JP2008520216A - 遺伝毒性を判定するための方法 - Google Patents
遺伝毒性を判定するための方法 Download PDFInfo
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Abstract
Description
別段の定めが無い限り、明細書および特許請求の範囲を含む本出願において使用される以下の用語は、以下に示す定義を有する。明細書および添付の特許請求の範囲において使用される場合、単数形「1つの(a)」、「1つの(an)」、および「その(the)」は、文脈が明らかに他の意味を規定するのでは無い限り、複数の指示対象を含むことに留意しなければならない。
本発明は、化合物の遺伝毒性を検出するための方法を提供する。本質的に、さらに分化することができる試験細胞が提供される。試験細胞を試験化合物または試験試料に接触させ、かつ試験化合物または試験試料が試験細胞と相互に作用するのに十分な期間、インキュベートする。次いで、試験細胞を誘導して分化させ、かつ1種または複数種の指標遺伝子の発現レベルの変化を測定する。
以下の調製法および実施例は、当業者がより明確に本発明を理解し、かつ実施することを可能にするために与えられる。これらは、本発明の範囲を限定するものとしてみなされるべきではなく、単に本発明を例示し、代表するものとしてみなされるべきである。
薬物製剤
すべての化合物は、Sigma-Aldrich Fine Chemicalsから購入した。MeOHに溶解したピレンを除いて、これらの薬物をDMSOに溶解した。遺伝毒性試験のために使用する各薬物の濃度は、インビトロで小核形成を誘導することが公知である濃度に基づいた。この濃度が公知ではなかった場合は、1nM〜5mMの範囲の広範な薬物濃度を試験した。遺伝毒性物質および非遺伝毒性物質の両方に関して、試験する最高濃度は、細胞毒性または化合物溶解度(表1)のいずれかによって決定した。
20%FBS、ピルビン酸ナトリウム、ペニシリン-ストレプトマイシン-グルタミンを含むDMEM中でC2C12細胞(ATCC)を増殖させ、コンフルエントに近い状態を維持した。P.L.Puri et al., Nature Gen(2002)32:585-93によって説明された方法に従って、1% DMSOまたは最終濃度1% DMSO中化合物(化合物および濃度については表Iを参照されたい)をさらに含む増殖培地中で、分化アッセイ法を実施した。これらの細胞を24時間インキュベートし、PBSで洗浄し、かつ、薬物もビヒクルも含まない、分化培地(DMEM、2%ウマ血清、ピルビン酸ナトリウム、およびペニシリン-ストレプトマイシ-グルタミン)中に入れた。48時間目および72時間目に、細胞の分化を視覚的に検査した。分化した細胞は筋管を形成するのに対し、阻止または遅延された細胞は、単層を維持し、筋管はほとんどない。阻止が極端である場合には、これらの細胞は3日後に分化培地中で死滅し始める(例えば、エトポシドまたはシスプラスチンによる処置)。化合物に24時間曝露した後の細胞数をビヒクルの場合と比べて評価することによって、薬物の細胞毒性を判定した。
遺伝子発現解析
溶媒(DMSO)または化合物(MMS-0.008μg/ml;MNNG-4μg/ml;シスプラスチン-0.6μg/ml;エトポシド-0.5μg/ml;ベロマイシン-0.5μg/ml;硫酸ビンクリスチン-0.6μg/ml)で24時間処理した後、C2C12細胞を洗浄して薬物を除去し、分化培地に変更して分化を誘導し、かつ誘導後6時間目、18時間目または24時間目に採取した。各薬物および時点に対して、3つの独立なレプリケートを作製した。試料の処理は、Affymetrix Expression Analysis Technical Manualにおいて説明されているプロトコールに従って実施した。手短に言えば、酸グアニジウムチオシアナート-フェノール-クロロホルム抽出法(Trizol(登録商標)、Invitrogen, Carlsbad, CA)によって細胞から全RNAを単離した。2回精製したpoly(A+)RNAを単離し、かつT7-プロモーターを結合したオリゴ(dT)プライマーを用いて逆転写し、続いてインビトロ転写を実施した。標識した試料をAffymetrix Murine Genome MOE430セットに添加し、かつ45℃/60 rpmで一晩ハイブリダイズさせ、FS450 Fluidics stationを用いて洗浄し、かつGS3000スキャナー上でスキャンした。Affymetrixソフトウェア(Microarray Analysis Suite 5.0バージョン)を用いて、得られた画像ファイルを解析した。
このインビトロの分化系における遺伝子のサブセットの発現変化は、DNA損傷の全般的な指標を提供し得る。したがって、直接作用性遺伝毒性物質のすべてに曝露された後にその発現が著しく増大する2種の遺伝子に対するRT-PCRアッセイ法を開発した。1つは機能が未知である新規の遺伝子、4833427G06Rikであった。もう一方は、Dda3、すなわち、その発現がp53およびp73の両方に応答性であることが示されており(P.K. Lo et al., Oncogene(1999)18:7765-74)、かつ過剰発現された場合は細胞増殖を抑制する遺伝子(S. C. Hsieh et al., Oncogene(2002)21:3050-57)であった。RT-PCRアッセイ法を用いて、12種の遺伝毒性物質(アクチノマイシンD(ACTD)、ジエチルスチルベストロール(DES)、ドキソルビシンHCl(DOX)、メタンスルホン酸エチルエステル(EMS)、硫酸ブレオマイシン(BLEO)、シスプラスチン(CIS)、エトポシド(ETOP)、メタンスルホン酸メチルエステル(MMS)、1-メチル-3-ニトロ-ニトロソグアニジン(MNG)、硫酸ビンクリスチン(VINC)、硫酸ビンブラスチン(VINB)、およびパクリタキセル(PACL))、ならびに9種の非遺伝毒性化合物(ジメチルスルホキシド(DMSO)、セフォペラゾンナトリウム(CER)、ファモチジン(FAM)、ピロカルピン HCl(PILO)、マレイン酸チモロール(TIM)、酢酸ベンジル(BA)、クロフィブラート(CLOF)、メサラミン(MES)、メチル尿素(MU)、およびフタル酸酸ジエステル(PTD))に曝露後のC2C12細胞から調製されたmRNAを解析した。細胞を各薬物に24時間曝露させた後、それらを誘導して18時間分化させてから、RNAを調製した。
Dog1(4833427G06Rik)に対する以下のsiRNAを、SMARTPOOL(Dharmacon)を用いて設計し;
Dog1-2は、以下の配列のプールである。
またはSTEALTH(Invitrogen)アルゴリズムを用いて設計した。
対照のsiRNAは、Dharmaconから入手した。
対照-1;CCCUAUUCUCCUUCUUCGCTT(ホタルルシフェラーゼ対照)(SEQ ID NO:31)
対照-2:RISCの無い登録配列(proprietary sequence)
Claims (7)
- (a)試験生細胞を試験化合物に接触させる段階と;
(b)Prelp(末端にプロリンとアルギニンを多く含むロイシンリッチリピート);Sesn2(セストリン2);4833427G06 Rik(RIKEN cDNA);Dda3(ディファレンシャルディスプレイ、およびp53により活性化される);Usp30(ユビキチン特異的プロテアーゼ30);0610013D04 Rik(RIKEN cDNA);Slc19a2(溶質運搬体ファミリー19(チアミントランスポーター)、メンバー2);Trp53inp1(形質転換関連タンパク質53、誘導性核タンパク質1);D4Ertd421e(DNAセグメント、Chr4、ERATO Doi 421、発現される);Shcbp1(Shc SH2-ドメイン結合タンパク質1);Mki67(Mab Ki67によって特定される抗原);Phex(リン酸を調節する中性エンドペプチダーゼ(X染色体));Tk1(チミジンキナーゼ1);Mmhead(ハツカネズミ(Mus musculus)15日胚頭部cDNAクローン);Osbpl6(オキシステロール結合タンパク質様6);Mphosph1(M期リンタンパク質);Ephx1(エポキシド加水分解酵素1(ミクロソームの生体異物加水分解酵素));Top2a(トポイソメラーゼ(DNA)IIα);Ccng1(サイクリンG1);Plf(プロリフェリン);Np95(核タンパク質95);Rad51ap1(RAD51関連タンパク質1);Nos3(一酸化窒素合成酵素3、内皮細胞);2610005B21 Rik(RIKEN cDNA);Brca1(乳癌1);Stk18(セリン/トレオニンキナーゼ18);Calmbp1(カルモジュリン結合タンパク質1);Lek1(ロイシン、グルタミン酸、リジンファミリー1タンパク質);Smc2l1(SMC2 染色体構造維持2様1);E2f7(E2F転写因子7);Hmmr(ヒアルロナンを介した運動性の受容体(RHAMM));Nusap1(核小体および紡錘体関連タンパク質1);Fbxo5(fボックスのみのタンパク質31);Slc19a2(溶質運搬体ファミリー19(チアミントランスポーター)、メンバー2);9030617O03 Rik(RIKEN cDNA);Ly6e(リンパ球抗原6複合体、遺伝子座E);6530401L14 Rik(RIKEN cDNA);Mad3(Max二量体化タンパク質3);Hmgb2(高移動度群ボックス2);Kif11(キネシン11);Mad2l1(MAD2(有糸分裂停止不完全、相同体)様1(酵母));Asf1b(ASF1抗サイレンシング機能1相同体B(サッカロミセス(Saccharomyces));Mcm3(ミニ染色体維持欠損3(サッカロミセス));MGC:32192(ハツカネズミcDNAクローン MGC:32192 IMAGE:5006129);Foxm1(フォークヘッドボックスM1);Anxa8(アネキシンA8);Slc35a5(溶質運搬体ファミリー35、メンバーA5);E030024M05 Rik(RIKEN cDNA);Cks2(CDC28タンパク質キナーゼ調節サブユニット2);Cilp(軟骨中間層タンパク質);Tacc3(コイルドコイルを含む形質転換酸性タンパク質3);Prc1(細胞質分裂のタンパク質調節因子1);2610509G12 Rik(RIKEN cDNA);2810417H13 Rik(RIKEN cDNA);Pbk(PDZ結合キナーゼ);Capn6(カルパイン6);Gmnn(ジェミニン);Mcmd4(ミニ染色体維持欠損4相同体);Ccna2(サイクリンA2);Pola1(DNAポリメラーゼα1、180kDa);Hmgb3(高移動度群ボックス3);Tagln(トランスゲリン(平滑筋22タンパク質));1600013K19 Rik(RIKEN cDNA);Serpine1(Ser(またはCys)プロテイナーゼインヒビター、クレードE、メンバー1);Wig1(野生型p53に誘導される遺伝子1);Hgf(肝細胞増殖因子(分散因子);Gnpi(グルコサミン-6-リン酸デアミナーゼ);Birc5(バキュロウイルスIAPリピート含有5);Prim1(DNAプライマーゼ、p49サブユニット);Rbl1(網膜芽細胞腫様1(p107));Pcna(増殖細胞核抗原);E130315B21 Rik(RIKEN cDNA);2610019I03 RIK(RIKEN cDNA)からなる群より選択される指標遺伝子の発現レベルの変化を測定する段階を含む、試験化合物の遺伝毒性を判定するための方法であって、
少なくとも1.5倍の発現の増大により、該試験化合物が遺伝毒性を示すことが示される方法。 - 指標遺伝子が、4833427G06RikおよびDda3からなる群より選択される、請求項1記載の方法。
- 試験細胞が筋芽細胞を含む、請求項1または2記載の方法。
- 試験細胞が、マウス、ラット、ゼブラフィッシュ、ヒト、チンパンジー、およびニワトリの芽細胞より選択される、請求項1または2記載の方法。
- 発現レベルの変化を測定する段階が、RT-PCRを用いて、産生されたmRNAの量を測定する段階を含む、請求項1〜4のいずれか一項記載の方法。
- 発現レベルの変化を測定する段階が、標識の発現の増大によって生成されるシグナルの増大を測定する段階を含む、請求項1〜4のいずれか一項記載の方法。
- 上記に記載した方法、キット、ポリヌクレオチド、ポリペプチド、マイクロアレイ、抗体、またはトランスジェニック非ヒト哺乳動物。
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US20090181415A1 (en) * | 2007-12-20 | 2009-07-16 | Hans Marcus Ludwig Bitter | Prediction of genotoxicity |
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EP2199794A1 (en) | 2008-12-17 | 2010-06-23 | Universiteit Maastricht | Method for the identification of carcinogenic compounds |
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