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 PDFInfo
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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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- 201000011510 cancer Diseases 0.000 title claims abstract description 8
- 239000000203 mixture Substances 0.000 title claims abstract description 7
- 206010028980 Neoplasm Diseases 0.000 title description 11
- 239000003814 drug Substances 0.000 title description 4
- AQLMHYSWFMLWBS-UHFFFAOYSA-N arsenite(1-) Chemical compound O[As](O)[O-] AQLMHYSWFMLWBS-UHFFFAOYSA-N 0.000 title description 2
- 229940079593 drug Drugs 0.000 title description 2
- 230000036210 malignancy Effects 0.000 title 1
- 208000029742 colonic neoplasm Diseases 0.000 claims abstract description 9
- 208000023958 prostate neoplasm Diseases 0.000 claims abstract description 9
- 206010061968 Gastric neoplasm Diseases 0.000 claims abstract description 7
- 230000003211 malignant effect Effects 0.000 claims description 13
- 239000007787 solid Substances 0.000 claims description 13
- 239000008194 pharmaceutical composition Substances 0.000 claims description 12
- 239000002671 adjuvant Substances 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 3
- PTLRDCMBXHILCL-UHFFFAOYSA-M sodium arsenite Chemical compound [Na+].[O-][As]=O PTLRDCMBXHILCL-UHFFFAOYSA-M 0.000 claims 4
- 238000002560 therapeutic procedure Methods 0.000 abstract description 3
- 238000000034 method Methods 0.000 abstract description 2
- 206010006187 Breast cancer Diseases 0.000 abstract 1
- 208000008839 Kidney Neoplasms Diseases 0.000 abstract 1
- 206010061535 Ovarian neoplasm Diseases 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 7
- -1 alkali metal salt Chemical class 0.000 description 4
- 239000001963 growth medium Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 210000004881 tumor cell Anatomy 0.000 description 4
- 230000012010 growth Effects 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- HJTAZXHBEBIQQX-UHFFFAOYSA-N 1,5-bis(chloromethyl)naphthalene Chemical compound C1=CC=C2C(CCl)=CC=CC2=C1CCl HJTAZXHBEBIQQX-UHFFFAOYSA-N 0.000 description 2
- 206010003445 Ascites Diseases 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- GOLCXWYRSKYTSP-UHFFFAOYSA-N arsenic trioxide Inorganic materials O1[As]2O[As]1O2 GOLCXWYRSKYTSP-UHFFFAOYSA-N 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- ICIWUVCWSCSTAQ-UHFFFAOYSA-M iodate Chemical compound [O-]I(=O)=O ICIWUVCWSCSTAQ-UHFFFAOYSA-M 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- NDMPLJNOPCLANR-UHFFFAOYSA-N 3,4-dihydroxy-15-(4-hydroxy-18-methoxycarbonyl-5,18-seco-ibogamin-18-yl)-16-methoxy-1-methyl-6,7-didehydro-aspidospermidine-3-carboxylic acid methyl ester Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 NDMPLJNOPCLANR-UHFFFAOYSA-N 0.000 description 1
- 208000036762 Acute promyelocytic leukaemia Diseases 0.000 description 1
- 206010057248 Cell death Diseases 0.000 description 1
- BELBBZDIHDAJOR-UHFFFAOYSA-N Phenolsulfonephthalein Chemical compound C1=CC(O)=CC=C1C1(C=2C=CC(O)=CC=2)C2=CC=CC=C2S(=O)(=O)O1 BELBBZDIHDAJOR-UHFFFAOYSA-N 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000001495 arsenic compounds Chemical class 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000007541 cellular toxicity Effects 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 101150042537 dld1 gene Proteins 0.000 description 1
- 238000003306 harvesting Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 238000005497 microtitration Methods 0.000 description 1
- 238000004264 monolayer culture Methods 0.000 description 1
- 229910052958 orpiment Inorganic materials 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229960003531 phenolsulfonphthalein Drugs 0.000 description 1
- 229940097322 potassium arsenite Drugs 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical group [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- HEQWEGCSZXMIJQ-UHFFFAOYSA-M potassium;oxoarsinite Chemical compound [K+].[O-][As]=O HEQWEGCSZXMIJQ-UHFFFAOYSA-M 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 229910052957 realgar Inorganic materials 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/36—Arsenic; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/34—Copper; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Inorganic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Solid-Sorbent Or Filter-Aiding Compositions (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
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
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：
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。
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/NL2002/000231 WO2003086424A1 (en) | 2002-04-10 | 2002-04-10 | Pharmaceutical composition comprising arsenite for the treatment of malignancy |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1625407A CN1625407A (zh) | 2005-06-08 |
| CN1298332C true CN1298332C (zh) | 2007-02-07 |
Family
ID=29244880
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB028287215A Expired - Lifetime CN1298332C (zh) | 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 |
Country Status (25)
| Country | Link |
|---|---|
| US (1) | US20050106262A1 (zh) |
| EP (2) | EP2042182B1 (zh) |
| JP (1) | JP2005525397A (zh) |
| CN (1) | CN1298332C (zh) |
| AP (1) | AP2004003167A0 (zh) |
| AU (2) | AU2002253713B2 (zh) |
| BG (1) | BG66356B1 (zh) |
| BR (1) | BR0215689A (zh) |
| CA (1) | CA2481602C (zh) |
| CY (1) | CY1114422T1 (zh) |
| DK (2) | DK2042182T3 (zh) |
| EC (1) | ECSP045408A (zh) |
| ES (2) | ES2425418T3 (zh) |
| FI (1) | FI1496918T3 (zh) |
| HU (1) | HU230851B1 (zh) |
| IL (2) | IL164470A0 (zh) |
| LT (1) | LT1496918T (zh) |
| MX (1) | MXPA04009898A (zh) |
| NO (1) | NO335317B1 (zh) |
| NZ (1) | NZ536452A (zh) |
| PT (2) | PT2042182E (zh) |
| RO (1) | RO123269B1 (zh) |
| TN (1) | TNSN04198A1 (zh) |
| UA (1) | UA80426C2 (zh) |
| WO (1) | WO2003086424A1 (zh) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1789030A2 (en) * | 2004-08-30 | 2007-05-30 | Interstitial Therapeutics | 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 |
| KR20120061908A (ko) * | 2009-09-10 | 2012-06-13 | 코미녹스 인코포레이티드 | 암 줄기세포-표적 및 약물 내성 암 치료 |
| AU2010295841A1 (en) * | 2009-09-18 | 2012-03-29 | Kominox, Inc. | Methods for treating brain tumors |
| 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 |
Citations (3)
| 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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2002
- 2002-04-10 ES ES08168243T patent/ES2425418T3/es not_active Expired - Lifetime
- 2002-04-10 EP EP08168243.7A patent/EP2042182B1/en not_active Expired - Lifetime
- 2002-04-10 WO PCT/NL2002/000231 patent/WO2003086424A1/en active Application Filing
- 2002-04-10 PT PT81682437T patent/PT2042182E/pt unknown
- 2002-04-10 LT LTEPPCT/NL2002/000231T patent/LT1496918T/lt unknown
- 2002-04-10 IL IL16447002A patent/IL164470A0/xx unknown
- 2002-04-10 AU AU2002253713A patent/AU2002253713B2/en not_active Expired
- 2002-04-10 ES ES02722968T patent/ES2944907T3/es not_active Expired - Lifetime
- 2002-04-10 RO ROA200400890A patent/RO123269B1/ro unknown
- 2002-04-10 JP JP2003583443A patent/JP2005525397A/ja active Pending
- 2002-04-10 NZ NZ536452A patent/NZ536452A/en not_active IP Right Cessation
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Patent Citations (3)
| 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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