疗药物组合,其组成中含有三氧化二砷或三氧化二砷的水溶产物亚砷酸或亚砷酸盐。
优选地,所述的三氧化二砷的水溶产物亚砷酸为H3AsO3。
优选地,所述的亚砷酸根指含有AsO3 3-。
如前面所述的一种膀胱癌灌注化疗药物组合在膀胱原位癌治疗中的应用。
优选地,所述的三氧化二砷的浓度为0.10~500.00mg/L,三氧化二砷的水溶产物亚砷酸的浓度为0.13~636.47mg/L,亚砷酸根的浓度为0.06~310.66mg/L。
如前面所述的一种膀胱癌灌注化疗药物组合在非肌层浸润性膀胱癌经尿道膀胱肿瘤电切术治疗后辅助膀胱内灌注化疗药物的应用。
优选地,所述的三氧化二砷的浓度为0.10~500.00mg/L,三氧化二砷的水溶产物亚砷酸的浓度为0.13~636.47mg/L,亚砷酸根的浓度为0.06~310.66mg/L。
所述的一种膀胱癌灌注化疗药物组合在肌层浸润性膀胱癌失去手术机会的膀胱癌或不耐受手术患者作为姑息性膀胱灌注化疗药物的应用。
优选地,所述的三氧化二砷的浓度为0.10~500.00mg/L,三氧化二砷的水溶产物亚砷酸的浓度为0.13~636.47mg/L,亚砷酸根的浓度为0.06~310.66mg/L。
优选地,所述的一种膀胱癌灌注化疗药物组合,其还包括与丝裂霉素、表柔比星、吡柔比星、顺铂、吉西他滨、甲氨蝶呤、长春花碱、紫杉醇、阿霉素、羟基喜树碱中一种或多种药物。
在本发明申请之前,也有人提出,能否将砷用于治疗膀胱癌症,但是根据现有资料,大都是认为三氧化二砷由于属于剧毒化合物,临床使用安全窗口小,无法口服给药(口服给药会导致肝脏蓄积和肝中毒,三氧化二砷肝毒性及其防治研究进展.中国药物警戒,2020,17(3):177-183.),临床上必须通过静脉方式给药,所以在临床上仅应用于白血病和肝脏肿瘤的治疗,在其他恶性肿瘤中由于较差的药代动力学及其剂量限制性毒性,会出现严重的毒副作用,难以达到明显的临床效果(三氧化二砷在HPV感染的宫颈癌治疗中的研究进展.世界最新医学信息文摘,2018,18(59):30-31,33.)。同时,由于膀胱癌治疗的特殊性(TUR-Bt术后辅助膀胱内灌注化疗),传统口服和静脉注射给药途径与膀胱灌注代谢途径不同(砒霜主要成分三氧化二砷口服与静脉给药后动物体内的砷形态差异分析.2019中国中西医结合学会临床药理与毒理专业委员会第三届学术研讨会),发挥药效作用和机制有显著差异,所以,目前理论上依然认为三氧化二砷在其他肿瘤治疗的应用研究并无直接借鉴价值和意义,同时也无法应用于膀胱癌症的治疗。而本发明人经过大量的实验和摸索,不但发现了如何借助三氧化二砷应用于膀胱癌的治疗,同时弄清了其用法、用量以及组合药物。
3、有益效果
相比于现有技术,本发明的有益效果为:
(1)本发明提供了一种膀胱癌灌注化疗药物组合,对于膀胱癌具有明显的增殖抑制作用,且可见明显的剂量依赖效应;
(2)本发明提供的一种膀胱癌灌注化疗药物组合在膀胱原位癌治疗中的应用,治疗成本低,操作简单;
(3)本发明的发明人,意外地发现,三氧化二砷的浓度为0.10~500.00mg/L,三氧化二砷的水溶产物亚砷酸的浓度为0.13~636.47mg/L,亚砷酸根的浓度为0.06~310.66mg/L;能解决了三氧化二砷严重的肝脏毒性,最大限度的降低了治疗产生的毒副作用;而且发现该膀胱癌灌注化疗药物组合可以应用在非肌层浸润性膀胱癌经尿道膀胱肿瘤电切术治疗后辅助膀胱内灌注化疗药物;
(4)本发明提供一种膀胱癌灌注化疗药物组合在肌层浸润性膀胱癌失去手术机会的膀胱癌或不耐受手术患者作为姑息性膀胱灌注化疗药物的应用,确定了该治疗方案的对象和时机,避免了无效者药物浪费;
(5)本发明提供的膀胱癌灌注化疗药物组合,其还包括与丝裂霉素、表柔比星、吡柔比星、顺铂、吉西他滨、甲氨蝶呤、长春花碱、紫杉醇、阿霉素、羟基喜树碱中一种或多种药物,实现了一种新的膀胱癌治疗药物的研发。
附图说明
图1为不同浓度三氧化二砷作用不同时间对RT4细胞生存率的影响;
图2为不同浓度三氧化二砷作用不同时间对5637细胞生存率的影响;
图3为不同浓度三氧化二砷作用不同时间对T24细胞生存率的影响。
具体实施方式
下面结合具体实施例和附图对本发明进一步进行描述。
实施例1
1、细胞培养
RT4和T24膀胱癌细胞系培养于含10%胎牛牛血清的McCOY’s 5A培养基中,5637细胞培养于含10%胎牛牛血清的RPMI-1640培养基中,37℃、5%CO2条件下生长传代,取对数生长期的细胞用于后续试验。
2、CCK-8法测定三氧化二砷对肿瘤细胞的增殖抑制作用
取对数生长期的膀胱癌细胞RT4、5637和T24,用0.25%胰酶消化后,制成单细胞悬液,将细胞接种于96孔板中,每孔接种细胞5×103/190μL。将培养板置于培养箱中37℃、5%CO2条件下培养24h后,取出培养板,每孔加入10μL工作液,使As2O3最终浓度为0.1,1,10,20,40,80,160,320mg/L,孵育12,24,48,72h后,取出培养板,吸去旧培养基,用PBS洗一遍后,每孔加入200μL培养基和20μL CCK-8试剂,培养箱内继续培养4h,取出后置于酶标仪中检测450nm处的吸光度(OD)值,并计算细胞存活率。
3、统计学方法
数据采用SPSS 19.0处理,以均值±标准偏差表示,组间两两比较采用t检验,P<0.05代表差异有统计学意义。
三、实验结果
结果如表1和图1~3所示,不同浓度三氧化二砷对不同级别人膀胱癌细胞RT4(分化良好的乳头状尿路上皮癌细胞系)、5637(高危浅表性膀胱癌细胞系)、T24(侵润性膀胱癌细胞系)均具有明显的增殖抑制作用,且可见明显的剂量依赖效应。
表1三氧化二砷对不同膀胱癌细胞作用的IC50
IC50单位mg/L
实施例2
一种膀胱癌灌注化疗药物组合,其组成中含有三氧化二砷或三氧化二砷的水溶产物亚砷酸或亚砷酸盐。所述的三氧化二砷的水溶产物亚砷酸为H3AsO3。所述的亚砷酸根指含有AsO3 3-。以上任意一种或者几种的组合,都可以在膀胱癌灌注化疗药物组合在膀胱原位癌治疗中应用。
该所述的一种膀胱癌灌注化疗药物组合可以在非肌层浸润性膀胱癌经尿道膀胱肿瘤电切术治疗后辅助膀胱内灌注化疗药物中应用。
所述的一种膀胱癌灌注化疗药物组合在肌层浸润性膀胱癌失去手术机会的膀胱癌或不耐受手术患者作为姑息性膀胱灌注化疗药物的应用。使用时,如果是三氧化二砷,则三氧化二砷的浓度为0.10~500.00mg/L,如果是三氧化二砷的水溶产物亚砷酸,则三氧化二砷的水溶产物亚砷酸的浓度为0.13~636.47mg/L,如果是三氧化二砷的水溶产物亚砷酸盐,则亚砷酸根的浓度为0.06~310.66mg/L。
一种膀胱癌灌注化疗药物组合,其还可以搭配丝裂霉素、表柔比星、吡柔比星、顺铂、吉西他滨、甲氨蝶呤、长春花碱、紫杉醇、阿霉素、羟基喜树碱中一种或任意几种。
TUR-BT术后24小时内完成表柔比星、吡柔比星或丝裂霉素等膀胱灌注化疗可以使肿瘤复发率降低39%。非肌层浸润性膀胱癌维持灌注治疗6个月以上时不能继续降低肿瘤的复发概率,因此建议术后维持膀胱灌注治疗6个月。但也有研究发现表柔比星维持灌注1年可以降低膀胱肿瘤的复发概率。非基层浸润性膀胱癌患者术后辅以膀胱灌注化疗,可使一年内复发率降低44%。表柔比星的常用剂量为50~80mg,丝裂霉素为20~60mg,吡柔比星为30mg,羟基喜树碱为10~20mg。表柔比星、吡柔比星、阿霉素是蒽环类抗癌药,抗癌作用具有细胞周期非特异性,具有多重抗癌机制,可以将蒽环平面嵌入DNA碱基对中、抑制拓扑异构酶II等。丝裂霉素也属于抗生素类抗癌药,抗癌作用具有细胞周期非特异性,可使DNA解聚,同时拮抗DNA的复制。羟基喜树碱属于植物类抗癌药,是DNA合成抑制剂,作用机制为抑制DNA拓扑异构酶Ⅰ,主要作用于DNA合成期(即S期)。吉西他滨为抗代谢类抗癌药,可以抑制DNA的合成,为细胞周期特异性,作用于S期。
本发明所述实例仅仅是对本发明的优选实施方式进行描述,并非对本发明构思和范围进行限定,在不脱离本发明设计思想的前提下,本领域工程技术人员对本发明的技术方案作出的各种变形和改进,均应落入本发明的保护范围。
Claims (10)
1.一种膀胱癌灌注化疗药物组合,其组成中含有三氧化二砷或三氧化二砷的水溶产物亚砷酸或亚砷酸根。
2.根据权利要求1所述的一种膀胱癌灌注化疗药物组合,其特征在于:所述的三氧化二砷的水溶产物亚砷酸为H3AsO3。
3.根据权利要求1所述的一种膀胱癌灌注化疗药物组合,其特征在于:所述的亚砷酸根指含有AsO3 3-。
4.权利要求1~3中任意一项所述的一种膀胱癌灌注化疗药物组合在膀胱原位癌治疗中的应用。
5.根据权利要求4所述的一种膀胱癌灌注化疗药物组合在膀胱原位癌治疗中的应用,其特征在于:所述的三氧化二砷的浓度为0.10~500.00mg/L,三氧化二砷的水溶产物亚砷酸的浓度为0.13~636.47mg/L,亚砷酸根的浓度为0.06~310.66mg/L。
6.权利要求1~3中任意一项所述的一种膀胱癌灌注化疗药物组合在非肌层浸润性膀胱癌经尿道膀胱肿瘤电切术治疗后辅助膀胱内灌注化疗药物的应用。
7.根据权利要求6所述的一种膀胱癌灌注化疗药物组合在非肌层浸润性膀胱癌经尿道膀胱肿瘤电切术治疗后辅助膀胱内灌注化疗药物的应用,其特征在于:所述的三氧化二砷的浓度为0.10~500.00mg/L,三氧化二砷的水溶产物亚砷酸的浓度为0.13~636.47mg/L,亚砷酸根的浓度为0.06~310.66mg/L。
8.权利要求1~3中任意一项所述的一种膀胱癌灌注化疗药物组合在肌层浸润性膀胱癌失去手术机会的膀胱癌或不耐受手术患者作为姑息性膀胱灌注化疗药物的应用。
9.根据权利要求8所述的一种膀胱癌灌注化疗药物组合在T4期失去手术机会的膀胱癌患者作为姑息性膀胱灌注化疗药物的应用,其特征在于:所述的三氧化二砷的浓度为0.10~500.00mg/L,三氧化二砷的水溶产物亚砷酸的浓度为0.13~636.47mg/L,亚砷酸根的浓度为0.06~310.66mg/L。
10.权利要求1~3中任意一项所述的一种膀胱癌灌注化疗药物组合,其还包括与丝裂霉素、表柔比星、吡柔比星、顺铂、吉西他滨、甲氨蝶呤、长春花碱、紫杉醇、阿霉素、羟基喜树碱中一种或多种药物。
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