JPH06503819A - Use of hirudin and its mutant proteins and their PEG derivatives for combination therapy of tumors - Google Patents
Use of hirudin and its mutant proteins and their PEG derivatives for combination therapy of tumorsInfo
- Publication number
- JPH06503819A JPH06503819A JP4500986A JP50098691A JPH06503819A JP H06503819 A JPH06503819 A JP H06503819A JP 4500986 A JP4500986 A JP 4500986A JP 50098691 A JP50098691 A JP 50098691A JP H06503819 A JPH06503819 A JP H06503819A
- Authority
- JP
- Japan
- Prior art keywords
- hirudin
- peg derivatives
- tumors
- mutant proteins
- proteins
- 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.)
- Pending
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- 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
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
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- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Tropical Medicine & Parasitology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Gastroenterology & Hepatology (AREA)
- Zoology (AREA)
- Immunology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
(57)【要約】本公報は電子出願前の出願データであるため要約のデータは記録されません。 (57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.
Description
【発明の詳細な説明】 膿瘍の併用療法へのヒルジン及びその突然変異タンパク質並びにそれらのＰＥＧ 誘導体の使用本発明は、腫瘍排除へのヒルジン及びその突然変異タンパク質並び にそれらのＰＥＧ誘導体の使用に関する。ヒルジンのＰＥＧ誘導体とは、ヒルジ ンポリエチレングリコール接合体のことである。[Detailed description of the invention] Hirudin and its mutant proteins and their PEGs for combination therapy of abscesses Use of derivatives The present invention describes the use of hirudin and its mutant proteins and their derivatives for tumor elimination. concerning the use of those PEG derivatives. The PEG derivative of hirudin is It is a polyethylene glycol conjugate.
ヒルジンが線維素溶解作用を有することは、公知である（Ｍｅｒｃｋ−１ｎｄｅ ｘ、１９８９ 、 Ｎｏ、 ４６３８を参照のこと）。It is known that hirudin has fibrinolytic action (Merck-Inde x, 1989, No. 4638).
ヒルジン及びその突然変異タンパク質並びにそれらのＰＥＧ誘導体が腫瘍の血液 潅流量を高めることが見出された。ヒルジン及びその突然変異タンパク質並びに それらのＰＥＧ誘導体と腫瘍治療に使用される抗腫瘍剤とを同時に与えることに よって血液潅流量が著しく高められ、その結果、腫瘍をより効果的に排除するこ とができるか又は、通常は特に良好には受け入れられていない抗腫瘍剤の投与量 を同じ作用のままで減少させることができる。これに関連して、器官又は身体部 分の孤立した潅流の場合のヒルジンもしくはその突然変異タンパク質並びにそれ らのＰＥＧ誘導体と抗腫瘍剤との組合せも特に重要である。破壊すべき腫瘍組織 に血液潅流しかつ酸素を供給する皿を増加すればするほど、より良好に作用する 放射線療法の場合の腫瘍組織の酸素飽和にも同様のことがあてはまる。Hirudin and its mutant proteins and their PEG derivatives are It was found to increase perfusion rate. Hirudin and its mutant proteins and By simultaneously providing those PEG derivatives and antitumor agents used for tumor treatment. Therefore, blood perfusion is significantly increased, resulting in more effective tumor elimination. Dosages of antineoplastic agents that are available or are not usually particularly well accepted can be decreased with the same effect. In this connection, an organ or body part hirudin or its mutant protein in case of isolated perfusion of minutes as well as its The combination of these PEG derivatives with antitumor agents is also of particular interest. Tumor tissue to be destroyed The more dishes you have that perfuse and oxygenate your body, the better it will work. The same applies to oxygen saturation of tumor tissue in the case of radiotherapy.
本発明の対象は、腫瘍の血液潅流量を高めるためのヒルジン及びその突然変異タ ンパク質並びにそれらのＰＥＧ誘導体の使用である。The subject of the present invention is hirudin and its mutant proteins for increasing blood perfusion of tumors. The use of proteins and their PEG derivatives.
ヒルジンの突然変異タンパク質とは、アミノ酸の交換、欠損及び付加の点でここ に記載されたタンパク質と異なる物質のことである。Hirudin mutant proteins are defined as having amino acid exchanges, deletions, and additions. It is a substance different from the proteins described in .
ヒルジン及びその突然変異タンパク質は種々の分子量のポリエチレングリコール （＝ＰＥＧ）に結合していてもよく、このことによって腫瘍内でのより長い半減 期、より良好な投与量及びより高い集中が達成される。このようなＰＥＧ誘導体 は、例えば欧州特許出願公開第３４５ ６１６号明細書及びドイツ連邦共和国特 許出願公開第３ ９３９ ８００号明細書に記載されている。Hirudin and its mutant proteins are produced by polyethylene glycol of various molecular weights. (=PEG), which results in a longer half-life within the tumor. During the period, better dosage and higher concentration are achieved. Such PEG derivatives For example, European Patent Application No. 345 616 and Patent Application of the Federal Republic of Germany It is described in the specification of Japanese Patent Application Publication No. 3,939,800.
ヒルジン及びその突然変異タンパク質並びにそれらのＰＥＧ誘導体は通常、体重 １ｋｇにつき約０．１〜１０ｍｇの投与量で使用される。投与は通常、静脈内で 抗腫瘍剤の投与と同時もしくは投与の少し前或いは放射開始の少し前に行なわれ る。Hirudin and its mutant proteins and their PEG derivatives are usually It is used in doses of about 0.1 to 10 mg per kg. Administration is usually intravenous It is carried out at the same time as the administration of an antitumor drug, or a little before the administration, or a little before the start of radiation. Ru.
抗腫瘍剤として例えば次の薬剤が考慮の対象となるａ） 抗生物質、例えばアド リアマイシンＤ、ドキソルビシン（Ｄｏｘｏｒｕｂｉｃｉｎ） （アドリアマイ シン（Ａｄｒｉａｍｙｃｉｎ））、ダウノルビシン（Ｄａｕｎｏｒｕｂｉｃｉｎ ）、ミトラマイシン（Ｍｉｔｈｒａｍｙｃｉｎ）、ベブレオマイシン（Ｐｅｐｌ ｅｏｍｙｃｉｎ）、マイトマイシンＣ及びプレオマイシン並びにその他の揮大作 用物質、例えばアモナフィド（Ａｍｏｎａｆｉｄ）及びミトナフィド（Ｍｉｔｏ ｎａｆｉｄ）、 ｂ） アルカロイド、例えばビンクリスチン（Ｖｉｎｃｒｉｓｔｉｎ）、ビンブ ラスチン、ビンデシン（Ｖｉｎｄｅｓｉｎ）、エトポシド（Ｅｔｏｐｏｓｉｄ） 及びテニボシド（Ｔｅｎｉｐｏｓｉｄ）、Ｃ） アルキル化作用物質、例えばシ クロホスファミド、チオテパ、メルフアラン、ニトロソ尿素及びシス白金並びに ｄ） 代謝拮抗物質、例えばメソトレキセート、５−フルオロウラシル（５−Ｆ Ｉｕｏｒｕｒａｃ ｉ ｌ）及びその類似体、６−メルカプトプリン、６−チ オグアニン及びシタラビン（Ｃｙｔａｒａｂ ｉｎ）。The following drugs may be considered as anti-tumor agents: a) Antibiotics, e.g. Riamycin D, Doxorubicin (Adriamycin) Adriamycin), Daunorubicin ), mithramycin, vebleomycin (Pepl eomycin), mitomycin C and pleomycin and other major works substances such as Amonafid and Mito nafid), b) Alkaloids, such as Vincristine, Vinbu Rustin, Vindesin, Etoposid and Teniposid, C) alkylating agents, e.g. Clophosphamide, thiotepa, melphalan, nitrosourea and cis-platinum and d) Antimetabolites such as methotrexate, 5-fluorouracil (5-F Iuorurac il) and its analogues, 6-mercaptopurine, 6-thi Oguanine and cytarabine (Cytarab in).
さらに、腫瘍治療のための抗腫瘍剤として適当なホルモン、例えばロイブロレリ ンアセテーｈ （Ｌｅｕｐｒｏｒｅｌｉｎａｃｅｔａｔ）又はブサレリン（Ｂｕ ｓａｒｅｌｉｎ）、並びに生体特有のタンパク質及び該タンパク質から誘導され た突然変異タンパク質、例えば腫瘍壊死因子（ＴＮＦ）、リンパ性毒素（ＬＴ） 、インターフェロン及びインターロイキン（Ｉｎｔｅｒｌｅｕｋｉｎｅ）、並び に抗体が考慮の対象となる。In addition, hormones suitable as anti-tumor agents for tumor treatment, such as leubroleri Leuprorelinacetat or Busarelin (Bu sarelin), as well as biologically specific proteins and proteins derived from these proteins. mutant proteins such as tumor necrosis factor (TNF), lymphoid toxin (LT) , interferon and interleukine, and Antibodies should be considered.
腫瘍薬剤は常用の投与量で使用される（Ｒｏｔｅ Ｌｉ５ｔｅ１９８８、 Ｇｒ ｕｐｐｅ ８５を参照のこと）。しかし、−連のケースの場合に、より僅かな量 で使用することも可能である。ＴＮＦ及びＬＴについての投与量範囲は、１〜５ ００μｇ／体表面積ｍ２であり、かつインターロイキンについては１〜１０００ μｇ／体表面積ｍ２である。Tumor drugs are used in conventional doses (Rote Li5te 1988, Gr. (see uppe 85). However, in the case of −2, a smaller amount It is also possible to use it in Dosage range for TNF and LT is 1-5 00 μg/m2 of body surface area, and 1 to 1000 for interleukins. μg/body surface area m2.
また放射線増感剤、例えばミソニダゾール（Ｍｉｓｏｎｉｄａｚｏｌ）及びメト ロニダゾール（Ｍｅｔｒｏｎｉｄａｚｏｌ）をヒルジンもしくはその突然変異タ ンパク質並びにそれらのＰＥＧ誘導体との組合せ物の形で補強されて腫瘍内に運 ぶことができる。即ち、例えばβ線及びγ線の放射効率を放射線量を変えること なくヒルジンもしくは突然変異タンパク質並びにそれらのＰＥＧ誘導体の投与す ることによって改善することができる。Also, radiosensitizers such as Misonidazol and meth Lonidazole (Metronidazol) is combined with hirudin or its mutants. It is reinforced in the form of proteins and their combinations with PEG derivatives and transported into tumors. can run. That is, for example, changing the radiation dose of β-rays and γ-rays administration of hirudin or muteins and their PEG derivatives. This can be improved by
国際調査報告 １″′ｍ″” ’０ＰＣＴ／ＥＰ ’Ｊ１７０２３６１１−ｍｍ−−−＋ ａ＋ −ｍｃ−＋＋＝−ｍ、 ＰＣＴ／ ＥＰ ９１ ／ ０２３６１international search report 1″’m″”’0PCT/EP’J17023611-mm---+a+ -mc-++=-m, PCT/EP 91/02361
Claims (4)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4041185.5 | 1990-12-21 | ||
| DE4041185A DE4041185A1 (en) | 1990-12-21 | 1990-12-21 | USE OF HIRUDINE AND ITS MUTEINS FOR COMBINATION TREATMENT OF TUMORS |
| PCT/EP1991/002361 WO1992011024A1 (en) | 1990-12-21 | 1991-12-10 | Use of hirudine and its muteines and their peg derivatives for the combined treatment of tumours |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH06503819A true JPH06503819A (en) | 1994-04-28 |
Family
ID=6421035
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP4500986A Pending JPH06503819A (en) | 1990-12-21 | 1991-12-10 | Use of hirudin and its mutant proteins and their PEG derivatives for combination therapy of tumors |
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 JP JP4500986A patent/JPH06503819A/en active Pending
- 1991-12-10 WO PCT/EP1991/002361 patent/WO1992011024A1/en not_active Application Discontinuation
- 1991-12-10 EP EP92901972A patent/EP0563209A1/en not_active Withdrawn
- 1991-12-10 CA CA002098707A patent/CA2098707A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| EP0563209A1 (en) | 1993-10-06 |
| DE4041185A1 (en) | 1992-06-25 |
| WO1992011024A1 (en) | 1992-07-09 |
| CA2098707A1 (en) | 1992-06-22 |
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