JP2010514426A - ヘパトポイエチン及びその使用 - Google Patents
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- C—CHEMISTRY; METALLURGY
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Abstract
【選択図】図1
Description
DEAEセルロース、ソース(Source)15Qなどのクロマトグラフィー;SDS−PAGEリカバリー;並びにMALDY−TOF及びQ−TOF質量分析により、タンパク因子であるヘパトポイエチンPCn(HPPCn)を新生児の仔ウシの肝臓から精製して識別した。ヒト胎児肝臓cDNAライブラリーのスクリーニングにより、ヒトHPPCnのcDNA配列を得た。BamH I及びXho1 I制限酵素認識部位を遺伝子配列の両端に付けて、次に配列を原核生物発現ベクターPET−24a中に組込み、プラスミドPET−24a−HPPCnを得た。IPTG誘導によって、プラスミドを大腸菌(E. coli)に変えて、発現させた。イオン交換及びゲルろ過により、95%を超える純度を有する組換え型タンパク質を得た。タンパク質のアミノ酸配列を図1に示し、タンパク質の電気泳動図を図2に示す。
肝細胞増殖を促進するHPPCnの活性を 3 H−TdR DNA組込み試験によって検出した。ラットの初代培養肝細胞を、in vitroでの生物活性の検出における対象細胞として使用した。100μLの細胞懸濁液(5×104cells/mL)を96ウェルのプレート上に添加して、6時間培養した。次に様々な濃度のHPPCnを加え、さらに24時間培養した。1.85×104Bqの3H−TdRを各ウェルに加え、3時間後に、液体シンチレーション計測を行なった。結果は、HPPCnが、肝細胞のDNA合成を著しく用量依存的な態様で促進できることを示した(表1)。肝再生(ALR)の他の増強因子は、HPPCnのこの特性を有しない。
組換え型タンパク質HPPCnが34%肝切除マウスの肝臓のDNA合成に及ぼす影響を検出することによって、組換え型タンパク質HPPCnが部分肝切除マウスに及ぼす保護作用を決定した。良好な健康状態のオスのC57マウスに、肝臓の中葉の外科的切除を受けさせた。2.5mgHPPCn/kg体重又は等体積の生理食塩水を異なる時点で肝切除マウスの尾静脈中に注射した。18時間の治療後、20μCi3H−TdRを腹腔内に注射した。2時間の組込み後、動物を犠牲にして、肝臓のゲノムDNAを抽出した。液体シンチレーション計測で3H−TdRの組込み量を決定した。結果は、治療群の3H−TdRの組込み量が、各時点で生理食塩水対照群のものより高いことを示し(表2)、HPPCnが、切除された肝臓の再生能力を強化できることを示唆した。
40匹のウィスター(Wistar)系ラットでは、エタノール及びCCl4を用いる合成法により肝線維症モデルを製造した。4週間後、ラットをランダムに4つの群に分けた:対照群、高用量群、中用量群、及び低用量群である。腹腔内投与を毎日行なった。8週間で、動物を犠牲にした。血液サンプルを採取し、血中のALT、ASTなどの生化学的指標の濃度を決定した。肝臓を取り出し、肝臓の外観の変化を観測し、ヒドロキシプロリン及びマロンアルデヒドの含有量を決定し、組織病理学検査を行なった。対照群と比較したときに、治療群は、アスパラギン酸アミノトランスフェラーゼ(AST)及びアラニンアミノトランスフェラーゼ(ALT)の濃度が減少し、ヒドロキシプロリン(Hyp)の含有量が著しく減少することを示す一方で、マロンアルデヒド(MDA)の含有量には目立った変化がないことが、結果から分かった(表4)。対照群のラットの肝臓は、灰黄色を示し、顆粒状の非平滑面を有したが、治療群のラットの肝臓は比較的赤かった。肝組織のHE染色及びマッソン・トリクローム(Masson’s trichrome)染色の結果は、対照群のラットの肝臓では、細胞壊死及び脂質沈着が起きて、線維性組織が増殖し、偽小葉が形成されたが;治療群では、特に中用量群では、線維性組織の増殖が著しく減少し、肝細胞壊死が減少したことを示す。これは、組換え型タンパク質HPPCnの投与が、慢性肝臓損傷による肝線維症を軽減できることを示唆する。
HPPCnを真核性発現ベクター、プラスミドpEGFP−N1中に組込み、それを使用してヒト肝臓癌SMMC7721細胞株にトランスフェクトした。36時間の培養後、4%パラホルムアルデヒド及び70%エタノールで、それぞれに、細胞を固定化した。PI染色後、細胞周期の変化をFACSにより検出した。結果は、トランスフェクトされた肝臓癌細胞には明白なG0/G1期の停止があり、トランスフェクトされた肝臓癌細胞の中でもG2/M期の細胞の比率が、何も組み込まれていないプラスミドをトランスフェクトされた群(pEGFP−N1をトランスフェクトされた群)のものより著しく低いことを示した(表5)。これは、細胞内のHPPCnの過剰発現が、肝臓癌細胞の増殖を著しく阻害できることを示唆する。
Claims (6)
- 配列番号1で示される配列、又は配列番号1と少なくとも80%、好ましくは、85%、90%若しくは95%の相同性を有する配列を含む、ヘパトポイエチンPCn(HPPCn)タンパク質。
- その配列が配列番号:1で示される、請求項1に記載のHPPCnタンパク質。
- 請求項1又は2に記載のHPPCnタンパク質をコードしている、核酸分子。
- 請求項1若しくは2に記載のHPPCnタンパク質又は請求項3に記載の核酸分子を含む、医薬組成物。
- 肝細胞増殖及び肝再生を促進し、様々な原因による肝臓損傷を治療し、腫瘍細胞の増殖を阻害し、様々な腫瘍を治療し、又は肝線維症を治療するのに使われる薬剤を調製するための、請求項1若しくは2に記載のHPPCnタンパク質又は請求項3に記載の核酸分子の使用。
- 前記薬剤が急性又は慢性肝臓損傷を治療するのに使われる、請求項5に記載の使用。
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CN200610156298.0 | 2006-12-26 | ||
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PCT/CN2007/003722 WO2008077311A1 (en) | 2006-12-26 | 2007-12-21 | Hepatopoietin and use thereof |
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US (1) | US8361795B2 (ja) |
EP (1) | EP2110384B1 (ja) |
JP (1) | JP5390397B2 (ja) |
CN (1) | CN101600733A (ja) |
WO (1) | WO2008077311A1 (ja) |
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JP2002536346A (ja) * | 1999-02-03 | 2002-10-29 | ザ・ジョーンズ・ホプキンス・ユニバーシティ | pp32の機能の回復により癌を治療する方法 |
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US5440022A (en) * | 1992-10-14 | 1995-08-08 | Panorama Research, Inc. | Hepatokine and methods for its use |
US5550037A (en) * | 1994-02-16 | 1996-08-27 | University Of Pittsburgh | Mammalian augmenter of liver regeneration (ALR): human and rat |
CN1896100B (zh) | 2005-06-01 | 2010-10-13 | 中国人民解放军军事医学科学院放射与辐射医学研究所 | 肝再生因子及其应用 |
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2007
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- 2007-12-21 EP EP07855737.8A patent/EP2110384B1/en active Active
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JP2002536346A (ja) * | 1999-02-03 | 2002-10-29 | ザ・ジョーンズ・ホプキンス・ユニバーシティ | pp32の機能の回復により癌を治療する方法 |
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JPN6012067014; Database DDBJ/EMBL/GenBank [online], Accession No.Q1AHP8 , 20061128 * |
JPN6012067016; World J Gastroenterol Vol.12, No.31, 20060821, p.4951-4958 * |
JPN6012067019; Hepatology Vol.47, No.3, 2008, p.986-995 * |
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JP5390397B2 (ja) | 2014-01-15 |
WO2008077311A1 (en) | 2008-07-03 |
US20100144628A1 (en) | 2010-06-10 |
US8361795B2 (en) | 2013-01-29 |
EP2110384A1 (en) | 2009-10-21 |
CN101600733A (zh) | 2009-12-09 |
EP2110384B1 (en) | 2016-07-06 |
EP2110384A4 (en) | 2010-10-13 |
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