EP0433323A1 - Verwendung von fibrinolytika zur kombinationsbehandlung von tumoren - Google Patents
Verwendung von fibrinolytika zur kombinationsbehandlung von tumorenInfo
- Publication number
- EP0433323A1 EP0433323A1 EP89909752A EP89909752A EP0433323A1 EP 0433323 A1 EP0433323 A1 EP 0433323A1 EP 89909752 A EP89909752 A EP 89909752A EP 89909752 A EP89909752 A EP 89909752A EP 0433323 A1 EP0433323 A1 EP 0433323A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- tumors
- fibrinolytics
- fibrinolytica
- combined treatment
- tumor
- 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- Withdrawn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 description 16
- 238000011282 treatment Methods 0.000 title description 2
- 230000003480 fibrinolytic effect Effects 0.000 claims description 17
- 239000002246 antineoplastic agent Substances 0.000 claims description 6
- 230000017531 blood circulation Effects 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims 2
- 239000003527 fibrinolytic agent Substances 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 238000000034 method Methods 0.000 claims 1
- 108090000373 Tissue Plasminogen Activator Proteins 0.000 description 4
- 102000003978 Tissue Plasminogen Activator Human genes 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 229960000187 tissue plasminogen activator Drugs 0.000 description 4
- 102000004083 Lymphotoxin-alpha Human genes 0.000 description 3
- 108090000542 Lymphotoxin-alpha Proteins 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 230000005855 radiation Effects 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
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 2
- 239000003795 chemical substances by application Substances 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
- WYWHKKSPHMUBEB-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 2
- 102000003390 tumor necrosis factor Human genes 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
- 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
- 108010058207 Anistreplase Proteins 0.000 description 1
- 108010006654 Bleomycin Proteins 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
- 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
- 108010057150 Peplomycin Proteins 0.000 description 1
- 108010086613 Streptodornase and Streptokinase Proteins 0.000 description 1
- 108010023197 Streptokinase Proteins 0.000 description 1
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 108090000435 Urokinase-type plasminogen activator Proteins 0.000 description 1
- 102000003990 Urokinase-type plasminogen activator Human genes 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
- 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
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000003712 anti-aging effect Effects 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
- 229960001561 bleomycin Drugs 0.000 description 1
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 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
- 238000011284 combination treatment Methods 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 229960000684 cytarabine 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
- 229960000975 daunorubicin Drugs 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
- 229960005420 etoposide Drugs 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 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
- 229960004338 leuprorelin Drugs 0.000 description 1
- 229960001924 melphalan Drugs 0.000 description 1
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 1
- 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
- 229950001745 mitonafide Drugs 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 238000006213 oxygenation reaction Methods 0.000 description 1
- 229940043138 pentosan polysulfate Drugs 0.000 description 1
- 229950003180 peplomycin Drugs 0.000 description 1
- QIMGFXOHTOXMQP-GFAGFCTOSA-N peplomycin Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCCN[C@@H](C)C=1C=CC=CC=1)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1NC=NC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C QIMGFXOHTOXMQP-GFAGFCTOSA-N 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 229960003171 plicamycin Drugs 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 108010073863 saruplase Proteins 0.000 description 1
- 229960005202 streptokinase Drugs 0.000 description 1
- 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
- 229960001278 teniposide Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229960001196 thiotepa Drugs 0.000 description 1
- 229960003087 tioguanine Drugs 0.000 description 1
- 229960005356 urokinase 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
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 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
- 229960004355 vindesine Drugs 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
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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
-
- 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
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/164—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
- A61K38/166—Streptokinase
-
- 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
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/465—Hydrolases (3) acting on ester bonds (3.1), e.g. lipases, ribonucleases
-
- 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
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
- A61K38/49—Urokinase; Tissue plasminogen activator
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
Definitions
- the present invention relates to the use of fibrinolytics in the fight against tumors.
- tPA and fibrinolytics have been used to treat thrombotic diseases such as Heart attack used (see Red List 1988, Group 41 - fibrinolytics).
- fibrinolytics increase the blood flow to tumors.
- the simultaneous administration of fibrinolytics and antitumor agents used in tumor therapy considerably increases the concentration of the latter in the tumor, so that tumors can be combated more effectively or the application doses of antitumor agents, which are generally not particularly well tolerated, are reduced with the same effectiveness can be.
- the combination of fibrinolytics and anti-tumor agents in the isolated perfusion of organs or parts of the body also appears to be particularly interesting in this context. The same applies to the oxygenation of the tumor tissue during radiation therapy, which works better the more blood is supplied to the tumor tissue to be destroyed.
- the invention relates to the use of fibrinolytics to increase the blood circulation of. Tumors.
- Suitable fibrinolytics are, in particular, urokinase, prourokinase, streptokinase and tPA (tissue plasminogen activator) and muteins derived from these substances. Muteins of these proteins are to be understood as meaning substances which differ from the proteins mentioned by the exchange, deletion or addition of amino acids.
- fibrinolytics are also suitable as fibrinolytics.
- eminase pentosan polysulfate and combinations of streptokinase and streptodornase (cf. Red List 1988, No. 41 004, 41 006, 41 012 and 41 013).
- the fibrinolytics are usually used in the usual dosages (cf. Rote Liste 1988, Group 41).
- tPA the dose is around 0.1 to 10 mg per kg body weight.
- Fibrinolytics are usually administered intravenously at the same time as, or shortly before, the antitumor agent or shortly before the start of radiation.
- anti-aging agents examples include:
- antibiotics such as actino ycin D, doxorubicin (adriamycin), daunorubicin, mithramycin, pepleomycin, mitomycin C and bleomycin, as well as other substances with an interchatory action, such as amonafluid and mitonafide,
- alkaloids such as vincristine, vinblastine, vindesine, etoposide and teniposide
- alkylating substances such as cyclophosphamide, thiotepa, melphalan, nitrosoureas and cisplatin and
- Antimetabolites such as methotrexate, 5-fluorouracil and its analogues, 6-mercaptopurine, 6-thioguanine and cytarabine.
- the tumor agents are used in the usual dosages (see Rote Liste 1988, monkey 85). In a number of cases, however, it is also possible to use smaller amounts.
- the dose ranges for TMF and LT are 1 to 500 ⁇ g / m body surface and for interleukins 1 to 1000 ⁇ g / m2 body surface.
- Radio sensitizers such as misonidazole and metronidazole, can also be increasingly transported into the tumor in combination with fibrinolytics.
- the efficiency of the radiation with ⁇ and j sites can thus be improved by adding fibrinolytics without changing the radiation dose.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Gastroenterology & Hepatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Molecular Biology (AREA)
- Biomedical Technology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Verwendung von Fibrinolytika zur Kombinationsbehandlung von Tumoren
Beschreibung
Die vorliegende Erfindung betrifft die Verwendung von Fibrinolytika in der Tumorbekämpfung.
Bislang werden tPA und Fibrinolytika zur Therapie von thrombotischen Erkrankungen wie z.B. Herzinfarkt eingesetzt (vgl. Rote Liste 1988, Gruppe 41 - Fibrinolytika).
Es wurde nun gefunden, daß Fibrinolytika die Durchblutung von Tumoren erhöhen. Durch die gleichzeitige Gabe von Fibrinolytika und von in der Tumortherapie eingesetzten Antitumormitteln 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 Fibrinolytika und Antitumormitteln bei der isolierten Perfusion von Organen oder Körperteilen. Entsprechendes gilt für die Oxygenierung des Turmorgewebes bei der Strahlentherapie, die umso besser wirkt, je stärker das zu zerstörende Tumorgewebe durchblutet wird.
Gegenstand der Erfindung ist die Verwendung von Fibrinolytika zur Erhöhung der Durchblutung von. Tumoren.
Als Fibrinolytika kommen insbesondere Urokinase, Prourokinase, Streptokinase und tPA (tissue plasminogen activator) sowie von diesen Substanzen abgeleitete Muteine in Betracht. Als Muteine dieser Proteine sind Substanzen zu verstehen, die sich von den genannten Proteinen durch Austausch, Deletion oder Addition von Aminosäuren unterscheiden. Solche Muteine sind beispielsweise beschrieben in DE 32 40 174, DE 35 37 176, DE 37 31 776, EP 152 736, EP 155 388, EP 184 363, EP 198 015, EP 200 451, EP 201 153, EP 207 589, EP 213 794, EP 225 286, EP 233 013, EP 238 304, EP 265 874, EP 266 032, WO 84/01786, WO 86/01538.
Weiter eignen sich als Fibrinolytika Eminase, Pentosanpolysulfat sowie Kombinationen aus Streptokinase und Streptodornase (vgl. Rote Liste 1988, Nrs. 41 004, 41 006, 41 012 und 41 013).
Die Fibrinolytika werden in der Regel in den üblichen Dosierungen angewendet (vgl. Rote Liste 1988, Gruppe 41). Für tPA liegt die Dosis bei etwa 0,1 bis- 10 mg pro kg Körpergewicht. Die Applikation der Fibrinolytika erfolgt in der Regel intravenös gleichzeitig mit oder kurz vor der Gabe des Antitumormittels bzw. kurz vor dem Beginn der Bestrahlung.
Als Antitu ormittel kommen beispielsweise in Betracht:
a) Antibiotica wie Actino ycin D, Doxorubicin (Adriamycin), Daunorubicin, Mithramycin, Pepleomycin, Mitomycin C und- Bleomycin sowie andere interchalatorisch wirkende Substanzen, wie Amonafϊde und Mitonafide,
b) Alkaloide wie Vincristin, Vinblastin, Vindesin, Etoposid und Teniposid,
c) alkylierend wirkende Substanzen, wie Cyclophosphamid, Thiotepa, Melphalan, Nitrosoharnstoffe und Cisplatin und
d) Antimetabolite wie Methotrexat, 5-Fluoruracil und dessen Analoge, 6-Mercaptopurin, 6-Thioguanin und Cytarabin.
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.
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 TMF und LT liegen bei 1 bis 500 μg/m- Körperoberfläche und für Interleukine bei 1 bis 1000 μg/m2 Körperoberfläche.
Auch Radiosensitizer, wie Misonidazol und Metronidazol können in Kombination mit Fibrinolytika verstärkt in den Tumor transportiert werden. Die Effizienz der Bestrahlung mit ß- und j--Stellen kann also durch Gabe von Fibrinolytika verbessert werden, ohne die Strahlendosis zu verändern.
Claims
1. Verwendung von Fibrinolytika zur Herstellung von Arzneimitteln zur Erhöhung der Durchblutung von Tumoren.
2. Arzneimittel, enthaltend ein Fibrinolytiku zur Erhöhung der Durchblutung von Tumoren.
3. Verfahren zur Behandlung von Tumoren in davon betroffenen Patienten, welches darin besteht, daß man dem Patienten eine wirksame Menge eines
Fibrinolytikums gleichzeitig mit oder kurz vor der Gabe des Antitumormittels verabfolgt.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3830924 | 1988-09-12 | ||
| DE3830924A DE3830924A1 (de) | 1988-09-12 | 1988-09-12 | Verwendung von fibrinolytika zur kombinationsbehandlung von tumoren |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP0433323A1 true EP0433323A1 (de) | 1991-06-26 |
Family
ID=6362757
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP89909752A Withdrawn EP0433323A1 (de) | 1988-09-12 | 1989-09-05 | Verwendung von fibrinolytika zur kombinationsbehandlung von tumoren |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP0433323A1 (de) |
| JP (1) | JPH04501705A (de) |
| DE (1) | DE3830924A1 (de) |
| WO (1) | WO1990002561A2 (de) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0637942B1 (de) * | 1992-04-24 | 1999-05-06 | Surgical Laser Technologies, Inc. | Medizinische vorrichtung |
| CZ283972B6 (cs) * | 1995-05-17 | 1998-07-15 | František Mudr. Trnka | Farmaceutický prostředek s modulačním účinkem na zhoubné nádory a jeho použití |
-
1988
- 1988-09-12 DE DE3830924A patent/DE3830924A1/de not_active Withdrawn
-
1989
- 1989-09-05 JP JP1509187A patent/JPH04501705A/ja active Pending
- 1989-09-05 EP EP89909752A patent/EP0433323A1/de not_active Withdrawn
- 1989-09-05 WO PCT/EP1989/001031 patent/WO1990002561A2/de not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| DE3830924A1 (de) | 1990-03-15 |
| JPH04501705A (ja) | 1992-03-26 |
| WO1990002561A2 (de) | 1990-03-22 |
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