JP2021185210A - 抗癌療法としての正常細胞および腫瘍細胞の小分子trail遺伝子誘導 - Google Patents
抗癌療法としての正常細胞および腫瘍細胞の小分子trail遺伝子誘導 Download PDFInfo
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Abstract
Description
本願は、2011年4月29日に出願された米国仮特許出願第61/480,743号の優先権を主張し、この米国仮特許出願の全体の内容は、本明細書中に参考として援用される。
本願は、国立衛生研究所により授与された助成金番号U54CA105008の下、政府支援により成された。合衆国政府は本発明に一定の権利を有する。
本発明は、概して、癌などの増殖性疾患の処置を必要とする被験体においてそのような疾患を処置するための方法および組成物に関する。
TNF関連アポトーシス誘導リガンド(TRAIL;Apo2L)は、癌細胞のアポトーシスを選択的に誘導する内因性タンパク質である。
本発明の態様によると、本明細書中でTIC10とも呼ばれる
、その薬学的に許容され得る誘導体、塩、エステル、アミド、水和物、溶媒和物および/またはプロドラッグ;ならびに薬学的に許容され得るキャリアを含む薬学的組成物が提供される。その組成物は、疾患の処置を必要とする被験体(ヒト被験体ならびに他の種の被験体を含む)においてそのような疾患を処置する際の有用性を有する。その組成物は、癌の処置を必要とする被験体(ヒト被験体ならびに他の種の被験体を含む)において癌を処置する際の有用性を有する。
本発明の好ましい実施形態において、例えば以下の項目が提供される。
(項目1)
、その薬学的に許容され得る誘導体、塩、エステル、アミド、水和物、溶媒和物および/またはプロドラッグ;ならびに薬学的に許容され得るキャリアを含む薬学的組成物。
(項目2)
第2の治療薬をさらに含む、項目1に記載の薬学的組成物。
(項目3)
前記第2の治療薬が、抗癌剤である、項目2に記載の薬学的組成物。
(項目4)
前記抗癌剤が、有糸分裂抑制剤である、項目3に記載の薬学的組成物。
(項目5)
前記抗癌剤が、パクリタキセル、ドセタキセルおよびそれらの組み合わせからなる群から選択される、項目3に記載の薬学的組成物。
(項目6)
前記第2の治療薬が、抗血管新生剤である、項目2に記載の薬学的組成物。
(項目7)
前記抗血管新生剤が、ベバシズマブである、項目6に記載の薬学的組成物。
(項目8)
経口投与用に製剤化されたものである、項目1に記載の薬学的組成物。
(項目9)
処置を必要とする被験体を処置する方法であって、
薬学的に有効な量の
、その薬学的に許容され得る誘導体、塩、エステル、アミド、水和物、溶媒和物および/またはプロドラッグ;ならびに薬学的に許容され得るキャリアの投与を包含する、方法。(項目10)
前記被験体から得られたサンプル中のTNF関連アポトーシス誘導リガンドをアッセイする工程をさらに包含する、項目9に記載の方法。
(項目11)
前記被験体が、癌を有するかまたは有するリスクがある、項目9に記載の方法。
(項目12)
追加の抗癌剤の投与をさらに包含する、項目11に記載の方法。
(項目13)
前記追加の抗癌剤が、抗有糸分裂剤である、項目12に記載の方法。
(項目14)
前記追加の抗癌剤が、パクリタキセル、ドセタキセル、ベバシズマブまたはそれらの任意の2つ以上である、項目12に記載の方法。
(項目15)
前記被験体から得られた血液サンプルにおいて、増加したTNF関連アポトーシス誘導リガンドがアッセイされる、項目10に記載の方法。
(項目16)
前記投与が、経口投与である、項目9に記載の方法。
(項目17)
前記投与が、直腸、鼻、肺、硬膜外、眼球、耳、動脈内、心臓内、脳室内、皮内、静脈内、筋肉内、腹腔内、骨内、髄腔内、膀胱内、皮下、局所的、経皮的、経粘膜的、舌下、頬側、膣および吸入の投与経路からなる群から選択される、項目6に記載の方法。
(項目18)
脳腫瘍を有するかまたは有するリスクがある被験体を処置する方法であって、
薬学的に有効な量の
、その薬学的に許容され得る誘導体、塩、エステル、アミド、水和物、溶媒和物および/またはプロドラッグ;ならびに薬学的に許容され得るキャリアの投与を包含する、方法。(項目19)
処置を必要とする被験体を処置する方法であって、
薬学的に有効な量の
、その薬学的に許容され得る塩、エステル、アミド、水和物または溶媒和物;および薬学的に許容され得るキャリアの投与を包含する、方法。
(項目20)
癌を処置するための医薬を製造するための、
、その薬学的に許容され得る誘導体、塩、エステル、アミド、水和物、溶媒和物および/またはプロドラッグの使用。
(項目21)
癌を処置するための化合物
、その薬学的に許容され得る誘導体、塩、エステル、アミド、水和物、溶媒和物および/またはプロドラッグ。
(項目22)
実質的に本明細書中に記載されるような薬学的組成物。
(項目23)
実質的に本明細書中に記載されるような処置方法。
本明細書中で使用される科学用語および専門用語は、当業者が通常理解している意味を有すると意図されている。そのような用語は、様々な標準的な参考文献中の文脈において定義され、使用されていると見出されており、そのような参考文献としては、例証的には、J.Sambrook and D.W.Russell,Molecular Cloning:A Laboratory Manual,Cold Spring Harbor Laboratory Press;3rd Ed.,2001;F.M.Ausubel,Ed.,Short Protocols in Molecular Biology,Current Protocols;5th Ed.,2002;B.Albertsら、Molecular Biology of the Cell,4th Ed.,Garland,2002;D.L.Nelson and M.M.Cox,Lehninger Principles of Biochemistry,4th Ed.,W.H.Freeman & Company,2004;Engelke,D.R.,RNA Interference(RNAi):Nuts and
Bolts of RNAi Technology,DNA Press LLC,Eagleville,PA,2003;Herdewijn,P.(Ed.),Oligonucleotide Synthesis:Methods and Applications,Methods in Molecular Biology,Humana Press,2004;A.Nagy,M.Gertsenstein,K.Vintersten,R.Behringer,Manipulating the Mouse Embryo:A Laboratory Manual,3rd edition,Cold Spring Harbor Laboratory Press;December 15,2002,ISBN−10:0879695919;Kursad Turksen(Ed.),Embryonic stem cells:methods and protocols in Methods Mol Biol.2002;185,Humana Press;Current Protocols in Stem Cell Biology,ISBN:9780470151808が挙げられる。
in drug and prodrug metabolism:chemistry,biochemistry,and enzymology,Wiley−VCH,Zurich,2003において例証されているように当該分野で周知である。
Laboratory Manual,Cold Spring Harbor Laboratory Press,1988;F.Breitling and S.Duebel,Recombinant Antibodies,John Wiley &
Sons,New York,1999;H.Zola,Monoclonal Antibodies:Preparation and Use of Monoclonal Antibodies and Engineered Antibody Derivatives,Basics:From Background to Bench,BIOS Scientific Publishers,2000;B.K.C.Lo,Antibody Engineering:Methods and Protocols,Methods in Molecular Biology,Humana Press,2003;F.M.Ausubelら、Eds.,Short Protocols in Molecular Biology,Current Protocols,Wiley,2002;S.Klussman,Ed.,The Aptamer Handbook:Functional Oligonucleotides
and Their Applications,Wiley,2006;Ormerod,M.G.,Flow Cytometry:a practical approach,Oxford University Press,2000;Givan,A.L.,Flow Cytometry:first principles,Wiley,New York,2001;Gorczyca,W.,Flow Cytometry in Neoplastic Hematology:morphologic−immunophenotypic correlation,Taylor & Francis,2006;Crowther,J.R.,The ELISA Guidebook(Methods in Molecular Biology),Humana Press,2000;Wild,D.,The Immunoassay Handbook,3rd Edition,Elsevier Science,2005およびJ.Sambrook and D.W.Russell,Molecular Cloning:A Laboratory Manual,Cold Spring Harbor Laboratory Press,3rd Ed.,2001が挙げられる。
Their Applications,Wiley,2006;およびJ.Sambrook and D.W.Russell,Molecular Cloning:A
Laboratory Manual,Cold Spring Harbor Laboratory Press,3rd Ed.,2001に記載されているように当該分野で公知である。
in Biology and Medicine,Humana Press,2000;およびD.M.Desiderio,Mass Spectrometry of
Peptides,CRC Press,1990に見られる。
Practice of Pharmacy,Lippincott Williams & Wilkins,21st ed.,2005、特に、chapter 89;およびJ.G.Hardmanら、Goodman & Gilman’s The Pharmacological Basis of Therapeutics,McGraw−Hill Professional,10th ed.,2001に詳述されているように当該分野で周知である。
York,1981)に見られる場合がある。
Bert Vogelstein(Johns Hopkins University,Baltimore,MA)から入手したHCT116 Bax−/−およびHCT116 p53−/−細胞ならびにAkiva Mintz(Wake Forrest
University,Winston−Salem,NC)から入手したGBM細胞株を除くすべての細胞株をATCCから入手した。TRAIL shRNAまたはベクターを使用してMDA−MB−231細胞を用いて、およびSigma−Aldrich(St.Louis,MO)から購入したFoxo3a shRNAまたはベクターを使用してHCT116を用いて、レンチウイルス感染を行った。デスドメインを含まないDR5フラグメントをコードするcDNAを使用して、DR5(1〜298)融合タンパク質を発現するpEGFP−N1ベクターにヒトDR5遺伝子のアミノ酸1〜298を挿入することによってH460 DR5ΔDD−EGFP細胞を構築した。その融合構築物を、Lipofectamine2000(Invitrogen)を用いてH460細胞にトランスフェクトし、G418を用いて選択した。蛍光(florescence)顕微鏡観察およびウエスタンブロット解析によって、陽性クローンを確かめた。NCI多様性セットIIを使用する生物発光ハイスループットスクリーニングを、ヒトTRAIL遺伝子の転写開始の上流のTRAILプロモーターの最初の504塩基対の転写調節下でホタルルシフェラーゼ構築物を発現するように安定的にコトランスフェクトしたHCT116
Bax−/−細胞において行った。20nM、200nM、500nMおよび1μMという作用濃度において化合物を試験し、処置の12、24、36および48時間後に転写活性の生物発光評価を行った。このスクリーニングの方法の詳細は、Wangら、2006,PNAS 103:11003−11008)に記載されている。TIC10(NSC350625)を、NCI DTPから入手し、DMSOにおいて20mMで再構成し、等分し、−20℃で保管した。A6730およびU0126モノエタノレートをSigmaから入手した。精製された組換えTRAILを、Kimら、2004,J.of Biol.Chem.279:40044−40052に記載されているように作製した。RIK−2抗体(Santa−Cruz Biotechnology)を1μg/mLで使用し、zVAD−fmk(Promega)を20μMで使用した。
ヒト患者からのすべての1次検体は、本明細書中に記載される実施例において使用するために、摘出の直後に受け取り、手作業にてコンプリートDMEM中で消化し、100μmナイロンメッシュで濾過し、コンプリートDMEMにおいて2×105細胞/mLでプレーティングした。
皮下異種移植の場合、4〜6週齢の雌の無胸腺nu/nuマウス(Charles River Laboratories)の各背面側腹部に1×106個(T98Gの場合2.5×106個)の表示の細胞株を1:1 Matrigel(BD):PBSの200μLの懸濁液として接種した。すべての腹腔内および静脈内注射を、200μLという総体積において行った。TIC10の経口製剤を、経口胃管栄養法を用いて投与し、20%Cremophor EL(登録商標)(Sigma)、10%DMSOおよび70%PBSを含む200μLの懸濁液として投与した。表示の時点においてデジタルノギスを使用して腫瘍をモニターした。すべての皮下腫瘍が、注射後1〜4週間、処置開始前に約125mm3の体積に達するまで確立された。腫瘍組織量の軽減を、腫瘍消失後3週間にわたってモニターし、安楽死後に目視検査によって確認した。
製造者の指示書に従うことによってRNeasy Minikit(Qiagen)を使用して、全RNAを抽出した。SuperScript II(Invitrogen)を1μgのRNAおよびoligodTとともに使用して、cDNAを生成した。プライマーは、TRAIL順方向(CAGAGGAAGAAGCAACACATT、配列番号1)、TRAIL逆方向(GGTTGATGATTCCCAGGAGTTTATTTTG、配列番号2)、GAPDH順方向(CCACATCGCTCAGACACCAT、配列番号3)、GAPDH逆方向(GGCAACAATATCCACTTTACCAGAGT、配列番号4)だった。Applied Biosystems 7900HT Fast Real−time Detection Systemを用いてPCR増幅を行った。サンプルを10ng/μlに標準化し、次いで、1サンプルあたり20ngのcDNAを、SYBR Green Master Mix(Qiagen Corp,USA)を使用するリアルタイムPCR用の鋳型として使用した。サンプルを、同一条件下で使用したGAPDHに対して正規化した。定量は、正規化用の内因性コントロールとしてのGAPDHと、Livakら、2001,Methods.2001 Dec;25(4):402−8に記載されている閾値を交差させる2ΔΔCt法を用いた。10μlの反応体積を用いて、7900HT機器(Applied Biosystems)において384ウェル光学プレートにおいて反応を行った。データ解析は、ABI PRISM 7900 Sequence Detection System2.2ソフトウェアを使用した。ゲノムDNAの混入の可能性を排除するために、各遺伝子特異的プライマーセットに対して、cDNA鋳型を含まないおよびRTを含まないコントロールサンプルを用いたコントロールPCR反応も行った。各PCR反応の四つ組を行い、得られたデータを平均した。
表示の細胞株を、72時間にわたって、表示の作用濃度のTIC10の非存在下の存在下の6ウェルプレートにおいて対数期の成長において増殖させた。細胞を固定し、Cytofix/Cytoperm溶液(BD Biosciences,San Jose,CA)溶液を使用して透過処理した。細胞を、Perm/Wash溶液(BD Biosciences)中において、1:100で抗TRAIL(ab2435,Abcam,Cambridge,MA)とともに、または1:250で抗活性カスパーゼ−3(559565,BD Pharmingen,San Diego,CA)とともに、光の非存在下において1時間インキュベートした。抗ウサギAlexa Fluor488を、Perm/Wash溶液中にて20分間、室温において1:200でインキュベートし、PBSですすいだ。Hoechst33342(Invitrogen)を、製造者のプロトコルに従って核対比染色として使用した。iVisionイメージングシステム(Biovision)を使用してAxiovert倒立顕微鏡(Carl Zeiss MicroImaging)において蛍光イメージングを行った。
すべてのフローサイトメトリー解析のために、浮遊細胞および接着細胞をCoulter−Beckman Elite Epics血球計算器において解析した。表面TRAIL実験のために、接着細胞を、短時間のトリプシン処理によって回収し、PBS中の4%パラホルムアルデヒドにおいて20分間固定し、抗TRAIL抗体とともに2時間(Abcam)インキュベートし、洗浄し、抗ウサギAlexafluor488(Invitrogen)とともに30分間インキュベートし、解析した。細胞に対して前方散乱および側方散乱のゲーティングを行うことにより、残骸および死細胞を解析から除外した。表面TRAILデータは、別段示されない限り、コントロールサンプルに対する蛍光強度の中央値として表される。Sub−G1および細胞周期プロファイル実験のために、すべての細胞をペレットにし、エタノール固定した後、RNAseの存在下においてヨウ化プロピジウム(Sigma)で染色した。CellTiter−Glo(登録商標)(Promega)を製造者のプロトコルに従って使用して、96ウェル黒壁透明底プレートにおいて、細胞生死判別アッセイを行った。これらのアッセイのイメージングおよび定量をIVISイメージングシステム(Xenogen)において行った。
表示の細胞株を、1ウェルあたり500個の細胞でプレーティングし、翌日、接着後に、新鮮完全培地で処理した。処理の3日後、その培地を、薬物を含まない培地に置き換え、3日ごとに1回新鮮培地を与えて、細胞を10日間にわたって増殖させた。その10日間の終わりに、定量のために、細胞をPBSで洗浄し、メタノールで固定し、クマシーブルーで染色し、すすぎ、乾燥した。
Laboratories)を用いて、サンプルをブロッキングした。1次抗体を、湿度チャンバー内において4℃で一晩インキュベートした。ビオチン化2次抗体とのインキュベーションおよびDABの沈着を製造者のプロトコルに従って行った(Vector Laboratories DAB Substrate Kit for Peroxidase)。サンプルを、ヘマトキシリン(DAKO)で6分間対比染色し、dH2O中で5分間すすぎ、PBSですすぎ、脱水し、カバーガラスで密封した。QCaptureソフトウェア(QImaging)を使用してAxioskop顕微鏡において像を記録した。
HCT116 p53−/−およびHFF細胞の共培養を、コンプリートDMEMおよびMcCoy’s 5A培地の1:1混合物において行った。蛍光イメージのために、その2種類の細胞を、Fluorescent Cell Linkers Kits for gene cell membrane labeling(Sigma)を製造者のプロトコルに従って使用して別々に標識した。免疫蛍光法の項に記載したようにHoechst33342で細胞を対比染色した。細胞死のフローサイトメトリー解析のために、細胞の2つの集団を、光散乱の差異によって判別し、細胞死アッセイの項のsub−G1解析について記載したように解析した。
TRAILに対するELISAを、Quantikine(登録商標)TRAIL/TNFSF10キットを製造者のプロトコルに従って使用して行った(DTRL00,R&D systems,Minneapolis,MN)。540nmにおける吸光度を用いて、製造者が提案するように光学的補正を行った。DTX880プレートリーダー(Beckman Coulter)を用いて吸光度を測定した。
TIC10の吸光度プロファイルを、Gene Spec III分光計(Hitachi Solutions American,South San Francisco,CA)において測定した。Eclipse XDB−C18カラム(Agilent)および100μL注入ループを使用するAgilent1200シリーズシステム(Agilent,Santa Clara,CA)での239nmにおける吸光度検出によって、HPLC解析を行った。1mL/分におけるアイソクラティック溶出を、dH2O中の.1%トリフルオロ酢酸において行った。アセトニトリル(ACN)グラジエントを、溶出のために、0〜5分では15〜20%ACN、5〜12分では20〜23%、12〜18分では25%として行った。無関係な実験の無胸腺ヌードマウスから回収された血漿にある濃度のTIC10を添加することによって、検量線を作成した。すべての血漿サンプルについて、左心室の末端心臓穿刺によって血液を得て、EDTAチューブ(BD)に回収した。サンプルを500gで10分間遠心分離した。血漿を、30μLの過塩素酸を100μLのサンプルに加えることによって脱タンパクし、15秒間ボルテックスし、2分間遠心分離し、直ちに上清をHPLCに注入した。AUCを、8.1分の保持時間を有する内部血清ピークに対して正規化した。時間に対するAUCデータを、式AUC=Ae−αt+Be−βt(ここで、t=時間であり、AおよびBは、2つの相(分布および排泄)の開始時の外挿された濃度である)を使用する中心コンパートメントからの1次排泄を用いる2コンパートメントオープンモデルに適合させた。半減期をt1/2α=.693/αおよびt1/2β=.693/βとして計算した。計算のために使用される他の式としては、CL=用量/AUC0−∞およびVd=用量/(AUC0−∞×β)が挙げられる。
HCT116 p53−/−細胞を対数期において増殖させ、DMSOまたはTIC10(10μM)で処理した。48時間後、RNeasy Mini Kit(Qiagen)を使用してRNAを単離した。Illumina HT−12 Beadchip(Illumina)を使用してマイクロアレイ解析を行った。RNAの質および濃度を、RNA Nano LabChip(登録商標)(Agilent)とともにAgilent 2100 Bioanalyzerを使用して評価した。製造者の指示書に従ってTotalPrepTMAmplification(Ambion)によって500ngのRNAからcRNAを合成した。T7オリゴ(dT)をプライマーとする逆転写を用いて、第1鎖(first strand)cDNAを生成した。次いで、cDNAにおいて第2鎖合成ならびにDNAポリメラーゼおよびRNase HによるRNA分解を行った後、濾過精製を行った。インビトロ転写(IVT)を使用して、複数コピー数のビオチン化cRNAを生成した。標識されたcRNAを、濾過を使用して精製し、NanoDropによって定量し、合計750ng/サンプルとなるように体積を調整した。サンプルを断片化し、変性させた後、58℃で18時間ハイブリダイゼーションした。ハイブリダイゼーション後、ビーズチップを洗浄し、蛍光標識した。BeadArray Reader(Illumina)を用いてビーズチップをスキャンした。得られたスキャンデータをGenomeStudio1.0(Illumina)にインポートして、プロジェクトを作成した。結果をGeneSpring Gxll(Agilent Technologies)にエクスポートした。次いで、0.01未満の測定値を0.01に設定し、アレイを50番目のパーセンタイルに対して正規化し、個別の遺伝子をコントロールの中央値に対して正規化した。TIC10によって誘導される転写の変化のネットワーク解析のために、Ingenuity Pathway Analysisソフトウェア(Ingenuity Systems)を使用してデータセットを解析した。
NuPAGE4−12%Bis−Trisを使用して、Wang,W.ら、PNAS 103,11003−11008,2006に記載されているようにウエスタンブロット解析を行い、Supersignal West Femto(Thermo Scientific)およびX線フィルムを使用して可視化した。細胞質溶解緩衝液(10mM
HEPES、10mM KClおよび2mM MgCl2、1mM DTT)に続いて核溶解緩衝液(20mM HEPES、420mM NaCl、1.5mM MgCl2、250μM EDTA、25%グリセロール)を使用して、核および細胞質の抽出物を調製した。すべての溶解緩衝液について、新鮮なプロテアーゼ阻害剤(Roche)および1mMオルトバナジン酸ナトリウムを使用直前に加えた。
Nebbioso,A.ら、Nat Med,11(1),77−84,2005にTRAILプロモーターついて記載されているように、Foxo3aに対するChIPグレードの抗体(Abcam)または非特異的コントロールとして等濃度のウサギIgG(SouthernBiotech)を使用して、クロマチン免疫沈降(ChiP)アッセイを行った。
TRAIL遺伝子プロモーターを使用するTRAIL抵抗性BaxヌルHCT116ヒト結腸癌細胞において行われた細胞ベースの生物発光レポータースクリーニングによって、小分子TIC10がTRAIL誘導化合物として得られた。
TIC10は、等用量において正常な線維芽細胞の細胞周期プロファイルを変更せずに、TRAIL感受性HCT116 p53−/−細胞における細胞死を示唆するsub−G1のDNA含有量を誘導した。図6は、TIC10で処理されたHCT116 p53−/−およびHFF細胞の細胞周期プロファイルを示している(5μM、72時間、n=3)。
TIC10は、両方を複数回投与として投与したとき、TRAILを用いたときに観察されるものに匹敵する程度にHCT116 p53−/−異種移植片において腫瘍退縮を引き起こした。図19は、灰色の垂直バーで示されているように0、3および6日目に投与された3回のTIC10(i.p.)、TRAIL(i.v.)またはビヒクル(i.p.)で処理されたHCT116 p53−/−異種移植片を示しているグラフである(n=10)。エラーバーは、反復実験の標準偏差(s.d.)を示している。別段示されない限り、表示の条件とコントロールとの間において*P<0.05および**P<.005。
免疫適格性の前臨床癌モデルにおいてTIC10の有効性を試験するために、リンパ腫を自然に発症するΕμ−Mycトランスジェニックマウスを使用した。9〜12週齢において安全であると証明された上記と同じ経口投薬スケジュールを使用した。TIC10は、これらのマウスの生存期間を4週間、有意に延長した。図28は、第9〜12週の間に毎週、経口TIC10(25mg/kg)で処置されたΕμ−mycの全生存を示しているグラフである。P値は、ログランク検定によって決定された。相対的な腫瘍体積のプロットについては、腫瘍サイズは、処置開始日と定義される0日目の腫瘍サイズに対して表されている。14週齢におけるΕμ−mycおよびWT C57/B6の腋窩リンパ節のH&E染色による組織学的解析から、TIC10に明らかな毒性が無いことが示された。
驚いたことに(Syrprisingly)、TIC10とタキサン類のパクリタキセルおよびドセタキセル(商品名Taxotere)との間のインビトロ相乗作用が観察される。図29は、表示の条件においてパクリタキセルとともにTIC10で処理されたDLD−1細胞の細胞生存率を示しているグラフである(72時間、n=3)。エラーバーは、反復実験のs.d.を示している。図30は、表示の条件においてパクリタキセルとともにTIC10で処理されたSW620細胞の細胞生存率を示しているグラフである(72時間、n=3)。エラーバーは、反復実験のs.d.を示している。図31は、表示の条件においてタキソテールとともにTIC10で処理されたDLD−1細胞の細胞生存率を示しているグラフである(72時間、n=3)。エラーバーは、反復実験のs.d.を示している。図32は、表示の条件においてタキソテールとともにTIC10で処理されたSW620細胞の細胞生存率を示しているグラフである(72時間、n=3)。エラーバーは、反復実験のs.d.を示している。
0日目にTIC10を単回投与(100mg/kg、i.p.)した後のHCT116
p53−/−異種移植腫瘍の免疫組織化学的(IHC)解析から、TRAIL、およびTRAIL媒介性アポトーシスに関与するイニシエーターカスパーゼである切断型カスパーゼ−8のタンパク質レベルの上昇が明らかになった。
TIC10は、脳においてTRAILを誘導し、脳腫瘍に対する抗腫瘍剤として有用である。この実施例において、GBM細胞株におけるTIC10の活性を試験したところ、TIC10が、TRAILを誘導し、他の癌細胞株と同程度の低マイクロモル濃度の範囲のp53非依存的GI50を有することが見出された。図45は、TIC10とともにインキュベートした後のGBM細胞株における表面TRAILを示しているグラフである(5μM、72時間、n=3)。表示の条件とコントロールとの間において*P<0.05。図46は、TIC10またはDMSOによる処置の72時間後における表示のGBM細胞株の細胞生死判別アッセイから外挿されたGI50値を示しているグラフである(n=3)。
TIC10誘導性TRAILのアップレギュレーションはFoxo3a依存的である
TIC10誘導性TRAILのアップレギュレーションを支持する分子事象を特定するために、TIC10で処理されたHCT116 p53−/−細胞における遺伝子発現プロファイルを測定した。FOXOファミリーの転写因子(Modur,V.ら、2002,J.Biol.Chem.277:47928−47937に記載されているように選択される領域内に含まれる結合部位におけるTRAIL遺伝子プロモーターを制御すると以前に示されているFoxo3aを含む)の標的遺伝子の転写の変化が観察された。図50は、DMSOと比べて、TIC10処理(10μM)の48時間後におけるHCT116 p53−/−細胞の遺伝子発現プロファイリングからのFOXOシグナル伝達に関連する転写の変化を示しているグラフである(n=3)。これらの変化のすべてが、DMSO処置群とTIC10処置群との間においてP<.05だった。エラーバーは、反復実験のs.d.を示している。別段示されない限り、表示の条件とコントロールとの間において*P<0.05。
p53−/−細胞におけるTIC10処置(左から右に向かって0、2.5、5または10μM)の48時間後の、TRAILプロモーターに対するFoxo3aのTIC10誘導性移行についてのクロマチン免疫沈降アッセイの結果の像である。
Foxo3aの制御因子(例えば、IKK、AktおよびERK)の、TIC10によって誘導される変化を測定した。図59は、TIC10(2.5、5、10μM)で72時間処理されたHCT116 p53−/−細胞のウエスタンブロット解析の像である。
inh)またはその両方とともにインキュベートした後のHCT116 p53−/−細胞の表面TRAIL解析を示しているグラフである(48時間、n=3)。
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