CN1471396A - 用于治疗癌症的含喜树碱和1,2-二苯乙烯衍生物的组合物 - Google Patents
用于治疗癌症的含喜树碱和1,2-二苯乙烯衍生物的组合物 Download PDFInfo
- Publication number
- CN1471396A CN1471396A CNA018179800A CN01817980A CN1471396A CN 1471396 A CN1471396 A CN 1471396A CN A018179800 A CNA018179800 A CN A018179800A CN 01817980 A CN01817980 A CN 01817980A CN 1471396 A CN1471396 A CN 1471396A
- Authority
- CN
- China
- Prior art keywords
- nsc
- cpt
- administration
- treatment
- dosage
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 title claims abstract description 62
- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 30
- 238000011282 treatment Methods 0.000 title claims abstract description 19
- PJANXHGTPQOBST-UHFFFAOYSA-N stilbene Chemical class C=1C=CC=CC=1C=CC1=CC=CC=C1 PJANXHGTPQOBST-UHFFFAOYSA-N 0.000 title claims abstract description 11
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 title abstract 2
- 229940127093 camptothecin Drugs 0.000 title abstract 2
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 title abstract 2
- 201000011510 cancer Diseases 0.000 title description 7
- LGZKGOGODCLQHG-CYBMUJFWSA-N 5-[(2r)-2-hydroxy-2-(3,4,5-trimethoxyphenyl)ethyl]-2-methoxyphenol Chemical group C1=C(O)C(OC)=CC=C1C[C@@H](O)C1=CC(OC)=C(OC)C(OC)=C1 LGZKGOGODCLQHG-CYBMUJFWSA-N 0.000 claims description 62
- 239000000890 drug combination Substances 0.000 claims description 35
- 241001597008 Nomeidae Species 0.000 claims description 10
- PJANXHGTPQOBST-VAWYXSNFSA-N Stilbene Natural products C=1C=CC=CC=1/C=C/C1=CC=CC=C1 PJANXHGTPQOBST-VAWYXSNFSA-N 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 9
- 235000021286 stilbenes Nutrition 0.000 claims description 9
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 230000001225 therapeutic effect Effects 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 230000002195 synergetic effect Effects 0.000 claims description 3
- 206010048832 Colon adenoma Diseases 0.000 claims 1
- 230000000694 effects Effects 0.000 description 15
- 239000003814 drug Substances 0.000 description 12
- 231100000252 nontoxic Toxicity 0.000 description 12
- 230000003000 nontoxic effect Effects 0.000 description 12
- 239000000825 pharmaceutical preparation Substances 0.000 description 11
- 229940079593 drug Drugs 0.000 description 10
- 210000004881 tumor cell Anatomy 0.000 description 10
- 206010009944 Colon cancer Diseases 0.000 description 9
- 241000699670 Mus sp. Species 0.000 description 9
- 230000003203 everyday effect Effects 0.000 description 9
- 239000002246 antineoplastic agent Substances 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 7
- 238000001990 intravenous administration Methods 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- 230000003213 activating effect Effects 0.000 description 6
- 125000000217 alkyl group Chemical group 0.000 description 5
- 230000004663 cell proliferation Effects 0.000 description 5
- 210000001072 colon Anatomy 0.000 description 5
- 210000000664 rectum Anatomy 0.000 description 5
- 201000001275 rectum cancer Diseases 0.000 description 5
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 4
- 230000000259 anti-tumor effect Effects 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- 231100000419 toxicity Toxicity 0.000 description 4
- 230000001988 toxicity Effects 0.000 description 4
- 125000000623 heterocyclic group Chemical group 0.000 description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 3
- 238000010253 intravenous injection Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 206010001167 Adenocarcinoma of colon Diseases 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- BKAYIFDRRZZKNF-VIFPVBQESA-N N-acetylcarnosine Chemical compound CC(=O)NCCC(=O)N[C@H](C(O)=O)CC1=CN=CN1 BKAYIFDRRZZKNF-VIFPVBQESA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 239000003005 anticarcinogenic agent Substances 0.000 description 2
- 239000003560 cancer drug Substances 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 201000010897 colon adenocarcinoma Diseases 0.000 description 2
- 201000010989 colorectal carcinoma Diseases 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000013583 drug formulation Substances 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 229960004768 irinotecan Drugs 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000007726 management method Methods 0.000 description 2
- 231100000682 maximum tolerated dose Toxicity 0.000 description 2
- 230000002062 proliferating effect Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- MQLACMBJVPINKE-UHFFFAOYSA-N 10-[(3-hydroxy-4-methoxyphenyl)methylidene]anthracen-9-one Chemical compound C1=C(O)C(OC)=CC=C1C=C1C2=CC=CC=C2C(=O)C2=CC=CC=C21 MQLACMBJVPINKE-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 101710112752 Cytotoxin Proteins 0.000 description 1
- 206010020880 Hypertrophy Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 101710183280 Topoisomerase Proteins 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 238000011226 adjuvant chemotherapy Methods 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 238000011319 anticancer therapy Methods 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- LGZKGOGODCLQHG-UHFFFAOYSA-N combretastatin Natural products C1=C(O)C(OC)=CC=C1CC(O)C1=CC(OC)=C(OC)C(OC)=C1 LGZKGOGODCLQHG-UHFFFAOYSA-N 0.000 description 1
- 231100000599 cytotoxic agent Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 239000002619 cytotoxin Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000011363 dried mixture Substances 0.000 description 1
- 230000007750 drug combination effect Effects 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 235000013569 fruit product Nutrition 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000003978 infusion fluid Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000011278 mitosis Effects 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 238000011369 optimal treatment Methods 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 239000006201 parenteral dosage form Substances 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000009781 safety test method Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 238000005728 strengthening Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000041 toxicology testing Toxicity 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
Classifications
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
用于治疗癌症的联合用药，含有1，2－二苯乙烯衍生物和喜树碱。
Description
本申请要求下列申请的优先权：2000年10月27日递交的第60/243,341号美国临时专利申请；2000年11月6日递交的第60/245,582号美国临时专利申请；2000年12月1日递交的第60/250,138号美国临时专利申请。
技术领域
本发明涉及用于治疗癌症的治疗联合用药，其中含有有效量的喜树碱(CPT-11)和有效量的1，2-二苯乙烯衍生物(例如风车子新碱(combretastatin))。
本发明涉及联合应用喜树碱衍生物和其它抗癌药物进行的癌症治疗，尤其涉及实体瘤的治疗，更特别涉及非小细胞肝癌和结肠直肠癌的治疗。本发明还涉及上述联合在增强治疗中的应用。
更具体地说，本发明涉及联合应用伊立替康(CPT-11；Campto)和1，2-二苯乙烯衍生物(例如风车子新碱)的抗癌治疗。
背景技术
直肠结肠癌是患病率和死亡率的一种主要因素，每年在欧美国家有大约300,000个新病例，并导致200,000例患者死亡(参见P.Boyle，“直肠结肠癌流行病学的一些最近进展”，《Management of ColorectalCancer》第19-34页，Bleiberg H.，Rougier P.，Wilke H.J.，编(MartinDunitz，伦敦1998)；和Midgley R.S.，Kerr D.J.，“直肠结肠癌的全身辅助化疗”，《Management of Colorectal Cancer》第126-27页，Bleiberg H.，Rougier P.，Wilke H.J.，编(Martin Dunitz，伦敦1998)。
虽然约50％的患者通过单独的外科手术治愈，但另一半患者由于疾病转移而最终死亡，其中包括约25％的患者在诊断时就已经有疾病转移迹象。
欧洲专利EP137,145(在此引入作为参考)记载了下式的喜树碱衍生物：
其中，具体地说，R1为氢、卤素或烷基，X为氯原子或NR2R3，其中R2和R3可以相同或不同，可以是氢原子、任选被取代的烷基、碳环或任选被取代的杂环；或者R2与R3为烷基(任选被取代)，该烷基与其相连的氮原子一起形成一个杂环，所述杂环任选含有选自O、S和/或NR4的另一个杂原子，R4为氢原子或者烷基；基团X-CO-O-位于A环的9、10或11位。
这些喜树碱衍生物是抑制I型拓扑异构酶的抗癌剂，其中X-CO-O-为[4-(1-哌啶子基)-1-派啶子基]羰基氧的化合物伊立替康或CPT-11是一种有效成分，对于治疗实体瘤特别是治疗结肠直肠癌特别有效。
欧洲专利申请EP74,256也记载了用作抗癌剂的其它喜树碱衍生物，特别是上述结构的结构类似物，其中X-CO-O-被基团-X′R′代替，所述X′为O或S，R′为氢原子或烷基或酰基。
其它喜树碱衍生物也已经被公开，例如公开于下列专利申请中：EP56,692、EP88,642、EP296,612、EP321,122、EP325,247、EP540,099、EP737,686、WO90/03169、WO96/37496、WO96/38146、WO96/38449、WO97/00876、US7,104,894、JP57116,015、JP57116,074、JP59005,188、JP60019,790、JP01249,777、JP01246,287和JP9112070；或者公开于Canc.Res.，38(1997)摘要1526或95(SanDiego-四月12-16日)；Canc.Res.，55(3)：603-609(1995)或AFMC Int.Med.Chem.Symp.(1997)摘要PB-55(汉城-7月27日至8月1日)。
通常以注射方式给药喜树碱衍生物，更具体地说以无菌溶液或乳液形式静脉内给药。然而，喜树碱衍生物还可以通过固体或液体组合物形式经口服方式给药。
喜树碱是一种细胞毒素生物碱，具有强的抗肿瘤活性。然而，在对直肠结肠癌具有抗肿瘤活性的物质中，喜树碱衍生物被认为是最有效的物质，在临床治疗中可以用其它抗肿瘤试剂增强这些化合物的用途。
发明内容
业已发现：把喜树碱衍生物与1，2-二苯乙烯衍生物联合给药对于治疗许多实体瘤(例如直肠结肠癌)特别有效。其中最有效的1，2-二苯乙烯衍生物是风车子新碱A-4以及简单称为风车子新碱的该化合物的一个衍生物。这两个化合物均显示强的有丝分裂抑制活性、细胞毒性和抑制微管蛋白聚合作用。
风车子新碱A-4的结构如下：
本发明的风车子新碱具有下列结构：
这些风车子新碱s在水中是可溶解的，并且能够以盐的形式应用，例如盐酸盐、乙酸盐、磷酸盐和甲磺酸盐等。
美国专利US5,525,632公开了1，2-二苯乙烯衍生物的制备方法，其中包括风车子新碱A-4、其可药用盐、水合物和溶剂合物的制备方法，该专利还公开了含有上述化合物、惰性可药用载体和/或稀释剂的口服和/或胃肠外给药剂型药物组合物的制备方法。该专利和US5,674,906公开了下列内容：1，2-二苯乙烯衍生物(包括风车子新碱)当单独应用时在体内具有低毒性和制癌活性。
最近业已发现：对于患肿瘤的哺乳动物，把喜树碱和风车子新碱联合用药比各个化合物单独用药能够显著降低肿瘤体积的发展。事实上，对于治疗癌症特别是结肠腺癌来说，把喜树碱衍生物CPT-11和1，2-二苯乙烯衍生物风车子新碱按顺序联合给药时，以较低的剂量联合给药比单独应用各个活性剂以最大非毒性剂量给药更有效。具体参见下列表IV。
可以通过治疗协同作用的测定表明联合用药的效果。如果联合用药的治疗效果优越于其中各个成分单独以最佳剂量用药时的效果，则这种联合用药显示了治疗协同作用(T.H.Corbett等，CancerTreatment Reports，66，1187(1982))。
联合用药的效果也可以这样确定：把联合用药的最大耐受剂量与研究中各个独立成分的最大耐受剂量进行比较。这种效果能够以定量形式表示，例如以log10细胞杀死数表示，其计算公式为：
log10细胞杀死数＝T-C(天数)/3.32×Td，
其中T-C表示细胞生长所需的时间，其为处理组(T)肿瘤达到预定体积(例如1g)所需的平均天数和对照组(C)肿瘤达到同样体积所需的天数，Td表示对照组肿瘤体积加倍所需天数(T.H.Corbett等，Cancer，40，2660.2680(1977)；F.M.Schabel等，Cancer Drug Development，B部，Methods in Cancer Research，17，3-51，纽约，Academic Press Inc.(1979))。如果产品的log10细胞杀死数大于或等于0.7，则认为该产品有效；如果其Log10细胞杀死数大于2.8，则认为该产品非常有效。
在本发明中，当1，2-二苯乙烯衍生物(例如风车子新碱)以足以抑制肿瘤增生的量可以与喜树碱衍生物(例如CPT-11)联合应用，用于给药至需要医治、减轻或预防肿瘤的哺乳动物，特别是用于给药至患有肿瘤细胞增生的病人，以抑制肿瘤细胞的生长。
抑制肿瘤细胞增生意味着抑制对治疗敏感的肿瘤细胞，包括将有效量的风车子新碱和有效量的CPT-11给药至患有肿瘤细胞增生的病人。在可接受的情况下，这种给药抑制肿瘤细胞的增生，或者减少肿瘤的可测量体积。在最佳情况下，肿瘤完全消退。
如上所述，对把本发明抗肿瘤试剂给药至所要治疗的哺乳动物的方法没有特别限制。它们可以是口服方式或者胃肠外给药方式，例如静脉内、皮下或肌肉内途径给药。为了提高效率，优选应用胃肠外给药风车子新碱，例如通过静脉内和皮下给药途径以输注方式给药。在本发明药物制剂的给药方法中，风车子新碱可以与CPT-11同时给药，或者这两者可以按照任意顺序先后给药。在实践应用中，给药方法和给药顺序可以根据下列情况的不同而加以变化：风车子新碱的具体制剂、CPT-11的具体制剂、所要治疗的具体肿瘤细胞和要治疗的具体宿主。本领域技术人员可以按照常规技术和本申请记载的内容适当地选择风车子新碱和CPT-11的最佳给药方法和给药顺序。
抑制肿瘤增生有效量的风车子新碱和喜树碱表示抑制肿瘤细胞增生的治疗单位，其对于患有肿瘤细胞增生的病人的给药敏感。实际上需要的治疗单位可以变化，所依赖的因素有：风车子新碱的具体用药剂型、CPT-11的具体用药剂型、要治疗的具体肿瘤细胞和要治疗的具体宿主。本领域技术人员根据治疗测试单位和本申请记载的内容可以合适地选择给定条件的最佳治疗单位。
本发明的抗肿瘤剂是一种药物制剂，其至少含有上述风车子新碱和喜树碱化合物，这样这两种活性成分可以包含在药物制剂混合物中。然而，本发明的两种活性成分也可以单独包含在不同的药物制剂中，按照先后顺序联合用药。需要注意的是：对于含有其它试剂例如其它抗肿瘤剂(第三种和第四种医药成分等)的药物制剂来说，只要所述药物制剂含有本发明所用的有效成分，则它们也自然包含在本发明范围之内。而且，本发明的抗肿瘤剂可以含有可药用载体、稀释剂和适合于任意本发明药物制剂(单独的药物制剂含有本发明的两种成分，各自独立的药物制剂各自含有联合用药的两种成分之一)的其它物质
本发明的抗肿瘤剂可以合适地应用合适的可药用载体和稀释剂，这些载体和稀释剂是药物制剂领域技术人员公知的物质。如上所述，本发明的抗肿瘤剂可以合适地以胃肠外方式给药。在此情况下，应用本领域技术人员公知的各种方法，把可药用载体和抗肿瘤剂一起制成静脉输注或注射制剂。优选地，药物试剂按照常规技术制备，例如，制备成两种有效成分的单位剂型，或制备成两种有效成分的冻干混合物，然后在输注给药用水或者其它合适液体中重新制备。
可以在本发明药物制剂的各个剂量中合并20-116.5mg、优选36-60mg的风车子新碱和144-400mg、优选240-400mg的CPT-11。用作注射或输注液体的药物组合物的生理学药物值可以通过本领域公知缓冲剂的含量进行调节。
具体实施方式
现在结合优选的实施方案更详细地解释本发明。需要注意的是它们仅仅作为实施例来举例说明，不能用于限定本发明。抗肿瘤效果和安全性试验
在患有结肠腺癌C51的小鼠中评价CPT-11和风车子新碱的联合用药效果。在第2-5天，口服给药CPT-11，每日四次，以不同剂量给药。在第1-5天，静脉内给药风车子新碱，每天两次。在联合给药方案中，在第2-5天每天口服给药三种不同剂量的CPT-11，每天给药两次；在第1-5天每天静脉内给药三种不同剂量的风车子新碱，每天给药两次。在单个活性剂给药CPT-11和风车子新碱和同时联合给药CPT-11/风
车子新碱的研究结果如下列表I所示。
表I
风车子新碱(静脉内注射)与CPT-11(口服)联合给药
肿瘤大小400-500mg；Td＝2.4天方案：CPT-11每天4次，在2-5天；风车子新碱每天2次，在1-5天1部分反应-测试小鼠中肿瘤体积降低至少50％的小鼠数；即测试的5只小鼠中，5例小鼠至少有部分反应。
| 风车子新碱 CPT-11s Log10细胞杀死数 结肠51PR1 |
| 单个活性剂 |
| - 400 1.1 - |
| 116.5 - 1.3 5/5 |
| 同时联合给药 |
| 51.5 180 1.1 3/5 |
表1表明风车子新碱和CPT-11作为单个活性剂以最大非毒性剂量(HNTD)给药的效果。表1还表明：当这些抗肿瘤化合物同时给药时，在较低的剂量下(单个活性剂最大非毒性剂量的45％)治愈率增加。因此，可以在降低毒性的条件下得到有效的治疗。
表II表明按顺序在给药风车子新碱后再给药CPT-11的效果
表II
按顺序联合给药风车子新碱(静脉内注射)和CPT-11(口服)，
其中首先给药风车子新碱
风车子新碱-HNTD＝116.5mg/kg/注射-HNTD剂量mg/kg/％；60(51％)；36(31％)；21.6(18％)。这些剂量单独应用不引起消退。
| 风车子新碱 | CPT-11 | Log10细胞杀死数 | 结肠51PR |
| 60 | 400 | 毒性 | - |
| 240 | 1.7 | 5/5 | |
| 144 | 1.5 | 5/5 | |
| 36 | 400 | 毒性 | - |
| 240 | 1.4 | 5/5 | |
| 21.6 | 400 | 1.4 | 5/5 |
| 240 | 1.4 | 4/5 |
当首先应用风车子新碱给药时，最有效的按顺序联合给药是：首先给药60mg/km的风车子新碱(HNTD的51％)，然后给药240mg/kgCPT-11(HNTD的60％)。这种联合给药使log10细胞杀死数为1.7，在5只测试小鼠中全部表现出结肠51肿瘤的部分消退。因此这种联合给药的治疗效果优越于各个试剂以最佳剂量应用的效果。
当风车子新碱以51％和31％最高非毒性剂量用药后，再把CPT-11(400mg/)以最大非毒性剂量应用时，这样用药对测试动物是有毒性的。仅仅当风车子新碱以18％和CPT-11以最高非毒性剂量联合用药时，log10细胞杀死数为1.4，在所有5只测试小鼠中有部分反应。这种联合用药的log细胞杀死数分别高于各个试剂的log细胞杀死数，从而表明这种联合用药的治疗效果。
令人意外地，当给药18％风车子新碱后再把CPT-11以最高非毒性剂量的60％给药，log细胞杀死数保持不变(1.4)，并且显示显著的效果。
下列表III显示首先把CPT-11以最大非毒性剂量(400mg/kg)给药，然后给药36mg/kg的风车子新碱(最大非毒性剂量的31％)，其log10细胞杀死数为1.9。同样，当把CPT-11和风车子新碱作为单个活性剂以最大非毒性剂量给药时，其log10细胞杀死数分别为1.1和1.3，这表明给药CPT-11后联合给药风车子新碱可以产生协同治疗效果。
表III风车子新碱(静脉注射)和CPT-11(口服)按顺序联合给药
首先给药CPT-11
2部分反应-肿瘤体积减少至少50％的测试小鼠的数量
| 风车子新碱 | CPT-11 | Log10细胞杀死数 | 结肠51PR2 |
| 60 | 400 | 毒性 | |
| 36 | 1.9 | 5/5 | |
| 60 | 240 | 毒性 | - |
| 36 | 1.4 | 5/5 |
在下列表IV所示的若干不同方案中测试静脉内给药风车子新碱和口服给药CPT-11的结果。当以单个活性剂给药时，以每天两次的频率给药风车子新碱，连续给药5天。单独给药CPT-11时，每天给药一次，连续给药4天。
当按顺序给药时，应用两种方案。当首先给药风车子新碱时，在第1天给药，然后在第2-5天以每天1次的频率给药CPT-11。当首先给药CPT-11时，在第1-4天以每天1次的频率给药，然后在第5天给药风车子新碱。
表IV风车子新碱(静脉内给药)和CPT-11(口服)以最大非毒性剂量联合给
药
按顺序联合给药，首先给药风车子新碱
按顺序联合给药，首先给药CPT-11
2部分反应-测试小鼠的肿瘤体积降低至少50％的数量。
| 风车子新碱 CPT-11 Log10细胞杀死数 结肠51PR2 |
| 单个活性剂 |
| - 400 1.1 - |
| 116.5 - 1.3 5/5 |
| 同时联合给药 |
| 51.5 180 1.1 3/5 |
| 60.0 240 1.7 5/5 |
| × 36.0 × 400 × 1.9 × 5/5 |
上述表IV显示：当把风车子新碱和CPT-11按顺序联合给药时，无论按照什么顺序，联合用药均比各个试剂单独用药或者将其同时联合用药的效果要好。从中可以看出：把CPT-11/风车子新碱按顺序给药对于抗结肠腺癌具有协同作用。另外，CPT-11/风车子新碱联合给药的效果比CPT-11或风车子新碱单独以最大非毒性剂量给药的效果要好。
这些测试表明：风车子新碱和CPT-11可以按不同方式给药以获得这些化合物联合用药的最佳效果。因此，本发明不限于通过这些药物物理联合获得的组合物，本发明还包括允许同时或者按顺序方式的独立给药的联合用药方式。
Claims (8)
1.药物组合物，含有喜树碱或其衍生物和1，2-二苯乙烯衍生物相联合。
2、权利要求1的组合物，其中1，2-二苯乙烯衍生物为风车子新碱。
3、治疗实体瘤的药物组合物，含有有效量的CPT-11和有效量的风车子新碱相联合，其中所述风车子新碱结构如下：
4、权利要求3的组合物，其中所述实体瘤为结肠腺瘤。
5、用于治疗实体瘤的权利要求3所述的药物组合物，其具有协同治疗作用，含有有效量的CPT-11和有效量的风车子新碱。
6、治疗实体瘤的方法，包括：把权利要求3所述的有效量的CPT-11和有效量的风车子新碱相联合按顺序给药。
7、权利要求6的方法，其中CPT-11的剂量为约180至约400mg/kg，风车子新碱的剂量为约36mg/kg至60mg/kg。
8、权利要求7的方法，其中联合给药中CPT-11的剂量为240mg/kg，风车子新碱的剂量为60mg/kg。
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US24343100P | 2000-10-27 | 2000-10-27 | |
| US60/243,431 | 2000-10-27 | ||
| US24558200P | 2000-11-06 | 2000-11-06 | |
| US60/245,582 | 2000-11-06 | ||
| US25013800P | 2000-12-01 | 2000-12-01 | |
| US60/250,138 | 2000-12-01 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1471396A true CN1471396A (zh) | 2004-01-28 |
| CN1200712C CN1200712C (zh) | 2005-05-11 |
Family
ID=27399663
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB018179800A Expired - Fee Related CN1200712C (zh) | 2000-10-27 | 2001-10-25 | 用于治疗癌症的含喜树碱和1,2－二苯乙烯衍生物的组合物 |
Country Status (22)
| Country | Link |
|---|---|
| US (1) | US6562834B2 (zh) |
| EP (1) | EP1333820A2 (zh) |
| JP (1) | JP2004517821A (zh) |
| KR (1) | KR100742524B1 (zh) |
| CN (1) | CN1200712C (zh) |
| AU (2) | AU1602902A (zh) |
| BG (1) | BG107806A (zh) |
| BR (1) | BR0114856A (zh) |
| CA (1) | CA2426898A1 (zh) |
| EA (1) | EA005400B1 (zh) |
| EE (1) | EE200300184A (zh) |
| HK (1) | HK1058623A1 (zh) |
| HR (1) | HRP20030382A2 (zh) |
| HU (1) | HUP0302629A3 (zh) |
| IL (1) | IL155509A0 (zh) |
| MX (1) | MXPA03002882A (zh) |
| NO (1) | NO324844B1 (zh) |
| NZ (1) | NZ524855A (zh) |
| PL (1) | PL365685A1 (zh) |
| SK (1) | SK5122003A3 (zh) |
| WO (1) | WO2002034244A2 (zh) |
| YU (1) | YU29803A (zh) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020183266A1 (en) * | 2001-03-15 | 2002-12-05 | Aventis Pharma, S.A. | Combination comprising combretastatin and anticancer agents |
| US7850990B2 (en) * | 2001-10-03 | 2010-12-14 | Celator Pharmaceuticals, Inc. | Compositions for delivery of drug combinations |
| CA2383259A1 (en) * | 2002-04-23 | 2003-10-23 | Celator Technologies Inc. | Synergistic compositions |
| US20080075762A1 (en) * | 2001-10-03 | 2008-03-27 | Paul Tardi | Compositions for delivery of drug combinations |
| TW200819409A (en) | 2006-10-19 | 2008-05-01 | Univ Taipei Medical | Z-stilbenes derivatives and the pharmaceutical composition thereof |
| CA2826034A1 (en) | 2011-01-28 | 2012-08-02 | University Of Kentucky Research Foundation | Stilbene analogs and methods of treating cancer |
| AU2012275841A1 (en) | 2011-06-27 | 2014-01-16 | The Jackson Laboratory | Methods and compositions for treatment of cancer and autoimmune disease |
Family Cites Families (26)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4399276A (en) | 1981-01-09 | 1983-08-16 | Kabushiki Kaisha Yakult Honsha | 7-Substituted camptothecin derivatives |
| JPS57116015A (en) | 1981-01-09 | 1982-07-19 | Yakult Honsha Co Ltd | Antitumor agent |
| JPS57116074A (en) | 1981-01-09 | 1982-07-19 | Yakult Honsha Co Ltd | Novel camptothecin derivative and its preparation |
| US4473692A (en) | 1981-09-04 | 1984-09-25 | Kabushiki Kaisha Yakult Honsha | Camptothecin derivatives and process for preparing same |
| JPS58154582A (ja) | 1982-03-10 | 1983-09-14 | Yakult Honsha Co Ltd | 新規なカンプトテシン誘導体およびその製造法 |
| JPS595188A (ja) | 1982-06-30 | 1984-01-12 | Yakult Honsha Co Ltd | １０−ヒドロキシカンプトテシンの製造法 |
| JPS6019790A (ja) | 1983-07-14 | 1985-01-31 | Yakult Honsha Co Ltd | 新規なカンプトテシン誘導体 |
| US4981968A (en) | 1987-03-31 | 1991-01-01 | Research Triangle Institute | Synthesis of camptothecin and analogs thereof |
| CA1332413C (en) | 1987-06-25 | 1994-10-11 | Kabushiki Kaisha Yakult Honsha | Camptothecin derivatives and process for preparing same |
| US5004758A (en) | 1987-12-01 | 1991-04-02 | Smithkline Beecham Corporation | Water soluble camptothecin analogs useful for inhibiting the growth of animal tumor cells |
| JPH0615547B2 (ja) | 1988-01-20 | 1994-03-02 | 株式会社ヤクルト本社 | 新規なカンプトテシン誘導体 |
| JP2524804B2 (ja) | 1988-03-29 | 1996-08-14 | 株式会社ヤクルト本社 | 新規なカンプトテシン誘導体及びその製造法 |
| JP2524803B2 (ja) | 1988-03-29 | 1996-08-14 | 株式会社ヤクルト本社 | 新規なカンプトテシン誘導体およびその製造法 |
| EP0540099B1 (en) | 1991-10-29 | 1996-04-17 | Glaxo Wellcome Inc. | Water soluble camptothecin derivatives |
| TW325458B (en) * | 1993-09-08 | 1998-01-21 | Ajinomoto Kk | Stilbene derivatives and pharmaceutical compositions comprising the same for anti-cancer |
| TW334418B (en) | 1995-03-07 | 1998-06-21 | Ajinomoto Kk | Stilbene derivatives and pharmaceutical compositions |
| US6504029B1 (en) | 1995-04-10 | 2003-01-07 | Daiichi Pharmaceutical Co., Ltd. | Condensed-hexacyclic compounds and a process therefor |
| GB9510716D0 (en) | 1995-05-26 | 1995-07-19 | Pharmacia Spa | Substituted camptothecin derivatives and process for their preparation |
| US5663177A (en) | 1995-05-31 | 1997-09-02 | Smithkline Beecham Corporation | Water soluble camptothecin analogs |
| US5670500A (en) | 1995-05-31 | 1997-09-23 | Smithkline Beecham Corporation | Water soluble camptothecin analogs |
| PT835258E (pt) | 1995-06-21 | 2003-02-28 | Sod Conseils Rech Applic | Novos analogos de camptotecina, processos para a sua preparacao, sua utilizacao como farmacos e composicoes farmaceuticas que os contem |
| JP3054669B2 (ja) | 1995-10-16 | 2000-06-19 | 余川商事株式会社 | 積雪落下防止装置 |
| JPH11296051A (ja) | 1998-04-08 | 1999-10-29 | Canon Inc | プロセスカートリッジ |
| DE69942128D1 (de) * | 1998-12-11 | 2010-04-22 | Coulter Pharm Inc | Prodrugs und verfahren zu deren herstellung |
| GB9903404D0 (en) * | 1999-02-16 | 1999-04-07 | Angiogene Pharm Ltd | Methods of treatment and compositions useful for the treatment of diseases involving angiogenesis |
| CA2432792C (en) | 2000-12-22 | 2012-04-03 | Bristol-Myers Squibb Company | Methods for modulating tumor growth and metastasis |
-
2001
- 2001-10-25 EP EP01988584A patent/EP1333820A2/en not_active Withdrawn
- 2001-10-25 CA CA002426898A patent/CA2426898A1/en not_active Abandoned
- 2001-10-25 EE EEP200300184A patent/EE200300184A/xx unknown
- 2001-10-25 JP JP2002537298A patent/JP2004517821A/ja active Pending
- 2001-10-25 KR KR1020037005754A patent/KR100742524B1/ko not_active IP Right Cessation
- 2001-10-25 AU AU1602902A patent/AU1602902A/xx active Pending
- 2001-10-25 WO PCT/EP2001/012985 patent/WO2002034244A2/en active IP Right Grant
- 2001-10-25 SK SK512-2003A patent/SK5122003A3/sk not_active Application Discontinuation
- 2001-10-25 MX MXPA03002882A patent/MXPA03002882A/es not_active Application Discontinuation
- 2001-10-25 YU YU29803A patent/YU29803A/sh unknown
- 2001-10-25 NZ NZ524855A patent/NZ524855A/en unknown
- 2001-10-25 PL PL01365685A patent/PL365685A1/xx not_active Application Discontinuation
- 2001-10-25 BR BR0114856-7A patent/BR0114856A/pt not_active IP Right Cessation
- 2001-10-25 AU AU2002216029A patent/AU2002216029B2/en not_active Ceased
- 2001-10-25 EA EA200300516A patent/EA005400B1/ru not_active IP Right Cessation
- 2001-10-25 CN CNB018179800A patent/CN1200712C/zh not_active Expired - Fee Related
- 2001-10-25 HU HU0302629A patent/HUP0302629A3/hu unknown
- 2001-10-25 IL IL15550901A patent/IL155509A0/xx unknown
- 2001-10-26 US US09/984,043 patent/US6562834B2/en not_active Expired - Fee Related
-
2003
- 2003-04-10 NO NO20031656A patent/NO324844B1/no unknown
- 2003-05-12 BG BG107806A patent/BG107806A/bg unknown
- 2003-05-14 HR HR20030382A patent/HRP20030382A2/hr not_active Application Discontinuation
-
2004
- 2004-02-26 HK HK04101397A patent/HK1058623A1/xx not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| JP2004517821A (ja) | 2004-06-17 |
| KR20030082544A (ko) | 2003-10-22 |
| NO20031656L (no) | 2003-04-10 |
| BG107806A (bg) | 2004-06-30 |
| IL155509A0 (en) | 2003-11-23 |
| HUP0302629A2 (hu) | 2003-11-28 |
| AU2002216029B2 (en) | 2006-01-05 |
| US20020115677A1 (en) | 2002-08-22 |
| HK1058623A1 (en) | 2004-05-28 |
| US6562834B2 (en) | 2003-05-13 |
| HUP0302629A3 (en) | 2005-05-30 |
| PL365685A1 (en) | 2005-01-10 |
| NO20031656D0 (no) | 2003-04-10 |
| EA200300516A1 (ru) | 2003-08-28 |
| NO324844B1 (no) | 2007-12-17 |
| HRP20030382A2 (en) | 2005-04-30 |
| WO2002034244A2 (en) | 2002-05-02 |
| MXPA03002882A (es) | 2004-12-03 |
| SK5122003A3 (en) | 2003-12-02 |
| BR0114856A (pt) | 2004-06-15 |
| KR100742524B1 (ko) | 2007-08-02 |
| EE200300184A (et) | 2003-08-15 |
| NZ524855A (en) | 2004-10-29 |
| AU1602902A (en) | 2002-05-06 |
| EA005400B1 (ru) | 2005-02-24 |
| WO2002034244A3 (en) | 2003-05-30 |
| CA2426898A1 (en) | 2002-05-02 |
| CN1200712C (zh) | 2005-05-11 |
| YU29803A (sh) | 2006-05-25 |
| EP1333820A2 (en) | 2003-08-13 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| TW386877B (en) | Antitumour compositions containing taxane derivatives | |
| DE69233169T2 (de) | Cisplatin und Topotecan enthaltende Zusammensetzung als antitumor. | |
| AU758191B2 (en) | Antitumor composition containing a synergistic combination of an anthracycline derivative with a camptothecin derivate | |
| CN1303294A (zh) | 抗肿瘤剂 | |
| CN1935134B (zh) | 包含考布他汀和抗癌剂的组合 | |
| CN1536995A (zh) | 含有紫杉烷衍生物的抗肿瘤组合物 | |
| EP1201247B1 (en) | Treatment of metastatic renal cell carcinoma | |
| CN1200712C (zh) | 用于治疗癌症的含喜树碱和1,2－二苯乙烯衍生物的组合物 | |
| JP2706371B2 (ja) | 癌治療用補助剤及びそれを用いたキット | |
| CN109528731B (zh) | 具有协同作用治疗多发性骨髓瘤的药物组合物及其应用 | |
| WO2019072014A1 (zh) | 含A-失碳-5α雄甾烷化合物的升白制剂及其应用 | |
| AU2002216029A1 (en) | A combination comprising camptothecin and a stilbene derivative for the treatment of cancer | |
| CN113786491A (zh) | 一种含汉防己甲素、二氢槲皮素或槲皮素的抗肿瘤联用制剂 | |
| KR20210039414A (ko) | 암의 치료를 위한 병용 요법 | |
| Marquet et al. | Combined effect of 5-fluorouracil and interferon on experimental liver metastases of rat colon carcinoma | |
| EP1169035B1 (en) | Anti-tumor synergetic composition | |
| CN115137831B (zh) | 虾青素在制备抗血管生成药物增效剂中的应用以及一种药物组合物 | |
| KR20220082862A (ko) | 혈액 악성 종양을 치료하기 위한 병용 요법 | |
| CN113456643A (zh) | 一种含普那布林的药物组合及其应用 | |
| ZA200302552B (en) | A combination comprising camptothecin and a stilbene derivative for the treatment of cancer. | |
| WO2004073719A1 (en) | A combined therapy comprising an indolopyrrolocarbazole derivative and another antitumor agent |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 1058623 Country of ref document: HK |
|
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| ASS | Succession or assignment of patent right |
Owner name: PFIZER ENTERPRISING CO., LTD. Free format text: FORMER OWNER: AVENTIS PHARMA S.A. Effective date: 20070629 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20070629 Address after: Luxemburg Kennedy Patentee after: Pfizer Enterprises Ltd Address before: French Anthony Patentee before: Awentis Pharmaceutical S. A. |
|
| C19 | Lapse of patent right due to non-payment of the annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |