JPH03204818A - Medicine composition containing human adf - Google Patents
Medicine composition containing human adfInfo
- Publication number
- JPH03204818A JPH03204818A JP2260260A JP26026090A JPH03204818A JP H03204818 A JPH03204818 A JP H03204818A JP 2260260 A JP2260260 A JP 2260260A JP 26026090 A JP26026090 A JP 26026090A JP H03204818 A JPH03204818 A JP H03204818A
- Authority
- JP
- Japan
- Prior art keywords
- agent
- therapeutic agent
- human adf
- adf
- human
- 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.)
- Granted
Links
- 239000003814 drug Substances 0.000 title claims abstract description 22
- 229940079593 drug Drugs 0.000 title description 4
- 101000883470 Homo sapiens Destrin Proteins 0.000 claims abstract description 61
- 102000052973 human DSTN Human genes 0.000 claims abstract description 61
- 101000852559 Homo sapiens Thioredoxin Proteins 0.000 claims abstract description 59
- 101001059150 Homo sapiens Gelsolin Proteins 0.000 claims abstract description 58
- 229940124597 therapeutic agent Drugs 0.000 claims abstract description 18
- 206010003210 Arteriosclerosis Diseases 0.000 claims abstract description 11
- 208000023275 Autoimmune disease Diseases 0.000 claims abstract description 11
- 208000011775 arteriosclerosis disease Diseases 0.000 claims abstract description 11
- 230000000302 ischemic effect Effects 0.000 claims abstract description 11
- 108090000623 proteins and genes Proteins 0.000 claims abstract description 11
- 125000003275 alpha amino acid group Chemical group 0.000 claims abstract description 10
- 239000000718 radiation-protective agent Substances 0.000 claims abstract description 9
- 239000002260 anti-inflammatory agent Substances 0.000 claims abstract description 7
- 229940121363 anti-inflammatory agent Drugs 0.000 claims abstract description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 12
- 239000004480 active ingredient Substances 0.000 claims description 9
- 206010013663 drug dependence Diseases 0.000 claims description 9
- 230000008816 organ damage Effects 0.000 claims description 9
- 208000011117 substance-related disease Diseases 0.000 claims description 9
- 241000588724 Escherichia coli Species 0.000 claims description 6
- 230000000694 effects Effects 0.000 abstract description 34
- 150000003254 radicals Chemical class 0.000 abstract description 23
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- 238000000034 method Methods 0.000 abstract description 12
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- 102000004196 processed proteins & peptides Human genes 0.000 abstract description 10
- 102000004190 Enzymes Human genes 0.000 abstract description 9
- 108090000790 Enzymes Proteins 0.000 abstract description 9
- 108060008226 thioredoxin Proteins 0.000 abstract description 8
- 239000002299 complementary DNA Substances 0.000 abstract description 3
- 239000012228 culture supernatant Substances 0.000 abstract description 3
- 206010070863 Toxicity to various agents Diseases 0.000 abstract description 2
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- 102000004169 proteins and genes Human genes 0.000 description 9
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- 102000019197 Superoxide Dismutase Human genes 0.000 description 6
- 108010012715 Superoxide dismutase Proteins 0.000 description 6
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- 230000006378 damage Effects 0.000 description 6
- 230000004223 radioprotective effect Effects 0.000 description 6
- 230000001603 reducing effect Effects 0.000 description 6
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 5
- 201000011510 cancer Diseases 0.000 description 5
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
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- 238000004519 manufacturing process Methods 0.000 description 4
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- 230000003449 preventive effect Effects 0.000 description 4
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- 230000007760 free radical scavenging Effects 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- 102000000589 Interleukin-1 Human genes 0.000 description 2
- 108010002352 Interleukin-1 Proteins 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- ACFIXJIJDZMPPO-NNYOXOHSSA-N NADPH Chemical compound C1=CCC(C(=O)N)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]2[C@H]([C@@H](OP(O)(O)=O)[C@@H](O2)N2C3=NC=NC(N)=C3N=C2)O)O1 ACFIXJIJDZMPPO-NNYOXOHSSA-N 0.000 description 2
- 108020002230 Pancreatic Ribonuclease Proteins 0.000 description 2
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- 238000009825 accumulation Methods 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 238000007385 chemical modification Methods 0.000 description 2
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 2
- 229960003180 glutathione Drugs 0.000 description 2
- 238000003119 immunoblot Methods 0.000 description 2
- 238000004255 ion exchange chromatography Methods 0.000 description 2
- 231100000053 low toxicity Toxicity 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 102000040650 (ribonucleotides)n+m Human genes 0.000 description 1
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 1
- 206010000830 Acute leukaemia Diseases 0.000 description 1
- 208000009746 Adult T-Cell Leukemia-Lymphoma Diseases 0.000 description 1
- 208000016683 Adult T-cell leukemia/lymphoma Diseases 0.000 description 1
- 208000032467 Aplastic anaemia Diseases 0.000 description 1
- 244000063299 Bacillus subtilis Species 0.000 description 1
- 235000014469 Bacillus subtilis Nutrition 0.000 description 1
- 102100035882 Catalase Human genes 0.000 description 1
- 108010053835 Catalase Proteins 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- 108010024636 Glutathione Proteins 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 102000004316 Oxidoreductases Human genes 0.000 description 1
- 108090000854 Oxidoreductases Proteins 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- XIXYTCLDXQRHJO-RFVHGSKJSA-N Ramosetron hydrochloride Chemical compound Cl.C12=CC=CC=C2N(C)C=C1C(=O)[C@H]1CC(NC=N2)=C2CC1 XIXYTCLDXQRHJO-RFVHGSKJSA-N 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 208000000389 T-cell leukemia Diseases 0.000 description 1
- 208000028530 T-cell lymphoblastic leukemia/lymphoma Diseases 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 201000006966 adult T-cell leukemia Diseases 0.000 description 1
- 238000001042 affinity chromatography Methods 0.000 description 1
- JKOQGQFVAUAYPM-UHFFFAOYSA-N amifostine Chemical compound NCCCNCCSP(O)(O)=O JKOQGQFVAUAYPM-UHFFFAOYSA-N 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 210000004102 animal cell Anatomy 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000037429 base substitution Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 1
- 238000011243 body radiation therapy Methods 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 238000010322 bone marrow transplantation Methods 0.000 description 1
- 230000005779 cell damage Effects 0.000 description 1
- 208000037887 cell injury Diseases 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 208000015114 central nervous system disease Diseases 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 238000011098 chromatofocusing Methods 0.000 description 1
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- 208000024207 chronic leukemia Diseases 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
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- 239000003292 glue Substances 0.000 description 1
- 208000037824 growth disorder Diseases 0.000 description 1
- 208000018706 hematopoietic system disease Diseases 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000000415 inactivating effect Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000001678 irradiating effect Effects 0.000 description 1
- -1 lipid peroxide Chemical class 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 125000001360 methionine group Chemical group N[C@@H](CCSC)C(=O)* 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
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- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
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- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
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- 230000008673 vomiting Effects 0.000 description 1
Landscapes
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明は、ヒト成人T細胞白血病由来因子(以下ヒトA
DFと称する)を有効成分とする放射線防護剤、抗炎症
剤、リウマチ治療剤、自己免疫疾患治療剤、虚血性臓器
障害治療剤、薬物中毒治療剤及び動脈硬化治療剤に関す
る。癌などの放射線療法時に、本発明に係るヒトADF
を併用することにより、放射線の副作用を大幅に軽減出
来る。Detailed Description of the Invention [Industrial Field of Application] The present invention relates to human adult T-cell leukemia-derived factor (hereinafter referred to as human A
The present invention relates to a radioprotective agent, an anti-inflammatory agent, a rheumatism treatment agent, an autoimmune disease treatment agent, an ischemic organ damage treatment agent, a drug addiction treatment agent, and an arteriosclerosis treatment agent, which contain DF (referred to as DF) as an active ingredient. Human ADF according to the present invention during radiotherapy for cancer etc.
By using it together, the side effects of radiation can be significantly reduced.
また、ヒトAI)Fはフリーラジカルの中和活性を有し
ており、フリーラジカルの生体過酸化による組織障害を
伴う炎症、リウマチ、自己免疫疾患。Furthermore, human AI)F has free radical neutralizing activity, and is associated with inflammation, rheumatism, and autoimmune diseases accompanied by tissue damage due to biological peroxidation of free radicals.
虚血性臓器障害、薬物中毒、動脈硬化などの治療薬ある
いは予防薬としても広く利用できる。It can also be widely used as a therapeutic or preventive drug for ischemic organ damage, drug addiction, arteriosclerosis, etc.
一方、Wol 1man等はヒトの生体内の酸化還元蛋
白質であるチオレドキシンのアミノ酸配列を公表してい
る(The Journal of Biologic
al ChemistryVol 263. (No
30)、 PP 15506−15512.1988)
。On the other hand, Wol 1man et al. published the amino acid sequence of thioredoxin, which is a redox protein in the human body (The Journal of Biologic
al Chemistry Vol 263. (No
30), PP 15506-15512.1988)
.
Wollman等が示したチオレドキシンのアミノ酸配
列はヒトADFのアミノ酸配列と2ケ所が異なる以外は
全てヒトADFと同一の配列を有していた。The amino acid sequence of thioredoxin shown by Wollman et al. had the same sequence as human ADF except for two differences from the amino acid sequence of human ADF.
またヒトADFもチオレドキシン様の酸化還元作用を有
している。従って、ヒトADFをチオレドキシンと呼ぶ
研究者もいるが、本発明においてはヒトADFという用
語で統一する。Human ADF also has thioredoxin-like redox activity. Therefore, some researchers call human ADF thioredoxin, but in the present invention, it is unified under the term human ADF.
放射線は、癌の治療に有効な手段の一つである。 Radiation is one of the effective means for treating cancer.
しかし、放射線は、非特異的に癌細胞だけでなく正常細
胞をも破壊するので、治療効果を上げる為に放射線量を
増せば増すほど、造血障害1発熱。However, radiation non-specifically destroys not only cancer cells but also normal cells, so the more the radiation dose is increased to increase the therapeutic effect, the more likely it is that hematopoietic disorders 1 and fever will occur.
嘔吐などの副作用は免れず、また、癌が治癒出来たとし
ても、内分泌異常による発育障害、中枢神経障害などの
後遺症が問題になってくる。治療の現場では、今まで、
腫瘍の縮小効果ばかりに目が向けられていたが、治療成
績が向上し生存率が高くなるにつれ、治療前後の患者の
、あるいは長期生存者の”生活の質(quality
of 1ife)″を確保することが不可欠になってき
た。従って、放射線治療時に、放射線防護剤を併用して
正常細胞の障害を出来るだけ抑え、治療成績を向上させ
ると共に、副作用を軽減させるという考え方は重要であ
る。放射線による細胞障害は、放射線により生体内に発
生したフリーラジカルが原因と考えられているが、この
フリーラジカルを不活性化して副作用を軽減しようとい
う考えから、還元型グルタチオン(GSH)、あるいは
その他のSH化合物が放射線防護剤として研究開発され
てきた。ところが、GSHは試験管内では確かに放射線
防護効果が認められたものの、細胞膜を通過出来ないた
め、動物に投与しても殆ど効果は認められなかった。Side effects such as vomiting are inevitable, and even if cancer can be cured, after-effects such as growth disorders and central nervous system disorders due to endocrine abnormalities become a problem. Until now, in the field of treatment,
Attention was focused only on the effect of shrinking tumors, but as treatment results improve and survival rates increase, the quality of life of patients before and after treatment, as well as of long-term survivors, has become more important.
Therefore, the idea is to use radioprotective agents in conjunction with radiation therapy to suppress damage to normal cells as much as possible, improve treatment results, and reduce side effects. Cell damage caused by radiation is thought to be caused by free radicals generated in the body by radiation, but with the idea of inactivating these free radicals and reducing side effects, reduced glutathione (GSH ), and other SH compounds have been researched and developed as radioprotective agents. However, although GSH has certainly shown radioprotective effects in vitro, it cannot pass through cell membranes, so it has little effect when administered to animals. No effect was observed.
また、米国で開発されたSH化合物の一つであるWR−
2721(S −2−(3−アミノプロピル−アミノ)
−エチルホスフォロチオ酸)は、放射線による骨髄幹細
胞の障害を防ぐことは出来たが、それ自身に強い副作用
があり日本では製造が中止されている。一方、生体由来
の蛋白質であるインターロイキン1 (ILI)にも
放射線防護作用があることが見いだされたが、ILLは
発熱活性があり、人体に投与する場合、投与量が制限さ
れる。In addition, WR- which is one of the SH compounds developed in the United States
2721 (S-2-(3-aminopropyl-amino)
- Ethylphosphorothioic acid) was able to prevent damage to bone marrow stem cells due to radiation, but it has strong side effects and its production has been discontinued in Japan. On the other hand, interleukin-1 (ILI), a protein derived from living organisms, has also been found to have a radioprotective effect, but ILL has thermogenic activity, which limits the dosage when administered to the human body.
また、作用機構もよくわかっていないので、活性を自由
に制御することが難しい。従って、現在、放射線治療時
の副作用を有効に抑え、しかもそれ自身の毒性が低いよ
うな防護剤は見いだされていない。Furthermore, since the mechanism of action is not well understood, it is difficult to freely control the activity. Therefore, at present, no protective agent has been found that effectively suppresses side effects during radiotherapy and has low toxicity itself.
放射線による生体障害の原因と考えられるフリーラジカ
ルは、炎症、あるいは、リウマチ、自己免疫疾患、虚血
性臓器傷害、薬物中毒などにおいても多量に生体内に発
生し、強力な酸化反応(過酸化反応)により生体膜、蛋
白質、酵素、あるいはDNAを攻撃し生体を傷害する原
因となる、と考えられている。また、動脈硬化はフリー
ラジカルの一種である過酸化脂質の蓄積が原因と考えら
れている。従って、放射線防護作用を有するSH化合物
が強力なフリーラジカル消去作用を持つとき、この物質
は炎症あるいはその他の生体過酸化を伴う上記の各種疾
患の治療薬あるいは予防薬としても有効に利用できる。Free radicals, which are thought to be the cause of biological damage caused by radiation, are generated in large amounts in the body during inflammation, rheumatism, autoimmune diseases, ischemic organ damage, drug poisoning, etc., and are caused by strong oxidation reactions (peroxidation reactions). It is believed that these substances attack biological membranes, proteins, enzymes, or DNA, causing damage to living organisms. Furthermore, arteriosclerosis is thought to be caused by the accumulation of lipid peroxide, which is a type of free radical. Therefore, when a radioprotective SH compound has a strong free radical scavenging effect, this substance can be effectively used as a therapeutic or preventive agent for the above-mentioned various diseases accompanied by inflammation or other biological peroxidation.
一方、スーパーオキシドジスムターゼ(SOD)は、フ
リーラジカルの一種である0!−を消去する活性を持ち
、現在抗炎症薬として開発が進められているが、生体内
半減期が10分以内と非常に短(、化学修飾あるいはリ
ポソームへの封入などを施して半減期を延ばす工夫が必
要であり、臨床応用をする上での難関となっている。On the other hand, superoxide dismutase (SOD) is a type of free radical. -, and is currently being developed as an anti-inflammatory drug, but its half-life in vivo is extremely short at less than 10 minutes (the half-life can be extended by chemical modification or encapsulation in liposomes). This requires some ingenuity, which poses a challenge in clinical application.
尚、酸化還元能を有するヒトADF (ヒトチオレオト
キシン)のフリーラジカル消去活性については、今日、
我々が報告するまで明らかになっていなかった。Furthermore, regarding the free radical scavenging activity of human ADF (human thioreotoxin), which has redox ability,
It wasn't revealed until we reported it.
本発明の課題は、癌放射線療法などに於いて、有効に放
射線の副作用を軽減する事が出来、更にフリーラジカル
による炎症や生体過酸化を伴う各種炎症の治療あるいは
予防に有効で、しかも生体に対する毒性が低いヒトAD
Fを含有する薬剤の提供である。The object of the present invention is to be able to effectively reduce the side effects of radiation in cancer radiotherapy, etc., and to be effective in treating or preventing inflammation caused by free radicals and various types of inflammation accompanied by biological peroxidation. Human AD with low toxicity
The present invention provides a drug containing F.
本発明者は、上記課題を解決する為に鋭意検討を行った
結果、ヒトADFに優れた放射線防護効果、抗炎症効果
、リウマチ治療効果、自己免疫疾患の治療効果、虚血性
臓器障害治療効口譜が薬物中毒治療効果及び動脈硬化治
療効果を見い出し本発明を完成するに至った。As a result of intensive studies to solve the above problems, the present inventors found that human ADF has excellent radiation protection effects, anti-inflammatory effects, rheumatism treatment effects, autoimmune disease treatment effects, and ischemic organ damage treatment effects. The present invention was completed after discovering the therapeutic effect on drug addiction and arteriosclerosis.
以下、本発明の詳細な説明する。The present invention will be explained in detail below.
ヒトADFは、ヒト成人型T細胞白血病患者より樹立さ
れたT細胞白血病細胞株(ATL−2)の培養上清中に
最初に見出された蛋白質であり、本発明者は既に、蛋白
質の精製及びcDNAのクローニングに成功し、さらに
遺伝子組み換え法によりリコンビナントヒトADFの大
量生産にも成功している。(特開平1−85097)。Human ADF is a protein that was first discovered in the culture supernatant of a T-cell leukemia cell line (ATL-2) established from a human adult T-cell leukemia patient, and the present inventor has already purified the protein. and cDNA, and also succeeded in mass production of recombinant human ADF using genetic recombination methods. (Unexamined Japanese Patent Publication No. 1-85097).
ヒトADFは、大腸菌、高等植物、兎などのチオレドキ
シンに共通の活性部位の構造を有しており、しかも、リ
コンビナントヒトADFはチオレドキシン様の還元活性
を有している事も確認された。さらに、ヒトADFはフ
リーラジカル消去能を有することも、今回の我々の発明
により初めて明らかにされた。Human ADF has an active site structure common to thioredoxins from E. coli, higher plants, rabbits, etc., and it was also confirmed that recombinant human ADF has a thioredoxin-like reducing activity. Furthermore, our invention revealed for the first time that human ADF has the ability to scavenge free radicals.
本発明で使用するヒトADF蛋白質は、次の方法あるい
はそれ以外の方法で製造したものなど、その製法に制限
はない。■ヒト由来細胞株(ATL−2など)の細胞培
養上清、または細胞抽出液から、塩析、ゲル濾過クロマ
トグラフィー、イオン交換クロマトグラフィー、アフィ
ニティークロマトグラフィー、クロマトフオーカシング
、逆相クロマトグラフィー、疎水性クロマトグラフィー
などの一般に用いられる手法により精製する。(特枯草
菌、酵母、高等動物細胞、植物細胞などの宿主細胞に導
入し、宿主細胞内で発現した組換えヒトADF蛋白質を
、■に記したような手法を用いて精製する。(特開平1
−85097)■ペプチド化学合成法により、(I)の
配列を有するポリペプチドを合成する。The human ADF protein used in the present invention may be produced by the following method or any other method, but there are no limitations on the method of production. ■ From cell culture supernatants or cell extracts of human-derived cell lines (ATL-2, etc.), salting out, gel filtration chromatography, ion exchange chromatography, affinity chromatography, chromatofocusing, reversed phase chromatography, Purify by commonly used techniques such as hydrophobic chromatography. (Introduced into host cells such as Bacillus subtilis, yeast, higher animal cells, and plant cells, and purified the recombinant human ADF protein expressed in the host cells using the method described in ①. 1
-85097) ■ Synthesize a polypeptide having the sequence (I) by a peptide chemical synthesis method.
くり返し述べるが、いずれの生産法を用いてもよい。As mentioned repeatedly, any production method may be used.
本発明のヒトADFを、放射線療法時に投与することに
より、放射線による副作用を大幅に軽減させることが出
来る。例えば、放射線全身あるいは局所照射による治療
を必要とする各種の癌、また、骨髄移植に先だって放射
線全身照射が必要な急性、慢性白血病、再生不良性貧血
など放射線療法を必要とする各種疾患に適用が可能であ
る。また、ヒトADFは、ヒト由来の蛋白質であるので
、人体に投与しても異物として認識されず、毒性は非常
に低い。ヒトADFの投与は、特に制限はないが放射線
照射の前、後、あるいは照射前後に渡って体重1 kg
当り1−30mgの用量を数回行う。By administering the human ADF of the present invention during radiation therapy, side effects caused by radiation can be significantly reduced. For example, it can be applied to various cancers that require treatment with whole-body or local radiation therapy, as well as various diseases that require radiotherapy, such as acute and chronic leukemia, which require whole-body radiation therapy prior to bone marrow transplantation, and aplastic anemia. It is possible. Furthermore, since human ADF is a human-derived protein, it is not recognized as a foreign substance even when administered to the human body, and its toxicity is extremely low. There are no particular restrictions on the administration of human ADF, but before and after radiation irradiation, or before and after irradiation, human ADF can be administered at a dose of 1 kg body weight.
Several doses of 1-30 mg per dose are given.
投与時期は、照射直前、直後各1日以内を含めるのが望
ましく、投与量は、10■/体重眩程度が望ましいが、
照射線量、患者の症状に応じて変化させる。また、投与
方法は、静脈内投与、筋肉内投与またはその他の投与方
法によればよい。The timing of administration is preferably within one day immediately before and immediately after irradiation, and the dose is preferably about 10 cm/body weight, but
Change the irradiation dose depending on the patient's symptoms. Further, the administration method may be intravenous administration, intramuscular administration or other administration methods.
本発明のヒトADFは、種々のフリーラジカルを還元し
消去する能力も有している。また、フリーラジカルがS
−3架橋を持った蛋白質あるいは酵素と反応すると分子
内あるいは分子間に誤ったS−S架橋が形成され、活性
を失うが、本発明のヒトADFはこのような失活した蛋
白質あるいは酵素のS−S架橋を矯正し、活性を回復さ
せる能力も有している。従って、フリーラジカルによる
生体傷害を伴う炎症、あるいは、リウマチ、自己免疫疾
患、虚血性臓器障害、薬物中毒などの疾患においてヒト
ADFを投与することにより症状を大幅に軽減できる。The human ADF of the present invention also has the ability to reduce and scavenge various free radicals. In addition, free radicals are S
When it reacts with proteins or enzymes that have -3 crosslinks, incorrect S-S crosslinks are formed within or between molecules, resulting in loss of activity. It also has the ability to correct -S crosslinks and restore activity. Therefore, by administering human ADF to diseases such as inflammation accompanied by biological damage caused by free radicals, rheumatism, autoimmune diseases, ischemic organ damage, drug addiction, etc., symptoms can be significantly alleviated.
更に、フリーラジカルの蓄積が原因と考えられる動脈硬
化の予防、治療薬としても利用できる。Furthermore, it can be used as a preventive or therapeutic agent for arteriosclerosis, which is thought to be caused by the accumulation of free radicals.
くり返し述べるが、本発明のヒトADFを含有する薬剤
は放射線防護剤や抗炎症剤としての用途以外にもリウマ
チ、自己免疫疾患、虚血性臓器障害、薬剤中毒及び動脈
硬化などの予防あるいは治療剤として広範囲に利用でき
る可能性がある。To reiterate, the human ADF-containing drug of the present invention can be used as a preventive or therapeutic agent for rheumatism, autoimmune diseases, ischemic organ damage, drug addiction, arteriosclerosis, etc., in addition to being used as a radioprotective agent or an anti-inflammatory agent. Potential for widespread use.
本発明で使用されるヒトADFは第1図に示した配列を
持つポリペプチドに限定されるものではない。The human ADF used in the present invention is not limited to the polypeptide having the sequence shown in FIG.
即ち、ヒトADF活性がある限り、N末端にメチオニン
残基が付加されたポリペプチド、化学修飾、塩基置換法
によりアミノ酸配列に置換が加わったポリペプチド、ア
ミノ酸配列の一部に欠損があるポリペプチド、アミノ酸
残基の挿入があるポリペプチド、あるいは側鎖に糖鎖等
が付加されたポリペプチドでもよい、好ましくは第1図
に示したアミノ酸配列を有するポリペプチド及び第1図
に示したアミノ酸配列のN末端にメチオニンが付加され
た構造を持つポリペプチドが良い。また、ヒトADFの
活性部位も既に明らかになっているので、蛋白質工学的
に自由に活性をコントロールすることも可能である。That is, as long as human ADF activity is present, polypeptides with a methionine residue added to the N-terminus, polypeptides with amino acid sequence substitutions made by chemical modification or base substitution methods, and polypeptides with deletions in part of the amino acid sequence. , a polypeptide with an inserted amino acid residue, or a polypeptide with a sugar chain etc. added to the side chain, preferably a polypeptide having the amino acid sequence shown in Figure 1 and the amino acid sequence shown in Figure 1. A polypeptide having a structure in which methionine is added to the N-terminus is preferable. Furthermore, since the active site of human ADF has already been clarified, it is also possible to freely control the activity using protein engineering.
はないが、通常いずれの場合も0.01〜100.0重
量%、好ましくは001〜50重量%含有させればよい
。またヒトADF以外にマンニトール、マルトースなど
の種々の安定化剤や賦形剤を添加すればよい。However, in either case, it is usually contained in an amount of 0.01 to 100.0% by weight, preferably 001 to 50% by weight. In addition to human ADF, various stabilizers and excipients such as mannitol and maltose may be added.
以下、本発明を実施例に基づいて説明する。Hereinafter, the present invention will be explained based on examples.
〔実施例1〕リコンビナントヒトADFの調製公知の方
法(特開平1−85097)に従い、リコンビナントヒ
トADFを調製した。まず、ヒトADFcDNAを組み
込んだプラスミドDNAで大腸菌をトランスフオームし
、大腸菌体内でヒトADFを発現させた後、イオン交換
クロマトグラフィーなどにより精製を行い、リコンビナ
ントADF標品を得た。201iterの大腸菌培養液
から1gの精製標品が得られた。この標品は、5O5−
PAGEで分子量12,000の単一のバンドを示し、
イムノブロッティングを行ったところ、抗ヒトADF抗
体と反応した。また、チオレドキシンとしての還元活性
を有し、その比活性は大腸菌由来チオレドキシンと同程
度であった。[Example 1] Preparation of recombinant human ADF Recombinant human ADF was prepared according to a known method (Japanese Patent Application Laid-open No. 1-85097). First, E. coli was transformed with plasmid DNA incorporating human ADF cDNA to express human ADF within the E. coli, and then purified by ion exchange chromatography or the like to obtain a recombinant ADF preparation. 1 g of purified sample was obtained from 201 iters of E. coli culture. This specimen is 5O5-
Showing a single band with a molecular weight of 12,000 on PAGE,
When immunoblotting was performed, it reacted with anti-human ADF antibody. It also had reducing activity as a thioredoxin, and its specific activity was comparable to that of E. coli-derived thioredoxin.
このリコンビナントヒトADFを、PBSに対して一晩
透析した後、0.22μmミリポアフィルタ−に通して
滅菌し、濃度を0.5■/meに調整した後以下の実験
に用いた。This recombinant human ADF was dialyzed against PBS overnight, sterilized by passing through a 0.22 μm Millipore filter, and the concentration was adjusted to 0.5 μm/me before use in the following experiments.
〔実施例2〕リコンビナントヒトADFのin viv
。[Example 2] In viv of recombinant human ADF
.
放射線防護効果
マウス(ICR)に8.5GyOX線を照射した直後(
0日月)から−日おきに、10日日目で計6回、腹腔内
にリコンビナントヒトADFを注射投与した。投与量は
、1匹、1回当り400μgとした。第2図に示したよ
うに、コントロールの無投与群では、照射後11日凹か
ら死亡し始め、21日日目でに全マウスが死亡したのに
対し、ADF投与群では、30日ローおいても全マウス
が生存した。Immediately after irradiating radioprotective mice (ICR) with 8.5 GyOX rays (
Recombinant human ADF was intraperitoneally injected a total of 6 times on the 10th day, every - day from day 0 (month and day). The dose was 400 μg per animal. As shown in Figure 2, in the control non-administered group, death began on the 11th day after irradiation, and all mice died on the 21st day, whereas in the ADF-administered group, death occurred on the 30th day. All mice survived.
〔実施例3〕リコンビナントヒトADFのフリーラジカ
ル還元能
本発明のヒトADFは、フリーラジカルの還元活性を有
することが明らかになった。第3図に示すように、リコ
ンビナントヒトADF、チオレド×
キシンレダクターゼ(TAR) 、NADPHからなる
還元型チオレドキシン再生系にキサンチンオキシダーゼ
とキサンチンから成るフリーラジカル(0□−、H,O
□)生成系を加えたところ、NADPHの消費に伴う3
40nmの吸光度の減少が観察された。[Example 3] Free radical reducing ability of recombinant human ADF It was revealed that the human ADF of the present invention has free radical reducing activity. As shown in Figure 3, a reduced thioredoxin regeneration system consisting of recombinant human ADF, thioredo x xine reductase (TAR), and NADPH is combined with free radicals (0□-, H, O
□) When adding the generation system, 3 due to consumption of NADPH
A decrease in absorbance at 40 nm was observed.
去酵素であるSODにより阻害されなかったのに対し、
過酸化水素(H20□)消去酵素であるカタラーゼによ
り阻害されたことから、ヒトADFは過酸化水素を還元
する能力を有することが明らかになった。While it was not inhibited by SOD, an enzyme that removes
Since it was inhibited by catalase, a hydrogen peroxide (H20□) scavenging enzyme, it was revealed that human ADF has the ability to reduce hydrogen peroxide.
尚、第3図のΔA 340 /minとは340nmの
吸光度の減少量を示す。Note that ΔA 340 /min in FIG. 3 indicates the amount of decrease in absorbance at 340 nm.
〔実施例4〕リコンビナントヒトADFの失活酵素の活
性回復効果
本発明のヒトADFは、フリーラジカルにより失活した
酵素の活性を回復させる活性を有することが明らかにな
った(第4図)。リボヌクレアーゼA (RNaseA
)は分子内に4つのS−S結合を有するが、還元剤であ
るジチオスレイトール(DTT)によるS−8結合の還
元に引き続き、フリーラジカルの一つである過酸化水素
(H2O2)と反応させると分子内あるいは分子間に間
違ったS−8架橋が形成され不活化されたスクランブル
RNaseを作ることができる。スクランブルRNas
eは活性を失っているが、ここに酸化型及び還元型のり
コンビナンドヒトADFを作用させると、時間と共にR
NaseAの活性が回復した。この反応は、第5図に示
すように還元型ADFにより間違ったS−S結合が切断
された後、酸化型ADFにより正しいSS結合がかけら
れたためと考えられる。RNase活性は、2’、3’
−cCMPの加水分解反応に伴う286 nmの吸光度
の増加速度を測定し算出した。[Example 4] Effect of recombinant human ADF on restoring the activity of a deactivated enzyme It was revealed that the human ADF of the present invention has the activity of restoring the activity of an enzyme deactivated by free radicals (Fig. 4). Ribonuclease A (RNaseA)
) has four S-S bonds in its molecule, but after the S-8 bond is reduced by the reducing agent dithiothreitol (DTT), it reacts with hydrogen peroxide (H2O2), a free radical. When this occurs, an incorrect S-8 bridge is formed within or between molecules, creating inactivated scrambled RNase. Scramble RNas
e has lost its activity, but when oxidized and reduced glue combination human ADF is applied here, R increases over time.
NaseA activity was recovered. This reaction is thought to be because, as shown in FIG. 5, after an incorrect SS bond was cleaved by reduced ADF, a correct SS bond was added by oxidized ADF. RNase activity is 2', 3'
The rate of increase in absorbance at 286 nm accompanying the hydrolysis reaction of -cCMP was measured and calculated.
結果は第4図に示した。The results are shown in Figure 4.
〔実施例5〕リコンビナントヒトADFの血中動態
リコンビンナントヒトADF (以下rADFと略する
)2.5■(生理食塩水1mlに溶解)をマウス(C5
7BL/6.4週齢、雌)の腹腔に投与後、−定時間経
過の後マウスをエーテル麻酔し心臓から採血し血清を採
取した。血清に含まれるrADFを5O5−PAGEと
イムノブロッティングにより検出した後、デンシトメー
ターによりプロッティング膜上のrADFのバンドを定
量し、血清中rADFの濃度を算出した。第6図に示す
ように、r ADFは投与15分後から血中に出現し、
1時間で血中濃度は最大に達しその後徐々に減少した。[Example 5] Blood dynamics of recombinant human ADF Recombinant human ADF (hereinafter abbreviated as rADF) (dissolved in 1 ml of physiological saline) was added to a mouse (C5
After administration into the abdominal cavity of a mouse (7BL/6.4 weeks old, female), after a certain period of time, the mouse was anesthetized with ether and blood was collected from the heart to collect serum. After rADF contained in the serum was detected by 5O5-PAGE and immunoblotting, the rADF band on the plotting membrane was quantified using a densitometer, and the concentration of rADF in the serum was calculated. As shown in Figure 6, rADF appears in the blood 15 minutes after administration.
The blood concentration reached the maximum in 1 hour and then gradually decreased.
この結果から、rADFの血中半減期は約1.5時間と
計算された。From this result, the blood half-life of rADF was calculated to be approximately 1.5 hours.
明らかにSODより血中半減期が長いという結果を得た
。The results clearly showed that the half-life in the blood was longer than that of SOD.
本発明のヒトADFは優れた放射線防護作用以外に優れ
たフリーラジカル消去活性及び、フリーラジカルにより
失活した酵素を再活性化させる能力をも有する有用な物
質である。従って、ヒトADFを有効成分として含有す
る医薬製剤は放射線防護剤以外にフリーラジカルによる
生体障害を伴う炎症の治療剤、あるいはリウマチ、自己
免疫疾患、虚血性臓器疾患、薬物中毒及び動脈硬化など
の治療及び予防剤として有用である。The human ADF of the present invention is a useful substance that has not only an excellent radioprotective effect but also an excellent free radical scavenging activity and the ability to reactivate enzymes that have been deactivated by free radicals. Therefore, in addition to being a radioprotective agent, pharmaceutical preparations containing human ADF as an active ingredient can be used as a therapeutic agent for inflammation accompanied by biological damage caused by free radicals, or for the treatment of rheumatism, autoimmune diseases, ischemic organ diseases, drug addiction, arteriosclerosis, etc. and useful as a prophylactic agent.
またヒトADFはヒト由来の蛋白質であるので、人体に
投与しても異物として認識されず、毒性は極めて低い。Furthermore, since human ADF is a human-derived protein, it is not recognized as a foreign substance even when administered to the human body, and its toxicity is extremely low.
さらに、血中半減期が1.5時間と、SODに比べ10
倍以上長いので、SODよりはるかに低濃度で効果を発
揮するという特徴を合せもつ。In addition, the half-life in the blood is 1.5 hours, which is 10 times longer than that of SOD.
Because it is more than twice as long, it also has the advantage of being effective at much lower concentrations than SOD.
第1図はヒトADFのアミノ酸配列を示す。 第2図はヒトADFの放射線防護効果を示す。 第3図はヒトADFのフリーラジカル還元能を示す。 第4図はヒトADFの失活酵素の活性回復効果を示す。 第5図はRNaseの構造変化を示す。 第6図はヒトADFの血中動態を示す。 Figure 1 shows the amino acid sequence of human ADF. Figure 2 shows the radioprotective effect of human ADF. Figure 3 shows the free radical reducing ability of human ADF. FIG. 4 shows the effect of restoring the activity of the inactivated enzyme of human ADF. FIG. 5 shows structural changes of RNase. FIG. 6 shows the blood dynamics of human ADF.
Claims (8)
剤。(1) A radioprotective agent containing human ADF as an active ingredient.
療剤。(3) A rheumatism therapeutic agent containing human ADF as an active ingredient.
患治療剤。(4) An autoimmune disease therapeutic agent containing human ADF as an active ingredient.
障害治療剤。(5) A therapeutic agent for ischemic organ damage containing human ADF as an active ingredient.
療剤。(6) A therapeutic agent for drug addiction containing human ADF as an active ingredient.
療剤。(7) A therapeutic agent for arteriosclerosis containing human ADF as an active ingredient.
る請求項(1)、(2)、(3)、(4)、(5)、(
6)又は(7)記載の放射線防護剤、抗炎症剤、リウマ
チ治療剤、自己免疫疾患治療剤、虚血性臓器障害治療剤
、薬物中毒治療剤、又は動脈硬化治療剤。 〔アミノ酸配列1〕 (N末端)【遺伝子配列があります】(C末端)(9)
ヒトADFが大腸菌で生産されたものである請求項(1
)、(2)、(3)、(4)、(5)、(6)又は(7
)記載の放射線防護剤、抗炎症剤、リウマチ治療剤、自
己免疫疾患治療剤、虚血性臓器障害治療剤、薬物中毒治
療剤又は動脈硬化治療剤。(8) Claims (1), (2), (3), (4), (5), (
6) or (7), the radioprotective agent, anti-inflammatory agent, rheumatism treatment agent, autoimmune disease treatment agent, ischemic organ damage treatment agent, drug addiction treatment agent, or arteriosclerosis treatment agent. [Amino acid sequence 1] (N-terminus) [Gene sequence available] (C-terminus) (9)
Claim (1) wherein the human ADF is produced by Escherichia coli.
), (2), (3), (4), (5), (6) or (7
) radioprotective agent, anti-inflammatory agent, rheumatism therapeutic agent, autoimmune disease therapeutic agent, ischemic organ damage therapeutic agent, drug addiction therapeutic agent or arteriosclerosis therapeutic agent.
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JP26026090A JP3409118B2 (en) | 1989-09-29 | 1990-09-28 | Pharmaceutical composition containing human ADF |
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JP25636989 | 1989-09-29 | ||
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JP (1) | JP3409118B2 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2002179588A (en) * | 2000-10-05 | 2002-06-26 | Jiyunji Yodoi | Inflammation prophylactic or therapeutic agent comprising polypeptide belonging to thioredoxin family |
WO2006090849A1 (en) * | 2005-02-25 | 2006-08-31 | Redox Bioscience Inc. | Preventive or remedy for inflammatory ocular surface diseases |
WO2007138961A1 (en) * | 2006-05-29 | 2007-12-06 | Redox Bioscience Inc. | Prophylactic or therapeutic agent for disorder induced by macrophage migration inhibitory factor |
-
1990
- 1990-09-28 JP JP26026090A patent/JP3409118B2/en not_active Expired - Fee Related
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2002179588A (en) * | 2000-10-05 | 2002-06-26 | Jiyunji Yodoi | Inflammation prophylactic or therapeutic agent comprising polypeptide belonging to thioredoxin family |
WO2006090849A1 (en) * | 2005-02-25 | 2006-08-31 | Redox Bioscience Inc. | Preventive or remedy for inflammatory ocular surface diseases |
JP2012167121A (en) * | 2005-02-25 | 2012-09-06 | Redox Bioscience Inc | Preventive or therapeutic agent for inflammatory ocular-surface disease |
JP5043644B2 (en) * | 2005-02-25 | 2012-10-10 | レドックス・バイオサイエンス株式会社 | Preventive or therapeutic agent for inflammatory ocular surface disease |
WO2007138961A1 (en) * | 2006-05-29 | 2007-12-06 | Redox Bioscience Inc. | Prophylactic or therapeutic agent for disorder induced by macrophage migration inhibitory factor |
US8440413B2 (en) | 2006-05-29 | 2013-05-14 | Redox Bioscience, Inc. | Method of screening for a substance that strengthens a bond between thioredoxin and macrophage migration inhibition factor |
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JP3409118B2 (en) | 2003-05-26 |
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