CN1298332C - 用于治疗恶性肿瘤的包含亚砷酸盐的药物组合物 - Google Patents

用于治疗恶性肿瘤的包含亚砷酸盐的药物组合物 Download PDF

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CN1298332C
CN1298332C CNB028287215A CN02828721A CN1298332C CN 1298332 C CN1298332 C CN 1298332C CN B028287215 A CNB028287215 A CN B028287215A CN 02828721 A CN02828721 A CN 02828721A CN 1298332 C CN1298332 C CN 1298332C
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arsenite
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S·B·李
Y·J·杨
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KEMY PHARMACEUTICAL INTERNATIONAL CO Ltd
Y J Yong
Yi Seung Baek
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    • A61K33/24Heavy metals; Compounds thereof
    • A61K33/36Arsenic; Compounds thereof
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    • A61K33/00Medicinal preparations containing inorganic active ingredients
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K45/00Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • AHUMAN NECESSITIES
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Abstract

本发明涉及用于治疗实体恶性肿瘤的药物组合物,所述实体恶性肿瘤选自由结肠瘤、胃瘤、乳房瘤、卵巢瘤、前列腺瘤和肾瘤组成的组,所说的组合物包含偏亚砷酸盐(AsO2 -)和药学上可接受的辅助剂。本发明还涉及其用途以及治疗方法。

Description

用于治疗恶性肿瘤的包含亚砷酸盐的药物组合物
技术领域
本发明涉及用于治疗恶性肿瘤的含砷的药物组合物。
背景技术
已知含砷的药物组合物用于癌症治疗。例如,Waxman S等的综述(The Oncologist  6(suppl.2),pp.3-10(2001))描述了二硫化二砷、三硫化二砷和三氧化二砷,包含偏亚砷酸盐(AsO2 -)和药学上可接受的辅助剂的所述组合物的用途。
由于砷化合物的内在毒性以及良好替代手段的出现,对它们的兴趣仍然较低。
发明内容
本发明的目的是提供一种适合用于癌症治疗的药物组合物,它允许用于治疗实体瘤。所述药物组合物可用于治疗目前没有治疗方法存在的这类实体瘤,或者作为这类实体瘤的一种替代或补充治疗。
要达到这一目的,按照本发明的药物组合物的特征在于它是一种用于治疗实体恶性肿瘤的药物组合物,所述实体恶性肿瘤选自由结肠瘤、胃瘤、乳房瘤、卵巢瘤、前列腺瘤和肾瘤组成的组,所说的组合物包含偏亚砷酸盐(AsO2 -)和药学上可接受的辅助剂。
现意外地发现,特定类型的肿瘤对偏亚砷酸盐敏感。在所述盐中,偏亚砷酸盐的抗衡离子可以是任何药学上可接受的抗衡离子。
在Waxman的论文中,提到了Tarnowski G.S.等的论文(CancerResearch, 26(2),pp.181-206(1966)),其中用14种不同的抗肿瘤化学物质研究了8种肿瘤类型。亚砷酸钾仅影响埃利希(Ehrlich)腹水瘤的生长。关于这种肿瘤类型,值得注意的是它呈腹水形式时比呈实体形式时更敏感。这突出了本发明的意外发现。
按照优选的实施方案,所述盐是碱金属盐或碱土金属盐。按照更优选的实施方案,所述碱金属盐是钾盐或钠盐。
这类盐易溶解并且易适合发挥它们的抗肿瘤活性。
本发明还涉及偏亚砷酸盐(AsO2 -)在制备用于治疗实体恶性肿瘤的药物组合物中的用途,所述实体恶性肿瘤选自由结肠瘤、胃瘤、乳房瘤、卵巢瘤、前列腺瘤和肾瘤组成的组。
已发现,属于由结肠瘤、乳房瘤、前列腺瘤和肾瘤组成的组的实体恶性肿瘤特别敏感。
最后,本发明涉及一种用药物有效剂量的偏亚砷酸盐(AsO2 -)治疗患有实体恶性肿瘤的人类个体的方法,所述实体恶性肿瘤选自由结肠瘤、胃瘤、乳房瘤、卵巢瘤、前列腺瘤和肾瘤组成的组。
现在参照下文非限制性的实施例阐明本发明。
具体实施方案
各种肿瘤细胞在37℃、湿润气氛(95%空气,5% CO2)、补充有10%胎牛血清的具有酚红的RPMI 1640培养基(Life Technologies,Karlsruhe,Germany)的单层培养物中生长。每周用胰蛋白酶消化和维持细胞。
细胞毒性试验
利用改进的碘化丙锭试验(基于W.A.Dengler et.al,Anti-CancerDrugs, 6,pp.522-532(1995))检验所研究化合物的抗增生活性。简述之,将通过胰蛋白酶消化从生长在补充有10%胎牛血清的RPMI 1640培养基中的指数期培养物中收获细胞,在96孔平底微量滴定板中计数和加样(140μl细胞悬液,8×104细胞/ml)。24小时恢复后,允许细胞重新进行指数生长,向孔中加入10μl培养基(每板6个对照孔)或者含有实验药物的培养基。一式三份加入每个药物浓度。温育4天后,用碘化丙锭水溶液(6μg/ml)置换培养基。使微量滴定板在-18℃放置24小时,致使全部细胞死亡。滴定板解冻后,利用MilliporeCytofluor 2350-微板读数器测定荧光(激发530nm,发射620nm)以定量总的细胞数目。该试验包括未处理的对照和阳性对照(5-FU和长春地辛)。
生长抑制表示为:处理的/对照×100(或T/C%)。通过将化合物浓度对细胞数目作图确定IC50和IC70值。按照下式计算平均IC50和IC70值:
Figure C0282872100051
x=特定肿瘤细胞系,而n=所研究细胞系的总数目。如果在所检验的剂量范围内不能确定IC50或IC70,就用所研究的最低或最高的浓度来计算。
只有当阳性对照(5-FU)诱导了T/C<30%的肿瘤生长抑制并且赋形剂处理的对照细胞具有>500单位的荧光强度时,才认为试验有效。
结果
结果总结在表1中,该结果表明,胃瘤、卵巢瘤类型的肿瘤细胞系,并且,特别是前列腺瘤、乳房瘤、肾瘤和结肠瘤对偏亚砷酸盐化合物特别敏感。相比之下,已知对三氧化二砷有应答的早幼粒细胞白血病表现出6.82μg/ml的IC70值。因此,本发明涉及的肿瘤细胞对按照本发明的偏亚砷酸盐化合物更敏感约2至20倍。
             表1
  肿瘤   细胞系   IC70(μg/ml)
  结肠   DLD1   0.48
  胃   GXF251L   3.08
  乳房   MXAF401NL   0.32
  卵巢   OVCAR3   3.02
  前列腺   PC3   0.85
  肾   RXF486L   0.63

Claims (5)

1.用于治疗实体恶性肿瘤的药物组合物,所述实体恶性肿瘤选自由结肠瘤、胃瘤、乳房瘤、卵巢瘤、前列腺瘤和肾瘤组成的组,所说的组合物包含偏亚砷酸钠和药学上可接受的辅助剂。
2.偏亚砷酸钠在制备用于治疗实体恶性肿瘤的药物组合物中的用途,所述恶性肿瘤选自由结肠瘤、胃瘤、乳房瘤、卵巢瘤、前列腺瘤和肾瘤组成的组。
3.按照权利要求2的用途,其特征在于实体恶性肿瘤选自由结肠瘤、乳房瘤、前列腺瘤和肾瘤组成的组。
4.用于治疗实体恶性肿瘤的药物组合物,所述的组合物包含偏亚砷酸钠和药学上可接受的辅助剂。
5.偏亚砷酸钠在制备用于治疗实体恶性肿瘤的药物组合物中的用途。
CNB028287215A 2002-04-10 2002-04-10 用于治疗恶性肿瘤的包含亚砷酸盐的药物组合物 Expired - Lifetime CN1298332C (zh)

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US20070292478A1 (en) * 2004-08-30 2007-12-20 Popowski Youri Medical Implant Provided with Inhibitors of Atp Synthesis
EP1721615A1 (en) * 2005-05-09 2006-11-15 Komipharm International Co., Ltd. Pharmaceutical compositions comprising sodium or potassium arsenite for the treatment of urogenital cancer and its metastasis
US8945505B2 (en) 2007-02-02 2015-02-03 Panaphix, Inc. Use of arsenic compounds for treatment of pain and inflammation
US20090246291A1 (en) * 2008-03-27 2009-10-01 Angelika Burger Method and compositions for treatment of cancer
US20100249210A1 (en) * 2008-09-30 2010-09-30 Michael Bastiani Methods and compositions related to dlk-1 and the p38 mapk pathway in nerve regeneration
CN102060722B (zh) * 2009-05-01 2014-06-11 常州高新技术产业开发区三维工业技术研究所有限公司 一种含砷化合物及其制备方法和用途
RU2568834C2 (ru) * 2009-09-10 2015-11-20 Коминокс, Инк. Противораковая терапия, направленная против раковых стволовых клеток и форм рака, устойчивых к лечению лекарственными препаратами
KR20120048706A (ko) * 2009-09-18 2012-05-15 코미녹스 인코포레이티드 뇌종양 치료 방법
CN101695501B (zh) * 2009-10-10 2013-08-14 广汉恒宇新材料有限公司 一种纳米尺寸亚砷酸的壳聚糖包载体及其制造方法

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EP0804928A1 (en) * 1994-02-18 1997-11-05 Tamara Vasilievna Vorobieva Agent having an immunomodulating effect and reducing disturbed functioning of the tissue cell propagation regulating system
WO1999018798A1 (en) * 1997-10-15 1999-04-22 Polarx Biopharmaceuticals, Inc. Compositions and methods for the treatment of primary and metastatic neoplastic diseases using arsenic compounds
CN1243706A (zh) * 1998-08-02 2000-02-09 哈尔滨医科大学第一临床医学院 治疗消化系统肿瘤注射液及其应用

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0804928A1 (en) * 1994-02-18 1997-11-05 Tamara Vasilievna Vorobieva Agent having an immunomodulating effect and reducing disturbed functioning of the tissue cell propagation regulating system
WO1999018798A1 (en) * 1997-10-15 1999-04-22 Polarx Biopharmaceuticals, Inc. Compositions and methods for the treatment of primary and metastatic neoplastic diseases using arsenic compounds
CN1243706A (zh) * 1998-08-02 2000-02-09 哈尔滨医科大学第一临床医学院 治疗消化系统肿瘤注射液及其应用

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CY1114422T1 (el) 2016-08-31
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AU2002253713A1 (en) 2003-10-27
EP1496918B1 (en) 2023-02-08
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US20050106262A1 (en) 2005-05-19
CN1625407A (zh) 2005-06-08
JP2005525397A (ja) 2005-08-25
PT2042182E (pt) 2013-08-28
BG66356B1 (bg) 2013-09-30
AU2008255139B2 (en) 2013-10-03
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NO335317B1 (no) 2014-11-10
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AU2002253713B2 (en) 2008-09-18
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IL164470A (en) 2010-12-30
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