JPH0426631A - Suppressing agent of vascularization - Google Patents
Suppressing agent of vascularizationInfo
- Publication number
- JPH0426631A JPH0426631A JP13020890A JP13020890A JPH0426631A JP H0426631 A JPH0426631 A JP H0426631A JP 13020890 A JP13020890 A JP 13020890A JP 13020890 A JP13020890 A JP 13020890A JP H0426631 A JPH0426631 A JP H0426631A
- Authority
- JP
- Japan
- Prior art keywords
- active ingredient
- piericidin
- antimycin
- inhibiting action
- angiogenesis
- 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
Links
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- 239000000126 substance Substances 0.000 claims abstract description 10
- 230000010627 oxidative phosphorylation Effects 0.000 claims abstract description 8
- 230000029058 respiratory gaseous exchange Effects 0.000 claims description 7
- 229940121369 angiogenesis inhibitor Drugs 0.000 claims description 5
- 239000004037 angiogenesis inhibitor Substances 0.000 claims description 5
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- 230000002401 inhibitory effect Effects 0.000 abstract description 22
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- 229930182661 Piericidin Natural products 0.000 abstract description 12
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- NQWZLRAORXLWDN-UHFFFAOYSA-N Antimycin-A Natural products CCCCCCC(=O)OC1C(C)OC(=O)C(NC(=O)c2ccc(NC=O)cc2O)C(C)OC(=O)C1CCCC NQWZLRAORXLWDN-UHFFFAOYSA-N 0.000 abstract description 11
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Landscapes
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Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明は呼吸能害作用及び酸化的リン酸化阻害作用を有
する物質を有効成分とする血管新生抑制剤に関するもの
であり、医薬品としては、血管の異常増殖を伴う疾病、
例えばリュウマチ性関節炎、糖尿病性網膜症、未熟児網
膜症、老人性黄斑部変性、創傷治癒時の過剰廠痕形成お
よび細胞の異常増殖に対する予防または治療薬として期
待される。Detailed Description of the Invention [Field of Industrial Application] The present invention relates to an angiogenesis inhibitor containing as an active ingredient a substance that has a respiratory function effect and an oxidative phosphorylation inhibitory effect. diseases accompanied by abnormal growth of
For example, it is expected to be used as a preventive or therapeutic agent for rheumatoid arthritis, diabetic retinopathy, retinopathy of prematurity, senile macular degeneration, excessive scar formation during wound healing, and abnormal cell proliferation.
血管新生抑制作用を有する物質としては、例えばプロタ
ミン、インドメサシン、メトロキシプロゲステロン、コ
ーチノンとヘパリンの併用、牛軟骨、大動脈壁の粗抽出
液等が知られている。Known substances having an angiogenesis-inhibiting effect include, for example, protamine, indomethacin, methoxyprogesterone, a combination of corchinone and heparin, bovine cartilage, and a crude extract of aortic wall.
上記の如くの血管新生押作用を有する物質は種々の障害
により、医薬品として実用化されているものは無く、新
たな血管新生抑制剤の開発が期待されている。Due to various obstacles, there are no substances that have the above-mentioned angiogenesis-promoting effect that have been put to practical use as pharmaceuticals, and the development of new angiogenesis inhibitors is expected.
そこで発明者らは種々検討した結果、ルクマイシン、ア
ンチマイシンＡ、ピエリシジン、オリゴマイシンＡ、、
Ｂ、Ｃ，，Ｄ、Ｅ等の呼吸阻害作用及び酸化的リン酸化
阻害作用を有する物質が血管新生抑制作用を有する事を
見出した。尚、本発明における呼吸とは細胞における酸
素消費、炭酸ガス発生を伴う代謝、即ち内呼吸を指す。As a result of various studies, the inventors found that lucumycin, antimycin A, piericidin, oligomycin A,
It has been found that substances such as B, C, , D, and E, which have a respiration inhibiting effect and an oxidative phosphorylation inhibiting effect, have an angiogenesis suppressing effect. Note that respiration in the present invention refers to metabolism accompanied by oxygen consumption and carbon dioxide gas generation in cells, that is, internal respiration.
本発明は上記知見に基づき完成されたものである。呼吸
阻害作用及び酸化的リン酸化阻害作用を有する物質とし
ては、ルクマイシン、アンチマイシンＡ、ピエリシジン
、ロチノン、トリヨードチロシン、オリゴマイシンＡ、
、Ｂ、Ｃ，，Ｄ、Ｅ、アントラクチロシド、カルボニル
シアニド−ｍ−りロロフェニルヒドラゾン、ジシクロへ
キシルカルボジイミド等が挙げられる。The present invention has been completed based on the above findings. Substances with respiration inhibiting action and oxidative phosphorylation inhibiting action include lucumycin, antimycin A, piericidin, rotinone, triiodotyrosine, oligomycin A,
, B, C,, D, E, anthractyloside, carbonyl cyanide-m-lylorophenylhydrazone, dicyclohexylcarbodiimide, and the like.
本有効成分が血管新生抑制剤として用いられる場合は、
単独または賦形剤あるいは担体と混合して注射剤、経口
剤または座剤などとして投与される。賦形剤および担体
としては薬剤学的に許容されるものが選ばれ、その種類
および組成は投与経路や投与方法によって決まる。例え
ば液状担体として、アルコールもしくは大豆油、ビーナ
ツツ油、ゴマ油、ミネラル油等の動植物油、または合成
油が用いられる。固体担体としてマルトース、シュクロ
ースなどのＦ’［、アミノ酸類、ヒドロキシプロピルセ
ルロースなどセルロース誘導体、ステアリン酸マグネシ
ュウムなどの有機酸塩類などが使用される。注射剤の場
合一般に各種緩衝液、グルコース、イノシトール、マン
ニトール等のＩｉＨｍ液、エチレングリコール、プロピ
レングリコール、ポリエチレングリコール等のグリコー
ル類が望ましい。また、イノシトール、マンニトール、
グルコース、マンノース、マルトース、シュクロース等
の糖類、フェニルアラニン等のアミノ酸類の賦形剤と共
に凍結乾燥剤とし、それを投与時に注射用の適当な溶剤
、例えば滅菌水、生理食塩水、ブドウ糖液、電解質溶液
、アミノ酸液等に熔解して投与することもできる。When this active ingredient is used as an angiogenesis inhibitor,
It is administered alone or mixed with excipients or carriers as injections, oral preparations, suppositories, etc. Pharmaceutically acceptable excipients and carriers are selected, and their types and compositions are determined by the route and method of administration. For example, alcohol, animal or vegetable oils such as soybean oil, peanut oil, sesame oil, mineral oil, or synthetic oils are used as liquid carriers. As solid carriers, F'[ such as maltose and sucrose, amino acids, cellulose derivatives such as hydroxypropyl cellulose, and organic acid salts such as magnesium stearate are used. In the case of injections, generally preferred are various buffer solutions, IiHm solutions such as glucose, inositol, and mannitol, and glycols such as ethylene glycol, propylene glycol, and polyethylene glycol. Also, inositol, mannitol,
It is made into a freeze-dried agent together with excipients of sugars such as glucose, mannose, maltose, and sucrose, and amino acids such as phenylalanine, and is then mixed with a suitable solvent for injection at the time of administration, such as sterile water, physiological saline, glucose solution, and electrolyte. It can also be administered after being dissolved in a solution, an amino acid solution, or the like.
製剤中における本有効成分の含量は製剤により種々異な
るが通常０．１〜５０重景％重量ましくは１〜１０重量
％である。例えば、注射液の場合には、通常０．１〜５
重景重量本有効成分を含むようにすることがよい。経口
投与する場合には、前記固体担体もしくは液状担体とと
もに錠剤、カプセル剤、粉剤、顆粒剤、液剤、ドライシ
ロップ剤等の形態で用いられる。カプセル、錠剤、顆粒
、粉剤の場合は一般に本有効成分の含量は約３〜５０重
量％、好ましくは５〜５０重量％であり、残部は担体で
ある。The content of the active ingredient in the formulation varies depending on the formulation, but is usually 0.1 to 50% by weight or 1 to 10% by weight. For example, in the case of injections, it is usually 0.1 to 5
It is preferable that the active ingredient is contained in a heavy weight. When administered orally, it is used in the form of tablets, capsules, powders, granules, liquids, dry syrups, etc. together with the solid carrier or liquid carrier. In the case of capsules, tablets, granules and powders, the content of the active ingredient is generally about 3 to 50% by weight, preferably 5 to 50% by weight, with the remainder being carrier.
投与量は、患者の年令、体重、症状、治療目的等により
決定されるが、治療量は一般に非経口投与で０．１〜５
０ ｍｇ／ｋｇ ・日、経口投与で０．５〜５０ｍｇ／
ｋｇ・日である。The dose is determined depending on the patient's age, weight, symptoms, therapeutic purpose, etc., but the therapeutic dose is generally 0.1 to 5 ml for parenteral administration.
0 mg/kg/day, 0.5-50 mg/day by oral administration
kg/day.
次に本有効成分の薬理作用を試験例により説明する。 Next, the pharmacological action of this active ingredient will be explained using test examples.
試験例１゜
呼吸阻害作用及び酸化的リン酸化阻害作用を有する物質
の代表として、オリゴマイシンＡ、Ｂ、Ｃ、アンチマイ
シンＡおよびピエリシジンの内皮細胞に対する増殖抑制
作用を検討した。Test Example 1 The growth-inhibiting effects of oligomycins A, B, C, antimycin A, and piericidin on endothelial cells as representative substances having respiration-inhibiting effects and oxidative phosphorylation-inhibiting effects were investigated.
牛副腎の毛細血管内皮細胞を１×１０′個／穴の割合で
６穴テストプレートに接種し、１目移上記化合物を種々
な濃度で培＃液に添加した。添加３目移細胞数をコール
クーカウンターにより測定し、各薬物の種々の濃度にお
ける血管内皮細胞の増殖抑制率を求めた。Bovine adrenal capillary endothelial cells were inoculated at a rate of 1 x 10' cells/well into a 6-well test plate, and the above compound was added to the culture medium at various concentrations. The number of transferred cells at the third addition site was measured using a Coulcoo counter, and the growth inhibition rate of vascular endothelial cells at various concentrations of each drug was determined.
結果を表１．２および３に示した。オリゴマイシンＡ、
、Ｂ、Ｃ，アンチマイシンＡおよびピエリシジンのｒｃ
５゜値はそれぞれ０．８４． １．４２．４．４４゜５
．８１．２．２４ ｎｇ／ｍｌであり、内皮細胞に対し
強い１殖抑制作用を示した。The results are shown in Tables 1.2 and 3. oligomycin A,
, B, C, antimycin A and piericidin rc
The 5° value is 0.84. 1.42.4.44゜5
．． The concentration was 81.2.24 ng/ml, and showed a strong monoproliferative inhibitory effect on endothelial cells.
表１
オリゴマイシンＡおよびＢの種々の濃
度における血管内皮細胞の増殖抑制率
表２．オリゴマイシンＣおよびアンチマ・イシンＡの種
々の濃度における血管内皮細胞の増殖抑制率表３．ピエ
リシジンの種々の
濃度における血管内皮細胞の
増殖抑制率
試験例２゜
鶏受精卵の漿尿膜内の血管新生に対するオリゴマイシン
Ａ、Ｂ、、Ｃ，アンチマイシンＡおよびピエリシジンの
抑制作用をり、 Ｈ，Ａｕ５ｐｒｕｎｋらの方法（Ａｍ
ｃｒｊｃａｎ Ｊｏｕｒｎａｌ ｏｆ Ｉ’ａｔｂｏｌ
ｏｇｙ ９７．５９７゜１９７５）を用いて検討した。Table 1. Growth inhibition rate of vascular endothelial cells at various concentrations of oligomycin A and B Table 2. Table 3. Inhibition rate of vascular endothelial cell proliferation at various concentrations of oligomycin C and antimycin A. Test example 2 on inhibition rate of vascular endothelial cell proliferation at various concentrations of piericidin: Inhibitory effects of oligomycin A, B, C, antimycin A, and piericidin on angiogenesis in the chorioallantoic membrane of fertilized chicken eggs. , Au5prunk et al.'s method (Am
crjcan Journal of I'atbol
ogy 97.597°1975).
９日令の鶏の受精卵の卵殻に１０ｍｍ’四方の小窓を開
け、漿尿膜上に上記化合物０．Ｏ１〜１００μｇ／ｍｌ
を含有する直径３ ｍｍのグラスファイツマディスクを
設置後、ビニールテープで小窓を封した。これを３７°
Ｃの卿卵器に入れ、５日後に漿尿膜内に新生される血管
に対する上記化合物の抑制作用の程度を観察した。A small window of 10 mm square was made in the eggshell of a 9-day-old fertilized chicken egg, and 0.0 mm of the above compound was added onto the chorioallantoic membrane. O1-100μg/ml
After installing a glass phytuma disk containing 3 mm in diameter, the small window was sealed with vinyl tape. This is 37°
After 5 days, the degree of inhibitory effect of the above compound on blood vessels generated in the chorioallantoic membrane was observed.
その結果、これら化合物の０．０１μｇ／ｍｌ投与群で
軽度な、ＩＯμｇ／ｍ１以上の投与群で強い血管新生抑
制作用が観察された。特にアンチマイシンＡおよびピエ
リシジンでは１０μｇ／ｍ１以上の投与群で完全な抑制
作用が観察された。As a result, a mild angiogenesis inhibitory effect was observed in the 0.01 μg/ml administration group of these compounds, and a strong angiogenesis inhibitory effect was observed in the IO μg/ml or more administration group. Particularly, for antimycin A and piericidin, a complete inhibitory effect was observed in the dose group of 10 μg/ml or more.
試験例３
家兎角膜内でのオリゴマイシンＡ、Ｂ、Ｃ、アンチマイ
シンＡおよびピエリシジンの血管新生に対する抑制作用
をＭ、 Ａ、 Ｇｉｍｂｒｏｎｅらの方法（Ｊｏｕｒｎ
ａｌ Ｎａｔｉｏｎａｌ Ｃａｎｃｅｒ Ｉｎ５ｔｉｔ
ｕｔｅ ５２．４１３゜１９７４）を用いて検討した。Test Example 3 The inhibitory effects of oligomycin A, B, C, antimycin A, and piericidin on angiogenesis in the cornea of rabbits were evaluated using the method of M. A. Gimbrone et al.
al National Cancer In5tit
ute 52.413°1974).
家兎の角膜中央部をメスを用いて約２ｍｍ切開し、角膜
壁に沿ったボッケトをつくり、これにあらかじめＲ，Ｌ
ａｎｇｅｒらの方法（Ｎａｔｕｒｅ ２６３．７９７
１９７９）で作製したプロスタグランデインＥ１１μｇ
またはエーリッヒ癌粗抽出物１００８ｇを含有する除放
性ペレットを挿入、設置した。更にあらかじめ作製して
おいた上記化合物０．１−１０００μｇを含有する製剤
例３の除放性ペレットをプロスタグランデインＥ１また
はエーリッヒ癌粗抽出物の除放性ペレットに接して設置
し、設置後４．６および８日目に血管新生の程度を観察
した。Using a scalpel, make an approximately 2 mm incision in the central part of the rabbit's cornea to create a socket along the corneal wall.
The method of Anger et al. (Nature 263.797
11 μg of prostaglandin E prepared in 1979)
Alternatively, a sustained release pellet containing 1008 g of Ehrlich's cancer crude extract was inserted and placed. Furthermore, the sustained release pellet of Formulation Example 3 containing 0.1 to 1000 μg of the above compound prepared in advance was placed in contact with the sustained release pellet of prostaglandin E1 or Ehrlich cancer crude extract, and after placement, The degree of angiogenesis was observed on days 6 and 8.
その結果、プロスタグランデインＥ、またはエーリッヒ
癌粗抽出物によって新生される血管に対し、検討した総
ての化合物の１μｇ／ｐｅｌｌｅｔ以上の投与群でその
伸長が用量に依存して抑制された。その抑制の程度はオ
リゴマイシンＣ＜Ａ＝Ｂ＜ピエリシジン〈アンチマイシ
ンＡの順であり、アンチマイシンＡは１００ μｇ／ｐ
ｅｌｌｅｔ以上で、ピエリシジンは１０００μｇ／ｐｅ
ｌｌｅｔで完全な抑制が見られた。As a result, the elongation of blood vessels generated by prostaglandin E or Ehrlich's cancer crude extract was inhibited in a dose-dependent manner in all of the tested compounds administered at doses of 1 μg/pellet or more. The degree of inhibition was in the order of oligomycin C < A = B < piericidin < antimycin A, and antimycin A was 100 μg/p.
ellet or higher, piericidin is 1000μg/pe
Complete inhibition was seen in llet.
以上の結果から、ルタマイシン、アンチマイシンＡ１ピ
エリシジン、オリゴマイシンＡ、Ｂ、Ｃ。From the above results, lutamycin, antimycin A1 piericidin, oligomycin A, B, and C.
Ｄ、Ｅ等の呼吸阻害作用及び酸化的リン酸化阻害作用を
有する物質は血管新生に対する抑制作用を有し、新規血
管新生抑制剤として期待される。Substances such as D and E that have a respiration inhibiting effect and an oxidative phosphorylation inhibiting effect have an inhibitory effect on angiogenesis, and are expected to be novel angiogenesis inhibitors.
製剤例１
本有効成分５０重量部、乳糖６００部、結晶セルロース
３３０部およびヒドロキシプロピルセルロース２０部を
よく混和し、ロール型圧縮機（ローラーコンパクタ−■
）を用いて圧縮し、破砕してＩ６メソシユと６０メツシ
ユの間に入るよう篩過し、顆粒とした。Formulation Example 1 50 parts by weight of the present active ingredient, 600 parts of lactose, 330 parts of crystalline cellulose and 20 parts of hydroxypropyl cellulose were thoroughly mixed, and
), crushed, and sieved to obtain granules between I6 mesh and 60 mesh.
製剤例２゜
本有効成分３０重量部、結晶乳糖１２０部、結晶セルロ
ース１４７部およびステアリン酸マグネシウム３部をＶ
型混合機で混和後、打錠し、１錠３００ ｍｇの錠剤を
得た。Formulation Example 2 30 parts by weight of this active ingredient, 120 parts of crystalline lactose, 147 parts of crystalline cellulose and 3 parts of magnesium stearate were added to V
After mixing with a mold mixer, the mixture was compressed to obtain 300 mg tablets.
製剤例３゜
本有効成分１０重量部を１０部濃度の塩化メチレンエチ
レンビニール酸共重合液１００部に混和し、次いでこの
混合液をドライアイスで冷却したガラス板上に滴下して
凍結乾燥し、除放性ベレットとした。Formulation Example 3: 10 parts by weight of the present active ingredient is mixed with 100 parts of methylene chloride ethylene vinyl acid copolymer solution having a concentration of 10 parts, and this mixed solution is then dropped onto a glass plate cooled with dry ice and freeze-dried. It was made into a sustained release pellet.
Claims (1)
物質を有効成分とする血管新生抑制剤。1. An angiogenesis inhibitor containing as an active ingredient a substance that inhibits respiration and inhibits oxidative phosphorylation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP13020890A JPH0426631A (en) | 1990-05-22 | 1990-05-22 | Suppressing agent of vascularization |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP13020890A JPH0426631A (en) | 1990-05-22 | 1990-05-22 | Suppressing agent of vascularization |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH0426631A true JPH0426631A (en) | 1992-01-29 |
Family
ID=15028678
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP13020890A Pending JPH0426631A (en) | 1990-05-22 | 1990-05-22 | Suppressing agent of vascularization |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0426631A (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6528489B1 (en) * | 1999-09-23 | 2003-03-04 | Ergon Pharmaceuticals Llc | Mycotoxin derivatives as antimitotic agents |
| EP1418932A4 (en) * | 2001-07-18 | 2006-03-15 | Univ Texas | An anti-angiogenic state in mice and humans with retinal photorecptor cell degeneration |
| US7420030B2 (en) | 2000-09-08 | 2008-09-02 | The Board Of Regents Of The University Of Texas System | Aminopeptidase A (APA) targeting peptides for the treatment of cancer |
| US7452964B2 (en) | 2001-09-07 | 2008-11-18 | Board Of Regents, The University Of Texas System | Compositions and methods of use of targeting peptides against placenta and adipose tissues |
| US8067377B2 (en) | 2000-09-08 | 2011-11-29 | The Board Of Regents Of The University Of Texas Systems | Peptide compositions for targeting adipose tissue |
-
1990
- 1990-05-22 JP JP13020890A patent/JPH0426631A/en active Pending
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6528489B1 (en) * | 1999-09-23 | 2003-03-04 | Ergon Pharmaceuticals Llc | Mycotoxin derivatives as antimitotic agents |
| US7420030B2 (en) | 2000-09-08 | 2008-09-02 | The Board Of Regents Of The University Of Texas System | Aminopeptidase A (APA) targeting peptides for the treatment of cancer |
| US7914780B1 (en) | 2000-09-08 | 2011-03-29 | Board Of Regents, The University Of Texas System | Aminopeptidase A (APA) targeting peptides for the treatment of cancer |
| US7951362B2 (en) | 2000-09-08 | 2011-05-31 | Board Of Regents, The University Of Texas System | Compositions and methods of use of targeting peptides against placenta and adipose tissues |
| US8067377B2 (en) | 2000-09-08 | 2011-11-29 | The Board Of Regents Of The University Of Texas Systems | Peptide compositions for targeting adipose tissue |
| US8252764B2 (en) | 2000-09-08 | 2012-08-28 | Board Of Regents, The University Of Texas System | Compositions and methods of use of targeting peptides against placenta and adipose tissues |
| US8710017B2 (en) | 2000-09-08 | 2014-04-29 | Board Of Regents, The University Of Texas Systems | Human and mouse targeting peptides identified by phage display |
| US8846859B2 (en) | 2000-09-08 | 2014-09-30 | Board Of Regents, The University Of Texas System | Compositions and methods of use of targeting peptides against placenta and adipose tissues |
| EP1418932A4 (en) * | 2001-07-18 | 2006-03-15 | Univ Texas | An anti-angiogenic state in mice and humans with retinal photorecptor cell degeneration |
| US7452964B2 (en) | 2001-09-07 | 2008-11-18 | Board Of Regents, The University Of Texas System | Compositions and methods of use of targeting peptides against placenta and adipose tissues |
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