EP0563209A1 - Use of hirudine and its muteines and their peg derivatives for the combined treatment of tumours - Google Patents
Use of hirudine and its muteines and their peg derivatives for the combined treatment of tumoursInfo
- Publication number
- EP0563209A1 EP0563209A1 EP92901972A EP92901972A EP0563209A1 EP 0563209 A1 EP0563209 A1 EP 0563209A1 EP 92901972 A EP92901972 A EP 92901972A EP 92901972 A EP92901972 A EP 92901972A EP 0563209 A1 EP0563209 A1 EP 0563209A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- hirudin
- peg derivatives
- muteins
- tumors
- muteines
- 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.)
- Withdrawn
Links
- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 19
- 238000011282 treatment Methods 0.000 title claims description 3
- WQPDUTSPKFMPDP-OUMQNGNKSA-N hirudin Chemical compound C([C@@H](C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC(OS(O)(=O)=O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H]1NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H]2CSSC[C@@H](C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)N[C@H](C(NCC(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N2)=O)CSSC1)C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]1NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=2C=CC(O)=CC=2)NC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)C(C)C)[C@@H](C)O)CSSC1)C(C)C)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 WQPDUTSPKFMPDP-OUMQNGNKSA-N 0.000 claims abstract description 19
- 102000007625 Hirudins Human genes 0.000 claims abstract description 18
- 108010007267 Hirudins Proteins 0.000 claims abstract description 18
- 229940006607 hirudin Drugs 0.000 claims abstract description 18
- 239000003814 drug Substances 0.000 claims abstract 4
- 238000004519 manufacturing process Methods 0.000 claims abstract 4
- 239000002246 antineoplastic agent Substances 0.000 claims description 7
- 239000000126 substance Substances 0.000 claims description 4
- 230000017531 blood circulation Effects 0.000 claims description 3
- 238000011284 combination treatment Methods 0.000 claims description 3
- 230000005855 radiation Effects 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 238000000034 method Methods 0.000 claims 1
- 229920001223 polyethylene glycol Polymers 0.000 description 14
- 102000004083 Lymphotoxin-alpha Human genes 0.000 description 3
- 108090000542 Lymphotoxin-alpha Proteins 0.000 description 3
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 3
- 102000003390 tumor necrosis factor Human genes 0.000 description 3
- 102000015696 Interleukins Human genes 0.000 description 2
- 108010063738 Interleukins Proteins 0.000 description 2
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 description 2
- 229940047122 interleukins Drugs 0.000 description 2
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- WYWHKKSPHMUBEB-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 2
- MWWSFMDVAYGXBV-MYPASOLCSA-N (7r,9s)-7-[(2r,4s,5s,6s)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione;hydrochloride Chemical compound Cl.O([C@@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 MWWSFMDVAYGXBV-MYPASOLCSA-N 0.000 description 1
- XXVLKDRPHSFIIB-UHFFFAOYSA-N 2-[2-(dimethylamino)ethyl]-5-nitrobenzo[de]isoquinoline-1,3-dione Chemical compound [O-][N+](=O)C1=CC(C(N(CCN(C)C)C2=O)=O)=C3C2=CC=CC3=C1 XXVLKDRPHSFIIB-UHFFFAOYSA-N 0.000 description 1
- 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
- UPALIKSFLSVKIS-UHFFFAOYSA-N 5-amino-2-[2-(dimethylamino)ethyl]benzo[de]isoquinoline-1,3-dione Chemical compound NC1=CC(C(N(CCN(C)C)C2=O)=O)=C3C2=CC=CC3=C1 UPALIKSFLSVKIS-UHFFFAOYSA-N 0.000 description 1
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 1
- 108010092160 Dactinomycin Proteins 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 description 1
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 1
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229960004701 amonafide Drugs 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 229940045719 antineoplastic alkylating agent nitrosoureas Drugs 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 229960000684 cytarabine Drugs 0.000 description 1
- 229960000640 dactinomycin Drugs 0.000 description 1
- 229960000975 daunorubicin Drugs 0.000 description 1
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- CFCUWKMKBJTWLW-UHFFFAOYSA-N deoliosyl-3C-alpha-L-digitoxosyl-MTM Natural products CC=1C(O)=C2C(O)=C3C(=O)C(OC4OC(C)C(O)C(OC5OC(C)C(O)C(OC6OC(C)C(O)C(C)(O)C6)C5)C4)C(C(OC)C(=O)C(O)C(C)O)CC3=CC2=CC=1OC(OC(C)C1O)CC1OC1CC(O)C(O)C(C)O1 CFCUWKMKBJTWLW-UHFFFAOYSA-N 0.000 description 1
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
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- 229940047124 interferons Drugs 0.000 description 1
- GFIJNRVAKGFPGQ-LIJARHBVSA-N leuprolide Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 GFIJNRVAKGFPGQ-LIJARHBVSA-N 0.000 description 1
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- 229960001428 mercaptopurine Drugs 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 229960000282 metronidazole Drugs 0.000 description 1
- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 description 1
- OBBCSXFCDPPXOL-UHFFFAOYSA-N misonidazole Chemical compound COCC(O)CN1C=CN=C1[N+]([O-])=O OBBCSXFCDPPXOL-UHFFFAOYSA-N 0.000 description 1
- 229950010514 misonidazole Drugs 0.000 description 1
- CFCUWKMKBJTWLW-BKHRDMLASA-N mithramycin Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@H](O)[C@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@@H](O)[C@H](O)[C@@H](C)O1 CFCUWKMKBJTWLW-BKHRDMLASA-N 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
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- 210000000056 organ Anatomy 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
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- -1 pepleoycin Chemical compound 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 229960003171 plicamycin Drugs 0.000 description 1
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- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
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- 229960003087 tioguanine Drugs 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
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- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/55—Protease inhibitors
- A61K38/57—Protease inhibitors from animals; from humans
- A61K38/58—Protease inhibitors from animals; from humans from leeches, e.g. hirudin, eglin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
Il est décrit l'utilisation d'hirudine et de ses mutéines ainsi que de leurs dérivés PEG pour la fabrication de médicaments servant à la lutte contre les tumeurs.The use of hirudin and its muteins as well as their PEG derivatives is described for the manufacture of medicaments used in the fight against tumors.
Description
Verwendung von Hirudin und dessen Muteinen sowie deren PEG-Oerivaten zur Kombinationsbehandlung von TumorenUse of hirudin and its muteins and their PEG derivatives for the combination treatment of tumors
Beschreibungdescription
Die vorliegende Erfindung betrifft die Verwendung von Hirudin und dessen Muteinen sowie deren PEG-Derivaten in der Tumorbekämpfung. Als PEG-Derivate des Hirudins sind Hirudinpolyethylenglykol- konjugate zu verstehen.The present invention relates to the use of hirudin and its muteins and their PEG derivatives in the fight against tumors. Hirudin-polyethylene glycol conjugates are to be understood as PEG derivatives of hirudin.
Es ist bekannt, daß Hirudin eine fibrinolytische Wirksamkeit besitzt (vgl. Merck-Index, 1989, Nr. 4638).It is known that hirudin has fibrinolytic activity (cf. Merck Index, 1989, No. 4638).
Es wurde nun gefunden, daß Hirudin und dessen Muteine sowie deren PEG-Derivate die Durchblutung von Tumoren erhöhen. Durch die gleichzeitige Gabe von Hirudin oder dessen Muteinen sowie deren PEG-Derivaten und von in der Tumortherapie eingesetzten AntitumormitteIn wird die Konzentration letzterer im Tumor beträchtlich erhöht, so daß Tumoren effektiver bekämpft werden können oder aber die Applikationsdosen von Antitumormitteln, die in der Regel nicht besonders gut vertragen werden, bei gleicher Effektivität herabgesetzt werden können. Besonders interessant erscheint in diesem Zusammenhang auch die Kombination von Hirudin bzw. dessen Muteinen sowie deren PEG-Derivaten mit Antitumor- mittein bei der isolierten Perfusion von Organen oder Körper¬ teilen. Entsprechendes gilt für die Oxygenierung des Turmor- gewebes bei der Strahlentherapie, die umso besser wirkt, je stärker das zu zerstörende Tumorgewebe durchblutet und mit Sauer¬ stoff versorgt wird.It has now been found that hirudin and its muteins and their PEG derivatives increase the blood flow to tumors. The simultaneous administration of hirudin or its muteins and their PEG derivatives and of anti-tumor agents used in tumor therapy increases the concentration of the latter considerably in the tumor, so that tumors can be controlled more effectively or the application doses of anti-tumor agents, which are usually not particularly good can be tolerated well, can be reduced with the same effectiveness. The combination of hirudin or its muteins and their PEG derivatives with antitumor agents in the isolated perfusion of organs or parts of the body also appears to be particularly interesting in this connection. The same applies to the oxygenation of the tower tissue in radiation therapy, which works better the more blood is supplied to the tumor tissue to be destroyed and the oxygen is supplied to it.
Gegenstand der Erfindung ist die Verwendung von Hirudin und dessen Muteinen sowie deren PEG-Derivaten zur Erhöhung der Durchblutung von Tumoren.The invention relates to the use of hirudin and its muteins and their PEG derivatives to increase the blood flow to tumors.
Als Muteine des Hirudins sind Substanzen zu verstehen, die sich von dem genannten Protein durch Austausch, Deletion oder Addition von Aminosäuren unterscheiden.Muteins of hirudin are substances that differ from the protein mentioned by the exchange, deletion or addition of amino acids.
Das Hirudin und dessen Muteine können an Polyethylenglykol (=PEG) unterschiedlichen Molekulargewichts gekoppelt sein, wodurch eine längere Halbwertzeit, eine bessere Dosierung und eine höhere
Anreicherung im Tumor erreicht wird. Solche PEG-Derivate sind beispielsweise beschrieben in der EP-OS 345 616 und der DE-OS 3 939800.The hirudin and its muteins can be coupled to polyethylene glycol (= PEG) of different molecular weights, which results in a longer half-life, a better dosage and a higher Enrichment in the tumor is achieved. Such PEG derivatives are described, for example, in EP-OS 345 616 and DE-OS 3 939800.
Das Hirudin und dessen Muteine sowie deren PEG-Derivate werden in der Regel in eine Dosierung von etwa 0,1 bis 10 mg pro kg Körpergewicht angewendet. Die Applikation erfolgt in der Regel intravenös gleichzeitig mit oder kurz vor der Gabe des Antitumor ittels bzw. kurz vor dem Beginn der Bestrahlung.The hirudin and its muteins and their PEG derivatives are generally used in a dosage of about 0.1 to 10 mg per kg body weight. The application is usually carried out intravenously simultaneously with or shortly before the administration of the antitumor agent or shortly before the start of the radiation.
Als Antitumormittel kommen beispielsweise in Betracht:Examples of possible antitumor agents are:
a) Antibiotica wie Actinomycin D, Doxorubicin (Adriamycin), Daunorubicin, Mithramycin, Pepleo ycin, Mitomycin C unda) Antibiotics such as actinomycin D, doxorubicin (Adriamycin), daunorubicin, mithramycin, pepleoycin, mitomycin C and
Bleo ycin sowie andere interchalatorisch wirkende Substanzen, wie Amonafide und Mitonafide,Bleoycin and other interchatory substances, such as amonafide and mitonafide,
b) Alkaloide wie Vincristin, Vinblastin, Vindesin, Etoposid und Teniposid,b) alkaloids such as vincristine, vinblastine, vindesine, etoposide and teniposide,
c) alkylierend wirkende Substanzen, wie Cyclophosphamid, Thiotepa, Melphalan, Nitrosoharnstoffe und Cisplatin undc) alkylating substances such as cyclophosphamide, thiotepa, melphalan, nitrosoureas and cisplatin and
d) Antimetabolite wie Methotrexat, 5-Fluoruracil und dessen Analoge, 6-Mercaptopurin, 6-Thioguanin und Cytarabin.d) Antimetabolites such as methotrexate, 5-fluorouracil and its analogues, 6-mercaptopurine, 6-thioguanine and cytarabine.
Weiter kommen als Antitumormittel zur Tumorbehandlung geeignete Hormone wie Leuprorelinacetat oder Busarelin, sowie körpereigene Proteine und davon abgeleitete Muteine wie Tumor-Nekrose-Faktor (TNF), Lymphotoxin (LT), Interferone und Interleukine, sowie Antikörper in Betracht.Suitable antitumor agents for tumor treatment include hormones such as leuprorelin acetate or busarelin, as well as the body's own proteins and muteins derived from them such as tumor necrosis factor (TNF), lymphotoxin (LT), interferons and interleukins, and antibodies.
Die Tumormittel werden in den üblichen Dosierungen verwendet (vgl. Rote Liste 1988, Gruppe 85). In einer Reihe von Fällen ist es allerdings auch möglich, geringere Mengen anzuwenden. Die Dosisbereiche für TNF und LT liegen bei 1 bis 500 μg/m2 Körperoberfläche und für Interleukine bei 1 bis 1000 g/r_2 Körperoberf1äche.
Auch Radiosensitizer, wie Misonidazol und Metronidazol können in Kombination mit Hirudin bzw. dessen Muteinen sowie deren PEG-Derivaten verstärkt in den Tumor transportiert werden. Die Effizienz der Bestrahlung beispielsweise mit ß- und y-Strahlen kann also durch Gabe von Hirudin bzw. Muteinen sowie deren PEG-Derivaten verbessert werden, ohne die Strahlendosis zu ver¬ ändern.
The tumor agents are used in the usual doses (see Rote Liste 1988, Gruppe 85). In a number of cases, however, it is also possible to use smaller amounts. The dose ranges for TNF and LT are 1 to 500 μg / m2 body surface and for interleukins 1 to 1000 g / r_2 body surface. Radio sensitizers, such as misonidazole and metronidazole, can also be increasingly transported into the tumor in combination with hirudin or its muteins and their PEG derivatives. The efficiency of the irradiation, for example with β and y rays, can thus be improved by adding hirudin or muteins and their PEG derivatives without changing the radiation dose.
Claims
1. Verwendung von Hirudin und dessen Muteinen sowie deren PEG-Derivaten zur Herstellung von Arzneimitteln zur Erhöhung der Durchblutung von Tumoren.1. Use of hirudin and its muteins and their PEG derivatives for the production of medicaments for increasing the blood flow to tumors.
2. Verwendung von Hirudin und dessen Muteinen sowie deren PEG-Derivaten zur Herstellung von Arzneimittel zur Kombinationsbehandlung von Tumoren mit Antitumormitteln.2. Use of hirudin and its muteins and their PEG derivatives for the production of medicaments for the combination treatment of tumors with antitumor agents.
3. Verwendung von Hirudin und dessen Muteinen sowie deren PEG-Derivaten zur Herstellung von Arzneimittel zur Kombinationsbehandlung von Tumoren mit Bestrahlung.3. Use of hirudin and its muteins and their PEG derivatives for the production of medicaments for the combination treatment of tumors with radiation.
4. Verfahren zur Behandlung von an Tumoren erkrankten4. Procedure for the treatment of tumors
Patienten, dadurch gekennzeichnet, daß man diese Patienten mit einem Tumormittel und Hirudin oder einem Hirudin-Mutein oder einem PEG-Derivat dieser Substanzen behandelt. Patients, characterized in that these patients are treated with a tumor agent and hirudin or a hirudin mutein or a PEG derivative of these substances.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4041185A DE4041185A1 (en) | 1990-12-21 | 1990-12-21 | USE OF HIRUDINE AND ITS MUTEINS FOR COMBINATION TREATMENT OF TUMORS |
| DE4041185 | 1990-12-21 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP0563209A1 true EP0563209A1 (en) | 1993-10-06 |
Family
ID=6421035
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP92901972A Withdrawn EP0563209A1 (en) | 1990-12-21 | 1991-12-10 | Use of hirudine and its muteines and their peg derivatives for the combined treatment of tumours |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0563209A1 (en) |
| JP (1) | JPH06503819A (en) |
| CA (1) | CA2098707A1 (en) |
| DE (1) | DE4041185A1 (en) |
| WO (1) | WO1992011024A1 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2694196B1 (en) * | 1992-07-30 | 1994-10-21 | Rochade | Medicinal composition usable as an antiviral agent. |
| US7795205B2 (en) * | 2004-04-12 | 2010-09-14 | Canyon Pharmaceuticals, Inc. | Methods for effecting regression of tumor mass and size in a metastasized pancreatic tumor |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1129148B (en) * | 1960-10-19 | 1962-05-10 | Egyt Gyogyszervegyeszeti Gyar | Process for the production of heparin derivatives with cytostatic substances |
| DE3631413A1 (en) * | 1986-09-16 | 1988-03-24 | Knoll Ag | THERAPEUTIC SYSTEM FOR LOCAL APPLICATION OF PHARMACEUTICAL ACTIVE SUBSTANCES |
| AU3098289A (en) * | 1988-03-04 | 1989-09-07 | Biogen, Inc. | Hirudin peptides |
| DE3819079A1 (en) * | 1988-06-04 | 1989-12-07 | Hoechst Ag | HIRUDINE DERIVATIVES WITH DELAYED EFFECT |
-
1990
- 1990-12-21 DE DE4041185A patent/DE4041185A1/en not_active Withdrawn
-
1991
- 1991-12-10 EP EP92901972A patent/EP0563209A1/en not_active Withdrawn
- 1991-12-10 CA CA002098707A patent/CA2098707A1/en not_active Abandoned
- 1991-12-10 JP JP4500986A patent/JPH06503819A/en active Pending
- 1991-12-10 WO PCT/EP1991/002361 patent/WO1992011024A1/en not_active Application Discontinuation
Non-Patent Citations (1)
| Title |
|---|
| See references of WO9211024A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| DE4041185A1 (en) | 1992-06-25 |
| JPH06503819A (en) | 1994-04-28 |
| CA2098707A1 (en) | 1992-06-22 |
| WO1992011024A1 (en) | 1992-07-09 |
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