EP0433323A1 - Use of fibrinolytica for the combined treatment of tumors - Google Patents

Use of fibrinolytica for the combined treatment of tumors

Info

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Withdrawn
Application number
EP89909752A
Other languages
German (de)
French (fr)
Inventor
Michael Kluge
Erich Schlick
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Abbott GmbH and Co KG
Original Assignee
Knoll GmbH
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Knoll GmbH filed Critical Knoll GmbH
Publication of EP0433323A1 publication Critical patent/EP0433323A1/en
Withdrawn legal-status Critical Current

Links

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.

Description

Verwendung von Fibrinolytika zur Kombinationsbehandlung von TumorenUse of fibrinolytics for the combination treatment of tumors
Beschreibungdescription
Die vorliegende Erfindung betrifft die Verwendung von Fibrinolytika in der Tumorbekämpfung.The present invention relates to the use of fibrinolytics in the fight against tumors.
Bislang werden tPA und Fibrinolytika zur Therapie von thrombotischen Erkrankungen wie z.B. Herzinfarkt eingesetzt (vgl. Rote Liste 1988, Gruppe 41 - Fibrinolytika).So far, tPA and fibrinolytics have been used to treat thrombotic diseases such as Heart attack used (see Red List 1988, Group 41 - fibrinolytics).
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.It has now been found that 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.
Gegenstand der Erfindung ist die Verwendung von Fibrinolytika zur Erhöhung der Durchblutung von. Tumoren.The invention relates to the use of fibrinolytics to increase the blood circulation of. Tumors.
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.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. Such muteins are described, for example, 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.Also suitable as fibrinolytics are 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). For 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.
Als Antitu ormittel kommen beispielsweise in Betracht:Examples of possible anti-aging agents are:
a) Antibiotica wie Actino ycin D, Doxorubicin (Adriamycin), Daunorubicin, Mithramycin, Pepleomycin, Mitomycin C und- Bleomycin sowie andere interchalatorisch wirkende Substanzen, wie Amonafϊde und Mitonafide,a) 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,
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 TMF und LT liegen bei 1 bis 500 μg/m- Körperoberfläche und für Interleukine bei 1 bis 1000 μg/m2 Körperoberfläche.The tumor agents are used in the usual dosages (see Rote Liste 1988, Gruppe 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 μg / m body surface and for interleukins 1 to 1000 μg / m2 body surface.
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. 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 β and j sites can thus be improved by adding fibrinolytics without changing the radiation dose.

Claims

Patentansprüche Claims
1. Verwendung von Fibrinolytika zur Herstellung von Arzneimitteln zur Erhöhung der Durchblutung von Tumoren.1. Use of fibrinolytics for the manufacture of medicaments to increase the blood flow to tumors.
2. Arzneimittel, enthaltend ein Fibrinolytiku zur Erhöhung der Durchblutung von Tumoren.2. Medicament containing a fibrinolytic to increase the blood flow to tumors.
3. Verfahren zur Behandlung von Tumoren in davon betroffenen Patienten, welches darin besteht, daß man dem Patienten eine wirksame Menge eines3. A method of treating tumors in affected patients, which consists in giving the patient an effective amount of a
Fibrinolytikums gleichzeitig mit oder kurz vor der Gabe des Antitumormittels verabfolgt. Fibrinolytic co-administered with or shortly before the antitumor agent is given.
EP89909752A 1988-09-12 1989-09-05 Use of fibrinolytica for the combined treatment of tumors Withdrawn EP0433323A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE3830924 1988-09-12
DE3830924A DE3830924A1 (en) 1988-09-12 1988-09-12 USE OF FIBRINOLYTICS FOR COMBINATION TREATMENT OF TUMORS

Publications (1)

Publication Number Publication Date
EP0433323A1 true EP0433323A1 (en) 1991-06-26

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
EP89909752A Withdrawn EP0433323A1 (en) 1988-09-12 1989-09-05 Use of fibrinolytica for the combined treatment of tumors

Country Status (4)

Country Link
EP (1) EP0433323A1 (en)
JP (1) JPH04501705A (en)
DE (1) DE3830924A1 (en)
WO (1) WO1990002561A2 (en)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE69229128T2 (en) * 1992-04-24 2000-02-24 Surgical Laser Tech MEDICAL DEVICE
CZ283972B6 (en) * 1995-05-17 1998-07-15 František Mudr. Trnka Pharmaceutical preparation exhibiting modulation effect on malignant tumors and the use thereof

Also Published As

Publication number Publication date
JPH04501705A (en) 1992-03-26
DE3830924A1 (en) 1990-03-15
WO1990002561A2 (en) 1990-03-22

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