JP5415952B2 - Dbaitおよびその使用 - Google Patents
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- JP5415952B2 JP5415952B2 JP2009528722A JP2009528722A JP5415952B2 JP 5415952 B2 JP5415952 B2 JP 5415952B2 JP 2009528722 A JP2009528722 A JP 2009528722A JP 2009528722 A JP2009528722 A JP 2009528722A JP 5415952 B2 JP5415952 B2 JP 5415952B2
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Description
放射線療法および化学療法は、単独でまたは手術と併用される、ヒトガンに対する必要不可欠な療法である。
1)PI3Kの阻害剤(ホスファチジルイノシトール−3−キナーゼ)(即ち、DNA−PKcs、ATM、ATR)(Boultonら,2000;DurantおよびKarran,2003;Willmoreら,2004;Vaugerら,2004);
2)ネガティブドミナントおよびペプチド(KU80のC末端)(Marangoniら,2000;Kimら,2002);
3)一本鎖抗体可変フラグメント(scFv)(DNA−PKcs)(Liら、2003);
4)RNAアプタマー(SELEX:RNA結合Ku)(YooおよびDynan,1998);
5)アンチセンス(Ku70、Ku80、DNA−PKcs)(Liら,2003b;Marangoniら,2000;Sakら,2002);
6)siRNA(DNA−PKcs)(Pengら,2000)。
本発明は、哺乳動物細胞におけるDNA修復経路を妨げる新規の組成物および方法に関する。本発明は、特に、非遺伝子特異的様式で、DNA損傷感知、シグナル伝達および/または修復経路を妨げる核酸分子、ならびに、特に抗ガン療法へ提示された腫瘍の細胞致死をトリガーするための、それらの使用に関する。
上述したように、本発明は、哺乳動物細胞におけるDNA修復システムを非遺伝子特異的様式で妨げ得る新規のクラスの治療分子を開示する。Dbait分子と呼ばれる、これらの新規の分子は、NHEJ経路(配列非依存性経路)に関与するタンパク質、特に、Kuおよび/またはDNA−PKcsタンパク質、のホロ複合体についての基質であり、細胞のDNA修復能を中和し、それによってDNA損傷治療に対するそれらの感受性を増大させ得る。
1)二本鎖Dbait分子は、薬学的に許容される担体/賦形剤と共に使用される場合、細胞/組織体によって細胞核中へ取り込まれ得る;
2)Dbait分子の少なくとも1つの遊離末端が、DSB損傷感知、シグナル伝達および/または修復プロセスに関与する酵素のホロ複合体によって認識可能である;
3)Dbait分子の少なくとも1つの遊離末端が、該複合体によって腫瘍細胞ゲノムDNAに組み入れられやすい。
−ガン細胞/組織中へ上記に定義されるようなDbait分子を導入すること、および
−DNA損傷法によってDNA切断を細胞内において誘導すること
を含む。
分子および細胞研究、ならびにヌードマウス上の異種移植されたヒト放射線耐性腫瘍(頭頸部扁平上皮癌、膠芽腫、黒色腫)における、およびトランスジェニックマウスの消化管中のRasv12G×Apc1638N二重突然変異誘発腫瘍におけるアッセイを以下のために行った:
i)Dbait分子の生物学的活性を評価するため;
ii)抗ガン療法を増感させることにおいてDbait分子を使用することによるDNAベイトアプローチを検証するため;
iii)観察されたDbait媒介増感の基礎となる分子および細胞機構を解明するため。これらの研究の結果を、実施例において概説しそして要約する。
2タイプのDbait分子を設計した:線形またはヘアピンdsDNAフラグメント。ヘアピンDbait分子について、ヘキサエチレングリコールリンカーまたはテトラデオキシチミジレートをループとして使用した。
表1.1:Dbait分子の配列および化学構造。大文字は、ホスホジエステル骨格を有するヌクレオチドである。ボールドの大文字は、ホスホロチオエート骨格を有するヌクレオチドである。半円の実線は、ヘキサエチレングリコールリンカーを象徴する。Dbait32−T4は、ヘキサエチレングリコールリンカーの代わりにリンカーとして4つのチミン(T4)を含む。Dbait32Cは、ダンベル(クローズド)分子である。Dbait32Hc−5’5’は、シャッフルされた配列(同一の塩基組成、しかし異なる順序;表1.1中のDbait32Hbを参照のこと)および3’−3’結合を有する。Dbait32Ha、Dbait32Hb、Dbait32HcおよびDbait32Hdは、Dbait32Hの配列と比べた場合、同一の塩基組成を有し、しかし順序が異なる。
表1.2:記載される種々の標識されたDbait分子の配列および化学構造。大文字は、ホスホジエステル骨格を有するヌクレオチドである。ボールドの大文字は、ホスホロチオエート骨格を有するヌクレオチドである。ボールドの小文字は、メチルホスホネート骨格を有するヌクレオチドである。半円の実線は、ヘキサエチレングリコールリンカーを象徴する。種々の標識された(シアニン3または5、FITC)Dbat8Hc、Dbait32H、Dbait32HcおよびDbait32Hd分子が記載されている。
表1.3:64−bp Dbait64およびDbait64L分子の配列および化学構造。大文字は、ホスホジエステル骨格を有するヌクレオチドである。ボールドの大文字は、ホスホロチオエート骨格を有するヌクレオチドである。実線は、ヘキサエチレングリコールリンカーを象徴する。
二重蒸留水中の各鎖の1:1ストック溶液(可能な限り最も高い濃度)の混合物を、各鎖の完全な変性のために、90℃で5分間加熱しなければならない。アニーリングを、滑らかに室温へ戻すことによって行い(サンプルを典型的に水浴中に置く)、そして得られた二本鎖分子を−20℃においてアリコートで保存した。
二重蒸留水中の200μMのヘアピンDbait分子を含有する溶液を、完全な変性のために、90℃で5分間加熱しなければならない。アニーリングを、氷水(0℃)中へサンプルを冷やすことによって行った。アリコートを−20℃で保存した。
Dbait分子の作用機構を分析する第1工程として、一連のバンドシフトアッセイを、標準プロトコルに従って、Hep2細胞由来の核タンパク質抽出物の存在下において種々の32P放射標識Dbait分子を用いて行った。典型的に、10nM 32P放射標識Dbait分子を、TBE緩衝液中、30℃で10分間、種々の濃度の核タンパク質(0、10、20、40、80、160、および320ng/μL)の存在下でインキュベーションした。次いで、サンプルを5%アクリルアミドネイティブゲル上にロードした。電気泳動を4℃にて2時間95Vで行った。ゲルを乾燥し、そしてホスホルイメージャー(phosphorimager)(Molecular Dynamics)によってスキャンした。
培養細胞中におけるDbait分子の活性を、外因性DNAフラグメントの異常組込みの阻害によって、およびDbait分子によってトランスフェクションされた細胞における放射線照射後の存続するDSBフォーカス(DSB foci)を検出することによって、電離放射線と共同しての、子宮頸癌(HeLa)およびHNSCC(Hep2)から誘導された2つの放射線耐性ヒトガン細胞株におけるクローン原性生存アッセイによって研究した。
Hela細胞中におけるDbait分子の8時間トランスフェクション、および137Cs源由来のγ線で行った2時間間隔を置いた0.5Gyの細分された放射線照射での4回の放射線照射(4×0.5Gy)によって、クローン原性生存の顕著な減少が、トランスフェクションされていない細胞と比較して観察された。結果を図2.1に与え、ここで、パネルAは、Dbait32およびDbait32Hの存在下での標準化生存クローン数の用量依存性を与え、パネルBは、83nM(培養培地中の濃度)での異なるDbait分子の存在下での標準化生存クローン数。細胞培養は、10%血清が補充されたMEMにおいてであった。Superfect(Qiagene)を、製造業者の指示に従って、トランスフェクション剤として使用した。クローン原性生存を、未処理細胞の数に対するコロニーを形成する処理細胞の数として評価した。
表2:放射線およびDbaitでの処理後のDNA−PKコンピテント細胞(MO59K)およびDNA−PK欠損細胞(MO59J)における細胞生存。細胞を希釈し、そして平板培養し、フラスコ上にコロニーを形成させ、次いでこれらに10Gyで放射線照射したおよび/または2μg Dbait32Hcをトランスフェクションした。両方の処理を合わせた場合、放射線照射をトランスフェクションの5時間後に行った。生存を、非処理サンプル中におけるクローン形成細胞数で割った処理後のクローン形成細胞数として算出する。平均値および標準偏差(括弧中)を、3つの独立した実験から算出した。
電離放射線は、放射線増強組込みと呼ばれるプロセスである、外因性DNAの異常組込みを増進することが公知である。Hela細胞培養をこのアッセイのために使用した。細胞を、ネオマイシン耐性をコードする遺伝子を有する線状プラスミド2μg、および3つの異なる比率のDNA/Superfect(1:2、1:5、1:10)によって8時間の間トランスフェクションした。トランスフェクション時間の間、細胞を種々の放射線照射プロトコルへ曝露した:放射線照射無し、1Gyおよび2Gyの単回放射線照射、ならびに2時間毎に0.5Gyの細分された線量によって送達した2Gy放射線照射(4×0.5Gy)。プラスミドの組込みを、0.6mg/mlのG418を含有する培地において増殖するNeoR細胞の選択によってモニタリングした。プラスミド組込みは、細分された放射線照射プロトコルによって顕著に増強された。2μgのDbait32H分子をトランスフェクションミックスへ添加すると、放射線増強組込みはなくなった(図2.3)。
核中のDSB部位は、リン酸化H2AX(ヒストンH2Aの変異体)上に結合するγ−H2AX抗体の免疫蛍光検査によってモニタリングされ得る。大部分のγ−H2AXフォーカスが、放射線照射後、迅速に出現し、そしてDSB修復プロセスが進行するにつれ消滅する。
放射線療法と共同してのDbait分子のin vivo活性を、放射線耐性細胞株(頭頸部扁平上皮癌HNSCC由来のHep2)または腫瘍フラグメント(膠芽腫由来のU87細胞株の皮下注射によって予め得た)の皮下注射によってヒト腫瘍が異種移植されたヌードマウスを使用して評価した。
表3.1:Dbait32H(1nmol/腫瘍内注射)によるヌードマウスにおける異種移植ヒト膠芽腫の放射線増感のアッセイ。2つのプロトコルの放射線照射(腫瘍内注射後5時間)を使用した:1×15Gy/週または3×5Gy/週、続いて1週間休息、第2治療サイクル。総放射線照射線量は、30Gyであった。コントロール群は、未治療群、または食塩水(PBS)注射を受容した群であった。
表3.2は、上記のデータの一部を要約しており、かつ、ヌードマウスにおいて皮下に異種移植された3つのヒト腫瘍細胞株における異なるプロトコル(種々のDbait32分子+放射線照射 対 放射線照射+偽注射)によって治療された異種移植された動物の生存の比較を提供している。さらに、それは、Dbait32Hと比べてのDbait32Hcの同様の結果によって証明されるように、Dbait分子の配列は重要ではないことを示している。それはまた、一本鎖Dbaut32ssは高用量であっても不活性であったことを示している。
内因性マウス腫瘍モデルを選択し、抗ガン化学療法を増感させるDbait分子の能力を評価した。このために、K−Rasv12GおよびApc1638N突然変異を有するトランスジェニックマウスを使用した。2つのトランスジェニックマウスを交配させることによってそれらを得た:一方は、マウスビリンプロモーターの制御下でK−Rasv12G突然変異体を有し(pVill/K−Rasv12G)(Janssenら,2002)、他方は、1アレル中にApc1638N突然変異を含む(Foddeら,1994)。pVill/K−Rasv12G×Apc1638N突然変異を有するトランスジェニックマウスは、約5月齢で消化管に自然発生腫瘍を発現し、そして急に死んだ。
Claims (16)
- 核酸分子であって、該分子が、少なくとも24bpの二本鎖部分を含み、少なくとも1つの遊離末端を有し、CpGを欠いており、ヒトゲノムにおける任意の遺伝子に対して70%未満の配列同一性を有し、各鎖の末端にまたは少なくとも鎖の3’末端に1または数個のホスホロチオエートまたはメチルホスホネート骨格を有するヌクレオチドを含み、かつ、該分子が、二本鎖切断DSB修復のNHEJ経路に関与する少なくともKuタンパク質による結合についての基質であり、ここで該分子は、配列番号17のDbait32Hcの配列の二本鎖部分を有する、核酸分子。
- 該分子が、ヘアピン核酸分子である、請求項1記載の分子。
- 該遊離末端が、平滑であるかまたは5’もしくは3’突出している、請求項1〜2のいずれか1項記載の分子。
- Dbait32Hc(配列番号17)、Dbait32Hc−3’mp(配列番号19)、およびDbait32Hc−5’3’mp(配列番号20)より選択される、請求項1〜3のいずれか1項記載の分子。
- Dbait32Hc(配列番号17)である、請求項4記載の分子。
- 請求項1〜5のいずれか1項記載の分子および薬学的に許容される担体もしくは賦形剤を含む、薬学的組成物。
- 経口経路、または静脈内、腫瘍内もしくは皮下注射、または頭蓋内もしくは動脈内注射もしくは注入、または局所投与に好適である、請求項6記載の薬学的組成物。
- ガンを治療するための使用のための併用調製物としての、請求項1〜5のいずれか1項記載の分子と、DNAの二本鎖切断を直接または間接的に引き起こし得る化学薬剤とを含む、医薬品。
- 該分子が、化学薬剤より前にまたは化学薬剤と同時に投与される、請求項8記載の医薬品。
- DNA損傷性抗ガン療法に対する腫瘍感受性を増強するための医薬の製造のための、請求項1〜5のいずれか1項記載の分子の使用。
- DNA損傷性抗ガン療法と併用して使用されるガンを処置するための医薬の製造のための、請求項1〜5のいずれか1項記載の分子の使用。
- 該DNA損傷性抗ガン療法が、放射線療法および化学療法より選択される、請求項10または11記載の使用。
- 該分子が、放射線療法より前に投与される、請求項10〜12のいずれか1項記載の使用。
- 該分子が、化学療法より前または化学療法と同時に投与される、請求項10〜12のいずれか1項記載の使用。
- 該ガンが、CNSガン、頭頸部ガン、結腸直腸ガン、肝臓ガン、消化管ガン、尿生殖路ガン、肺ガン、皮膚ガン、乳ガンおよび子宮頸ガンより選択される、請求項10〜14のいずれか1項記載の使用。
- 該分子が、経口経路、または静脈内、腫瘍内もしくは皮下注射、または頭蓋内もしくは動脈内注射もしくは注入、または局所投与によって投与される、請求項10〜15のいずれか1項記載の使用。
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