CA2065157A1 - Gamma glutamyl transferases for treating diseases - Google Patents
Gamma glutamyl transferases for treating diseasesInfo
- Publication number
- CA2065157A1 CA2065157A1 CA002065157A CA2065157A CA2065157A1 CA 2065157 A1 CA2065157 A1 CA 2065157A1 CA 002065157 A CA002065157 A CA 002065157A CA 2065157 A CA2065157 A CA 2065157A CA 2065157 A1 CA2065157 A1 CA 2065157A1
- Authority
- CA
- Canada
- Prior art keywords
- glutamyl
- transferases
- gamma
- human
- controlling diseases
- 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.)
- Abandoned
Links
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
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/45—Transferases (2)
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Gastroenterology & Hepatology (AREA)
- Epidemiology (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Enzymes And Modification Thereof (AREA)
Abstract
BASF Aktiengesellschaft - 6 - O.Z. 0050/41110 .gamma.-Glutamyl-transferases for controlling diseases Abstract The use of .gamma.-glutamyl-transferases for use for control-ling diseases is described.
Description
BASF Aktiengesellschaft O.Z. 005~/41110 ~-Glutamyl-transfera~es for the treatment of disea~es Description It is already known that blood clots can be dissolved with pro~eins such as TPA, urokinase or streptokinase.
S ~hese proteins lead to depolymerization and solubil-ization of the fibrin present in the blood clot owing to cleavage of peptide linkages.
~-Gl~tamyl-transferases are also known. These proteins have hitherto been used only a~ marker enzymes (Clin. Chem. 15, 124 (1969)) attributed with cellular tasks. They have not to date been used therapeuticallyJ
on the ccntrary they have been u-~ed only or diagnostic purposes. Surprisingly, it has now been possible to show tha~ ~-glutamyl-transferases are able to depolymerize fibrin.
The invention relates to ~glutamyl-transferases for use for controlling diseases.
The diseases which can be treated with ~-glutamyl-trans-ferases and which should be particularly mentioned are those caused by formation of blood clots. These include myocardial infarct~ atherosclerosis and vein thrombosis.
Other disorders amenable to treatment with ~-glutamyl-trans~erases are those caused by metastatic tumors. These include, in particular, carcinomas of the bronchi, prostate and breast, and melanomas.
The treatment can be carried out bo~h in the acute case and for prophyla~is.
~-Glutamyl-transf0rases of human origin are preferred because they do not cau~e any antibody formation in the human body.
pg) ~ASF Aktiengesellschaft - 2 - O.Z. 0050/41110 ~-Glutamyl-transferases specifically cleave~-glukamyl(~
ly5yl) isopeptide linkages or other ~-glutamyl-isopeptide linkages by the transfer of a ~-glutamyl radical to another amino acid or by hydrolysis. Such ~-glutamyl-isopeptide linkages occur in blood clots. ~-Glutamyl-transferases thus act spPcifically on the crosslinking in the blood clot without attacklng normal peptide linkages.
Noreover, detached tumor cells may also become anchored via such isopeptide linkages in forei~n tissues and escape the immune system owing to a fibrin envelope. This gives rise to the possibility of using ~-glutamyl-trans ferases also for controlling oncoses.
The fibrinolytic activity of ~-glutamyl-transferases can be Lmproved further by combination with other fibrino-lytics such as urokinase, streptokinase or tPA. The sameapplies to combinations with antithrombotics such as heparin or hirudin.
Important for the use as therapeutics is, on the one hand, the en~ymatic activity of the ~-glutamyl-trans-ferases and, on the other hand, the similarity with theendogenous protein. ~hese requirements are also met by trunca~ed polypeptides based on the human enzyme as well as by slightly modified peptide sequences. Those muteins which differ from human ~-glutamyl-transferase by exchange, deletion or addition of one or more amino acids can be prepared more easily by gene manipulation in some cases and may have improved properties such as reduced degradation by proteolytic enzymes.
Treatment with ~-glutamyl-transferases can be carried out with the substances them~elves or else with substances which induce in the body the formation o ~-glutamyl-transferases or the secretion thereof into the blood-stream. An example of a substance of this type is 2 ~ r~
aASF Aktiengesellschaft - 3 - O.Z. 0050/41110 vitamin A.
Leukotriene C4 which is produced in inflammatory processes is converted by ~-glutamyl-tran~ferase into leukotriene D4. A dipeptidase converts leukotriene D4 into the virtu-ally inactive leukotriene E4. This is why inflammatoryprocesses can be controlled by administration of glutamyl-transferases, preferably combined with dipeptidases.
The ~-glutamyl-transferases are adminis~ered in amounts of from 10 to 500 mg per patient and day. The treatment extends over a lengthy period. The ~-glutamyl-trans ferases are administered parenterally, preferably intra-venously.
E~amp~e 10 g of ~-glutamyl-transera~es are dissolved in 250 ml of PBS (0.15 M phosphate-buffered physiological saline, pE 7.4) and, after sterilization by filtrati3n, dispensed in~o ampoules each containing 5 ml.
S ~hese proteins lead to depolymerization and solubil-ization of the fibrin present in the blood clot owing to cleavage of peptide linkages.
~-Gl~tamyl-transferases are also known. These proteins have hitherto been used only a~ marker enzymes (Clin. Chem. 15, 124 (1969)) attributed with cellular tasks. They have not to date been used therapeuticallyJ
on the ccntrary they have been u-~ed only or diagnostic purposes. Surprisingly, it has now been possible to show tha~ ~-glutamyl-transferases are able to depolymerize fibrin.
The invention relates to ~glutamyl-transferases for use for controlling diseases.
The diseases which can be treated with ~-glutamyl-trans-ferases and which should be particularly mentioned are those caused by formation of blood clots. These include myocardial infarct~ atherosclerosis and vein thrombosis.
Other disorders amenable to treatment with ~-glutamyl-trans~erases are those caused by metastatic tumors. These include, in particular, carcinomas of the bronchi, prostate and breast, and melanomas.
The treatment can be carried out bo~h in the acute case and for prophyla~is.
~-Glutamyl-transf0rases of human origin are preferred because they do not cau~e any antibody formation in the human body.
pg) ~ASF Aktiengesellschaft - 2 - O.Z. 0050/41110 ~-Glutamyl-transferases specifically cleave~-glukamyl(~
ly5yl) isopeptide linkages or other ~-glutamyl-isopeptide linkages by the transfer of a ~-glutamyl radical to another amino acid or by hydrolysis. Such ~-glutamyl-isopeptide linkages occur in blood clots. ~-Glutamyl-transferases thus act spPcifically on the crosslinking in the blood clot without attacklng normal peptide linkages.
Noreover, detached tumor cells may also become anchored via such isopeptide linkages in forei~n tissues and escape the immune system owing to a fibrin envelope. This gives rise to the possibility of using ~-glutamyl-trans ferases also for controlling oncoses.
The fibrinolytic activity of ~-glutamyl-transferases can be Lmproved further by combination with other fibrino-lytics such as urokinase, streptokinase or tPA. The sameapplies to combinations with antithrombotics such as heparin or hirudin.
Important for the use as therapeutics is, on the one hand, the en~ymatic activity of the ~-glutamyl-trans-ferases and, on the other hand, the similarity with theendogenous protein. ~hese requirements are also met by trunca~ed polypeptides based on the human enzyme as well as by slightly modified peptide sequences. Those muteins which differ from human ~-glutamyl-transferase by exchange, deletion or addition of one or more amino acids can be prepared more easily by gene manipulation in some cases and may have improved properties such as reduced degradation by proteolytic enzymes.
Treatment with ~-glutamyl-transferases can be carried out with the substances them~elves or else with substances which induce in the body the formation o ~-glutamyl-transferases or the secretion thereof into the blood-stream. An example of a substance of this type is 2 ~ r~
aASF Aktiengesellschaft - 3 - O.Z. 0050/41110 vitamin A.
Leukotriene C4 which is produced in inflammatory processes is converted by ~-glutamyl-tran~ferase into leukotriene D4. A dipeptidase converts leukotriene D4 into the virtu-ally inactive leukotriene E4. This is why inflammatoryprocesses can be controlled by administration of glutamyl-transferases, preferably combined with dipeptidases.
The ~-glutamyl-transferases are adminis~ered in amounts of from 10 to 500 mg per patient and day. The treatment extends over a lengthy period. The ~-glutamyl-trans ferases are administered parenterally, preferably intra-venously.
E~amp~e 10 g of ~-glutamyl-transera~es are dissolved in 250 ml of PBS (0.15 M phosphate-buffered physiological saline, pE 7.4) and, after sterilization by filtrati3n, dispensed in~o ampoules each containing 5 ml.
Claims (11)
1. .gamma.-Glutamyl-transferases for use for controlling diseases
2. Human .gamma.-glutamyl-transferases for use for control-ling diseases.
3. Muteins or partial sequences of human .gamma.-glutamyl-transferases for use for controlling diseases.
4. Use of .gamma.-glutamyl-transferases for controlling diseases caused by blood clots.
5. Use of .gamma.-glutamyl-transferases for controlling diseases caused by metastatic tumors.
6. Use of human .gamma.-glutamyl-transferases according to claim 3, 4 and 5.
7. Pharmaceutical which can be administered parenter-ally and contains a .gamma.-glutamyl-transferase and a fibrinolytic.
8. Pharmaceutical which can be administered parenter-ally and contains a .gamma.-glutamyl-transferase and an antithrombotic.
9. Pharmaceutical which can be administered parenter-ally according to claim 6, 7 or 8, characterized in that the .gamma.-glutamyl-transferases are of human origin.
10. Use of .gamma.-glutamyl-transferase inducers for control-ling diseasas caused by blood clots.
11. Use of .gamma.-glutamyl-transferases alone or in BASF Aktiengesellschaft - 5 - O.Z. 0050/41110 combination with a dipeptidase for controlling diseases caused by an elevated leukotriene level.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3930961 | 1989-09-15 | ||
| DEP3930961.4 | 1989-09-15 | ||
| DEP3936594.8 | 1989-11-03 | ||
| DE3936594A DE3936594A1 (en) | 1989-09-15 | 1989-11-03 | (GAMMA) GLUTAMYL TRANSFERASES FOR THE TREATMENT OF DISEASES |
| PCT/EP1990/001541 WO1991004046A1 (en) | 1989-09-15 | 1990-09-12 | Gamma glutamyl transferases for treating diseases |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2065157A1 true CA2065157A1 (en) | 1991-03-16 |
Family
ID=25885236
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002065157A Abandoned CA2065157A1 (en) | 1989-09-15 | 1990-09-12 | Gamma glutamyl transferases for treating diseases |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0491755A1 (en) |
| JP (1) | JPH05501546A (en) |
| CA (1) | CA2065157A1 (en) |
| DE (1) | DE3936594A1 (en) |
| WO (1) | WO1991004046A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5241065A (en) * | 1992-02-25 | 1993-08-31 | Schering Corporation | 2,3,4,5-tetrahydro-1h-3-benzazepines having anti-psychotic activity |
-
1989
- 1989-11-03 DE DE3936594A patent/DE3936594A1/en not_active Withdrawn
-
1990
- 1990-09-12 JP JP2512375A patent/JPH05501546A/en active Pending
- 1990-09-12 EP EP90913328A patent/EP0491755A1/en not_active Withdrawn
- 1990-09-12 CA CA002065157A patent/CA2065157A1/en not_active Abandoned
- 1990-09-12 WO PCT/EP1990/001541 patent/WO1991004046A1/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| DE3936594A1 (en) | 1991-03-28 |
| EP0491755A1 (en) | 1992-07-01 |
| WO1991004046A1 (en) | 1991-04-04 |
| JPH05501546A (en) | 1993-03-25 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Dead |