JP2012102099A - 癌を治療するための医薬の製造におけるPARP活性阻害性RNAiの使用 - Google Patents
癌を治療するための医薬の製造におけるPARP活性阻害性RNAiの使用 Download PDFInfo
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Abstract
【解決手段】相同的組換えを仲介する遺伝の欠陥によって引き起こされる疾患を治療するための医薬製造における、DNA鎖切断の修復を仲介する酵素の活性を阻害する薬剤。肺癌、大腸癌、膵臓癌、胃癌、卵巣癌、子宮頸癌、乳癌及び前立腺癌、特に乳癌の治療における、DNA鎖切断(又は切断部)の修復を仲介する酵素の活性を阻害する薬剤。
【選択図】なし
Description
a)図9、10、11、12、13若しくは14中の配列によって表される核酸配列又はその断片、
b)図9、10、11、12、13若しくは14の核酸配列にハイブリダイズし、かつPARPの遺伝子をコードする核酸配列、
c)遺伝子コードにより、(a)及び(b)に記載される核酸配列と縮退している配列を含む核酸配列、
からなる群より選択された核酸配列を含む核酸分子から誘導されることが好ましい。
HR-欠陥性細胞(XRCC2、XRCC3又はBRCA2)に対するPARP阻害剤の細胞毒性
細胞培養
irs1、irs1X2.1及びV79-4細胞系はJohn Thackerから寄贈され(非特許文献40)、AA8、irs1SF及びCXR3細胞系はLarry Thompsonによって提供された(非特許文献41)。
3-AB、ISQ又はNU1025の添加前に、培地中で懸濁した500個の細胞をペトリ皿上で4時間平板培養した。ISQ及びNU1025をDMSO中に溶かし、処理培地中0.2%の最終濃度とした。7〜12日後、コロニーを観察できた際に、これらのコロニーを固定し、メタノール中のメチレンブルー(4g/l)で染色した。続いて50個を超える細胞からなるコロニーをカウントした。
NU1025による処理前に、0.25x106個の細胞をペトリ皿にプレーティングし、4時間増殖させた。72時間後、細胞をトリプシン処理し、そのサンプル由来の浮遊細胞を含む培地で再懸濁した。細胞を遠沈によってペレット化し、アポトーシス分析のためにFITC-結合型アネキシンV及びヨウ化プロピジウム(PI)(ApoTarget, Biosource International)と共に製品のプロトコールに従って再懸濁した。サンプルをフローサイトメトリー(Becton-Dickenson FACSort, 488 nmレーザー)によって分析し、アポトーシス細胞の割合を、FITC-結合型アネキシンVと結合した生存細胞(PI陰性)の比率から測定した。
細胞を24時間の処理の前にカバーガラス上で4時間平板培養した。処理後、培地を除去し、カバーガラスをPBS中37℃で1回洗浄し、他に記載されるように(非特許文献2)固定した。この研究で使用された一次抗体及び希釈度は、ラビットポリクローナル抗PAR(Trevigen;1:500)、ヤギポリクローナル抗Rad51(C-20, Santa Cruz; 1:200)及びラビットポリクローナル抗Rad51(H-92, Santa Cruz; 1:1000)であった。二次抗体は、Cy-3-結合型ヤギ抗ラビットIgG抗体(Zymed; 1:500)、Alexa 555ヤギ抗ラビットF(ab')2IgG抗体(Molecular Probes; 1:500)、Alexa 546ロバ抗ヤギIgG抗体(Molecular Probes; 1:500)及びAlexa 488ロバ抗ラビットIgG抗体(Molecular Probes; 1:500)であった。抗体を、3%ウシ血清アルブミンを含むPBSで希釈した。DNAを1μg/mlのTo Pro(Molecular Probes)で染色した。Zeiss社のLSM 510倒立共焦点顕微鏡により、プラナポクロマット(planapochromat)63X/NA 1.4油浸レンズと488、546及び630nmの励起波長を用いて画像を得た。最大焦点を介して、0.50μm離れた厚さ1.0μmの光学切片から投影画像を得た。画像をAdobe PhotoShop(Abacus Inc)を用いて処理した。各スライド上で少なくとも300個の核がカウントされ、10を超えるRAD51フォーカス又はPARP活性部位を含むものを陽性として分類した。
水溶性テトラゾリウム塩(5mM WST-8)を用いて、NAD(P)Hの量をその黄色ホルマザンダイへの還元によってモニターした(非特許文献43)。5000個の細胞を96ウェル平板のウェルに少なくとも3重にプレーティングし、100μlの通常の増殖培地中で、4時間37℃で培養した。次いで、WST-8を含む、CK8バッファー(Dojindo Molecular Technology, Gaithersburg, USA)を、示される濃度のDNA損傷剤の処理と共に又はDNA損傷剤の処理なく添加した。NAD(P)Hの存在下でのWST-8の減少を、30分毎に可視吸光度(OD450)を測定することによって測定した。培地とCK8バッファーのみを含むブランクの培地も調製した。NAD(P)Hレベルの変化は、DNA損傷剤で処理した細胞を含むウェルの吸光度と、DMSOのみで処理した細胞を含むウェルの吸光度とを比較することによって算出した。あるいは、個々の細胞系のNAD(P)Hの相対レベルをCK8バッファー中4時間のインキュベーション後に算出した。
1.5x106個の細胞を100mmディッシュ上にプレーティングし、4時間放置して接着させた。細胞を18時間薬剤へ曝露した後、トリプシン処理し、106個の細胞を各1%アガロースインサート中に融解させた。これらのインサートを他で記載されるようにインキュベートし(非特許文献8)、24時間のパルスフィールドゲル電気泳動により分離した(BioRad;角度120°、切り替え時間60〜240秒、4V/cm)。次いで、ゲルを分析のためにエチヂウムブロマイドで染色した。
予め設計されたBRCA2 SMARTプール及びスクランブルsiRNAを購入した(Dharmacon, Lafayette, CO)。10000個の細胞を6ウェル平板に蒔き、一晩放置し、その後オリゴフェクタミン(Oligofectamine)試薬(Invitrogen)を製品説明書に従って用いて100nM siRNAをトランスフェクトした。次いで、細胞を通常の増殖培地で48時間培養し、その後、毒性アッセイのためにトリプシン処理し、再塗布した。BRCA2の抑制を、BRCA2に対する抗体(Oncogene, Nottingham, UK)を用いた、siRNAで処理したタンパク質抽出物のウエスタンブロッティング(非特許文献46で既に記載される)によって確認した。
相同的組換え欠陥性細胞はPARP-1阻害に過敏である
PARP-1阻害に対する細胞応答におけるHRの関与を研究するために、HR修復欠陥性細胞系の生存に与えるPARP-1阻害剤の効果を調査した。HRに欠陥のある細胞(すなわち、XRCC3に欠陥のあるirs1SF又はXRCC2に欠陥のあるirs1(表1を参照されたい))が、3−アミノベンズアミド(3−AB)の毒作用及び2つのより強力なPARP-1阻害剤(1,5-ジヒドロキシイソキノリン(ISQ;非特許文献37)又は8−ヒドロキシ−2−メチルキナゾリノン(NU1025、非特許文献38、39))に対して非常に敏感であることが見出された(図1)。3−AB、ISQ又はNU1025に対するirs1SF細胞の感度は、機能的XRCC3遺伝子(CXR3)を含むコスミドの導入によって矯正された。同様に、3-AB、ISQ又はNU1025に対するirs1細胞の感度は、機能的XRCC2遺伝子(irs1X2.2)を含むコスミドの導入によって矯正された。
PARP-1阻害剤の存在下での、BRCA2欠陥性細胞(VC8)及び野生型細胞(V79Z)の生存を調査した。VC8細胞がNU1025の毒作用に非常に敏感であることが見出された(図2)。VC8細胞の感度は、第13染色体(VC8#13)又は過剰発現ベクター(VC8+B2)のいずれかへの機能的BRCA2遺伝子の導入によって矯正された。この結果は、PARP-1阻害剤に対する感度が、BRCA2機能の喪失の直接的な結果であることを証明している。
MCF7(野生型p53)及びMDA-MB-231(変異型p53)乳癌細胞系が、BRCA2の欠乏時にNU1025に対して類似の感度を示すか否かを調査した。BRCA2がBRCA2 siRNAの混合物によって除去された際にのみ、PARP阻害剤がMCF7及びMDA-MB-231細胞の生存を大きく減少させることが見出された(図4)。これは、BRCA2が除去された乳癌細胞がp53の状態に関係なくPARP阻害剤に対して敏感であることを示している。
HRはDNA複製の間に生じるDSB及び他の損傷の修復に関与することが知られている(非特許文献2)。BRCA2欠陥性細胞の感度が、NU1025処理後にDSBを修復する能力の欠如の結果であるかどうかを判定するために、V79及びV-C8細胞におけるDSBの蓄積を、高い毒性レベルのNU1025による処理後に測定した。処理した細胞から得たDNAのパルスフィールドゲル電気泳動分析によって検出可能なDSBは存在しなかったことが分かり(図5A)、これは、PARP阻害後、HR欠陥性細胞にγH2Axを誘発する低レベルのDSB又は他の組換え基質(recombinogenic substrate)が蓄積したことを示している(図5B)。BRCA2欠陥性細胞がこれらの組換え障害の誘導後に死滅する理由は、かかる損傷を修復する能力の欠如に起因すると思われる。これを試験するために、BRCA2欠陥性V-C8細胞及びBRCA2が補充された細胞の、NU1025に応答してRAD51フォーカスを形成する能力を判定した。RAD51フォーカスは、実際に、NU1025による処理後にV-C8+B2細胞で誘導されることがわかった(t検定において統計的に有意なp<0.05;図5D)。これは、組換え障害が、これらの細胞中でその生存を可能とするHR修復を誘発することを示している。これに対し、BRCA2欠陥性V-C8細胞は、NU1025処理に応答してRAD51フォーカスを形成することができなかった(図5D)。これは、HRがないことを示し、組換え障害を未修復のままにする結果、細胞死を引き起こす。
哺乳動物細胞の核には2種類の主要なPARPであるPARP-1とPARP-2が存在しており、報告された全てのPARP阻害剤は両者を阻害する。どちらのPARPがその作用を引き起こすかを見極めるために、本発明者らは、PARP-1及び/又はPARP-2の不在下で毒性障害の蓄積を引き起こすか否かを、ヒト細胞中で、PARP-1及び/又はPARP-2並びにBRCA2をsiRNAで除去することによって試験した(図6a)。本発明者らは、PARP-1及びBRCA2タンパク質の両方がヒト細胞から共に除去される際に、クローン的生存(clonogenic survival)をかなり減少させることを見出した(図6b)。BRCA2と共にPARP-2が除去されることは、クローン的生存にいかなる作用も有さず、PARP-1除去細胞及びBRCA2除去細胞におけるPARP-2の除去は、追加の毒性を生じなかった。これらの結果は、PARP-1はヒト細胞で毒性の組換え障害を低減するが、PARP-2は低減しないことを示唆する。クローニング効率は、PARP-1とBRCA2が共に除去された細胞においてわずかに対照の60%まで低減されたが、PARP阻害剤による処理ではHR欠陥性細胞は生存しなかった。これはsiRNAによる豊富なPARP-1タンパク質の不完全な除去(一部の細胞でPARP-1機能を維持するのに十分であり得る)によるものと考えられる(図6c)。
HRは、停止した複製フォークで生じている損傷(検出可能なDSBは含み得ない)の修復にも関与する(非特許文献2)。PARPが複製フォークでの役割を有するか否かを試験するために、DNA複製フォークの進行を遅らせるか又は停止させる薬剤(チミジン又はヒドロキシ尿素)で処理した細胞におけるPARP活性化を調査した。チミジンは細胞のdCTPを除去し、DSBを生じさせることなく複製フォークを遅らせる。ヒドロキシ尿素は、数種のdNTPを除去し、複製フォークを抑止し、複製フォークでのDSBの形成に関与する(非特許文献2)。これらの薬剤はいずれもHRを強力に誘導する(非特許文献2)。チミジン又はヒドロキシ尿素で24時間処理したV79ハムスター細胞を、PARポリマーについて染色した。これはPARP活性部位を含む細胞数の実質的な増加を明らかにした(図7C)。この結果は、停止した複製フォークでのPARPの機能を示唆する。また、NU1025によるPARPの阻害が、V-C8+B2細胞でチミジン又はヒドロキシ尿素に対する感度を増強することも示された(図7D、E)。この結果は、PARP活性が停止した複製フォークの修復に重要であること、あるいは、停止した複製フォークを有する細胞における細胞死の誘導を防止することを示唆する。
未処理のBRCA2欠陥性V-C8細胞におけるPARP活性部位の数を測定した。V-C8細胞は、V-C8+B2細胞と比較してより多くのPARP活性部位を含むことが分かった(図8A、B、C)。また、V-C8細胞は矯正された細胞よりも低い遊離NAD(P)Hレベルを有し(図8D)、これは増加したPARP活性の結果と予想される。重要なことは、これらのPARP活性部位がRAD51フォーカスと重複しないことである(図8E)。
Claims (20)
- 相同的組換え(HR)に欠陥のある癌細胞を処置するための医薬の製造における、ポリ(ADP-リボース)ポリメラーゼ-1(PARP-1)阻害剤の使用。
- 癌細胞がHRを仲介する遺伝子に欠陥を有する、請求項1に記載の使用。
- 欠陥がHRに関与するタンパク質をコードする遺伝子中の突然変異である、請求項2に記載の使用。
- 欠陥がHRに関与するタンパク質をコードする遺伝子の欠如である、請求項2に記載の使用。
- 欠陥がHRに関与するタンパク質をコードする遺伝子の発現にある、請求項2に記載の使用。
- HRを仲介する遺伝子が、XRCC1、CTPS、RPA、RPA1、RPA2、RPA3、XPD、ERCC1、XPF、MMS19、RAD51、RAD51B、RAD51C、RAD51D、DMC1、XRCC2、XRCC3、BRCA1、BRCA2、RAD52、RAD54、RAD50、MRE11、NBS1、WRN、BLM、Ku70、Ku80、ATM、ATR、chk1、chk2、FANCA、FANCB、FANCC、FANCD1、FANCD2、FANCE、FANCF、FANCG、RAD1、RAD9、FEN-1、Mus81、Eme1、DDS1及びBARDからなる群より選択されたものである、請求項2〜5のいずれか1項に記載の使用。
- 癌が、肺癌、大腸癌、膵臓癌、胃癌、卵巣癌、子宮頸癌、乳癌及び前立腺癌からなる群より選択されたものである、請求項1〜6のいずれか1項に記載の使用。
- 癌がヒトにおける癌である請求項7に記載の使用。
- 癌が遺伝子に関連する遺伝性癌である、請求項1〜8のいずれか1項に記載の使用。
- 癌が乳癌である、請求項9に記載の使用。
- 処置対象の癌細胞がBRCA1発現に欠陥を有する、請求項1〜10のいずれか1項に記載の使用。
- 処置対象の癌細胞がBRCA2発現に欠陥を有する、請求項1〜10のいずれか1項に記載の使用。
- 癌細胞がBRCA1発現及び/又はBRCA2発現に部分的に欠陥を有する、請求項11又は12に記載の使用。
- 癌細胞がBRCA1発現及び/又はBRCA2発現に全体的に欠陥を有する、請求項11又は12に記載の使用。
- HRを仲介する遺伝子が腫瘍抑制遺伝子である、請求項2〜14のいずれか1項に記載の使用。
- 腫瘍抑制遺伝子がBRCA1又はBRCA2である、請求項15に記載の使用。
- HR欠陥性細胞のアポトーシスを誘導するための医薬の製造におけるPARP-1阻害剤の使用。
- HR欠陥性細胞が癌細胞である請求項17に記載の使用。
- HRに欠陥のある癌細胞がHRに部分的に欠陥を有する、請求項18に記載の使用。
- HRに欠陥のある癌細胞がHRに全体的に欠陥を有する、請求項18に記載の使用。
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