JP5662822B2 - 腫瘍細胞致死性をトリガーするのに有用な核酸 - Google Patents
腫瘍細胞致死性をトリガーするのに有用な核酸 Download PDFInfo
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- Saccharide Compounds (AREA)
Description
1)PI3K(ホスファチジルイノシトール−3−キナーゼ)(即ち、DNA−PKsc、PARP−1、ATM、ATR)の阻害剤(Boulton et al., 2000; Durant & Karran, 2003; Willmore et al., 2004; Vauger et al., 2004)
2)ネガティブドミナント&ペプチド(KU80のC末端)(Marangoni et al., 2000; Kim et al., 2002)
3)一本鎖抗体可変性断片(scFv)(DNA−PKsc)(Li et al. 2003)
4)RNAアプタマー(SELEX:RNA結合Ku)(Yoo & Dynan, 1998)
5)アンチセンス(Ku70、Ku80、DNA−PKsc)(Li et al., 2003b; Marangoni et al., 2000; Sak et al., 2002)
6)siRNA(DNA−PKsc)(Peng et al, 2000)。
−該二本鎖DRIL分子が、薬学的に許容されうる担体と共に使用されるとき、細胞核中に細胞/組織体(cell/tissue body)により摂取されることができるようなもの、
−DRIL分子の自由端(free ends)が二本鎖切断修復及び損傷シグナリングに関与するDNA結合タンパク質により認識されうるようなもの、
−DRIL分子の自由端が前記酵素により腫瘍細胞ゲノムDNAに組み込まれやすいようなものである。
a)DNA複製のためのテンプレートとして使用することができないユニット、例えばポリエチレングリコール鎖、好ましくはヘキサエチレングリコール鎖、又は場合により1個以上のヘテロ原子、例えば、酸素、硫黄、窒素により中断されている及び/又は置換されたいかなる炭化水素鎖、又は1個以上のヘテロ原子を含むヘテロ原子基若しくは複素環基;
b)DNAポリメラーゼ又はエキソヌクレアーゼによって作用されにくい(not amenable)ブロッキングエレメントであるユニット、例えば、いかなる3’−修飾されたヌクレオチド又は当業者により知られている他のヌクレオチド;
c)ヘアピン断片のループにおいて使用されるときの、ネイティブオリゴヌクレオチド、例えば、Tn、好ましくは、テトラデオキシチミジレート(T4)、
を含むことができる。
上記した如きDRIL分子をがん細胞/組織に導入すること、及び
細胞においてDNA損傷方法によりDNA切断を誘発すること、
を共に含む抗がん性治療に対する腫瘍感受性を促進する方法にも関する。
i)DRIL分子の生物学的活性を評価するため、ii)抗がん性治療を増感させることにおいて、DRIL分子を使用することによるDNA Baitアプローチを確証するため、iii) 観察されたDRIL効果の基礎をなす分子及び細胞機構を解明するために、行なった。これらの研究の結果を下記の節(実施例)において慨述しそして要約する。
2つのタイプのDRIL分子:線状又はヘアピンdsDNA断片をデザインした。ヘアピンDRIL分子では、ヘキサエチレングリコールリンカー(PEGと略記する)又はテトラデオキシチミジレート(T4と略記する)をループとして使用した。dsDNAステムの端部(1つ又は複数)を、ホスホロチオエート又は3’−3’ヌクレオチド結合の組込みにより3’−エキソヌクレアーゼによる化学的分解に対して保護することができる。一般に、他の化学的修飾を使用することができるが、但し、それらはKu70/Ku80−DNA PKsc結合と適合性であるものとする(Martensson & Hammarten,2002)。種々のステム長さ8bp、(DRIL8−PEG)、16bp(DRIL16−PEG)、24bp(DRIL24−PEG)及び32bp(DRIL32−PEG)、並びに種々のステム配列を有する種々のDRIL分子が使用された。両端が2つのPEGループによりシールされているダンベルdsDNA断片(DRIL32−2xPEG)もコントロールとしてデザインされた。いくらかのDRIL分子は、フルオレセイン(DRIL32−FITC)、シアニン3(DRIL32−Cy3)又はビオチン(DRIL32−Bt)でタグ付けされたTを介して標識された。表1.1及び1.2はこの研究で使用したDRIL分子の配列及び化学構造を要約した。
二分子DRIL分子(DRIL32、DRIL64及びDRIL64−PEG)について:
二回蒸留水中の各ストランドの1:1ストック溶液(可能な最も高い濃度)の混合物は、各ストランドの完全な変性のために90℃で5分間加熱されなければならない。室温に円滑に戻す(サンプルを典型的には水浴中に放置した)ことによりアニーリングを行いそして得られる二本鎖分子を−20℃でアリコートにおいて保存した。
二回蒸留水中のヘアピンDRIL分子200μMを含有する溶液は、完全な変性のために90℃で5分間加熱されなければならない。サンプルを氷水(0℃)中に冷却することによりアニーリングを行なわなければならない。アリコートの保存は−20℃であった。
DRIL分子の作用の機構を細かく調べるための第一の工程として、一連のバンドシフトアッセイを、標準プロトコールに従ってHep2細胞からの核内タンパク質抽出物(nuclear protein extracts)の存在下に種々の32P放射線標識されたDRIL分子で行なった。典型的には、32P放射線標識されたDRIL分子10nMを、TBE緩衝剤中で30℃で10分間種々の濃度の核内タンパク質(0、10、20、40、80、160及び320ng/μl)の存在下に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。4℃で2時間95Vで電気泳動を行なった。ゲルを乾燥しそしてホスホルイメージャー(phosphor imager)(Molecular Dynamics)により走査した。
電離放射線と共同して、婦人の頚部がん(Hela)及び喉頭がん(Hep2)に由来する2つの放射線耐性のヒトがん細胞系におけるクローン原性生存アッセイ(clonogenic survival assay)により、培養された細胞におけるDRIL分子の活性を研究した。
Hela細胞におけるDRIL分子の8時間のトランスフェクション及び137セシウムからの 線( rays)行なわれた、2時間の間隔をおいた0.5Gy分割線量による4回の照射(4×0.5Gy)をすると、トランスフェクションされていない細胞に比べて、クローン原性生存の有意な減少が観察された。結果は、図2.1に示され、この図2.1においては、パネルAは、DRIL32及びDRIL32−PEGの存在下に正規化された生存クローン数の用量依存性を与え、そしてパネルBは、83nM(培養培地中の濃度)における種々のDRIL分子の存在下に正規化された生存クローン数を与える。
電離放射線は、外因性DNAのトランスフェクション、放射線で高められた組込みと呼ばれる方法を改良することが知られている。Hela細胞培養物をこのアッセイのために使用した。細胞を、線状プラスミド(ネオマイシン耐性をコードする遺伝子を有する)2μg及び3つの異なる割合のDNA/スーパーフェクト(1:2、1:5、1:10)により8時間の期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期間中、細胞を種々の照射プロトコール:照射なし、1Gy及び2Gyの1回の単一照射、並びに2時間毎に0.5Gyの分割線量により送達された2Gy照射(4×0.5Gy)、にさらした。プラスミドの組込みは、G418の0.6mg/mlを含有する培地中で増殖するNeoR細胞の選択により監視された。プラスミド組込みは、分割照射プロトコールにより有意に高められた。DRIL32−PEG分子2μgがトランスフェクション混合物に加えられると、放射線で高められた組込みは無効にされた(図2.2)。
核におけるDSB損傷は、DNA切断を標識するγ−H2AX抗体を使用することにより免疫検出されうる。H2AXフォーカス(H2AX foci)の大部分は、照射後に急速に現れ、そしてDSBs修復プロセスが進行するにつれて消失した。少数のH2AXフォーカスはトランスフェクションされていない細胞において照射の2時間後に検出された。
DNA切断を許容するGMA32チャイニーズハムスター繊維芽細胞を、ピルビン酸ナトリウム1mM、グルタミン2mM、1xMEM非必須アミノ酸、1xペニシリン/ストレプトマイシン及び10%ウマ血清を補充したMEM培地(Gibco)中に維持した。典型的には、2×105〜4×105個の細胞を、製造者の指示に従ってトランスフェクション剤(1:3割合の)としてリポフェクタミン2000(Life Technologies)を伴う種々のDRIL分子(4.5μg)のトランスフェクションの24時間前に5cm直径のペトリ皿中で抗体なしの培地中に播種した。トランスフェクションの終わりに、細胞を照射するか(4GY)又は有糸分裂阻害剤:ノコダゾール(200nM)、ナベルビン(100nM)又はタキソール(200nM)により処理した。約16時間後に、薬物を除去しそして細胞を回復させた。137セシウム源からのγ線により細胞照射を行った。24時間の回復(recovery)の後に、細胞を集めそしてFACS、ウエスタンブロット分析のため使用し又はクローン原性(生存)及び各処理の効果を決定するために使用した。
放射線治療と共同のDRIL分子のin vivo活性は、放射線耐性細胞系(喉頭がんに由来するHep2)の皮下注射によりを又は腫瘍断片(グリオブラストーマに由来するU87細胞系の皮下注射により前もって得られた)によりヒト腫瘍を異種移植されたヌードマウスを使用することにより評価された。
1)照射の分割、3×2Gy/週は、ヒト臨床プロトコールを回顧すると、最善の放射線増感を与え;
2)放射線増感は用量依存性である:1ナノモル(20μg)DRIL32−PEG>0.3ナノモル(6μg)DRIL32−PEGであり、0.1ナノモル(2μg)DRIL32−PEGにおいて効果なし;
3)放射線増感はDRIL32−PEGの腫瘍内注入と電離放射線との間の滞留時間(dwell time)に依存する:5時間>>1時間
4)DRIL分子は製造者の指示に従ってトランスフェクション剤(superfect、DOGS又はPEI)と共に使用されなければならない、
ということが示された。
DRIL分子が抗がん剤化学療法を増感する能力を評価するために、内因性マウス腫瘍モデルが選ばれた。このために、K−RasV12G及び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。それらは、2つのトランスジェニックマウスを交配させる(breeding)ことにより得られた:1つはマウスビリンプロモーターの制御下のK−RasV12G突然変異体(pVill/K−rasV12G)を有し(Janssen et al., 2002)、他方は、1つの対立遺伝子におけるApc1638N突然変異を含有する(Fodde et al., 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ヶ月齢で消化管に自然発生的腫瘍を発生しそして急に死亡した。
Claims (20)
- DNA損傷抗がん性治療に対する腫瘍感受性を高めるための医薬組成物であって、
2’−デオキシヌクレオチド主鎖またはDNAでできた24〜100bpの二本鎖部分を含み;少なくとも1つの自由端を有し;ヘアピン分子であり;そして二本鎖切断修復のNHEJ経路に関与する少なくともKuタンパク質により結合するための基質である核酸分子
を含む医薬組成物。 - DNA損傷抗がん性治療と組み合わせてがんを処置するための医薬組成物であって、
2’−デオキシヌクレオチド主鎖またはDNAでできた24〜100bpの二本鎖部分を含み;少なくとも1つの自由端を有し;ヘアピン分子であり;そして二本鎖切断修復のNHEJ経路に関与する少なくともKuタンパク質により結合するための基質である核酸分子
を含む医薬組成物。 - 該分子が、DNA断片である、請求項1又は2に記載の医薬組成物。
- 該分子がヘアピン核酸分子であり、そしてそのループが核酸又は化学的基を含む、請求項1〜3のいずれか1項に記載の医薬組成物。
- ループが、リンカー、ヘキサエチレングリコール又はテトラデオキシチミジレートである、請求項1〜4のいずれか1項に記載の医薬組成物。
- 自由端が、平滑、又は5’−若しくは3’−突き出しである、請求項1〜5のいずれか1項に記載の医薬組成物。
- 該分子が、in vitroで放射線で高められた変則的な外来性DNA組込みを阻害する、請求項1〜6のいずれか1項に記載の医薬組成物。
- 該分子が、細胞核中に細胞により摂取されることができる、請求項1〜7のいずれか1項に記載の医薬組成物。
- 該分子が、ホスホジエステル主鎖、又は化学的に修飾されたホスホジエステル主鎖、又は一又は複数の化学的基を有する他の主鎖を含む、請求項1〜8のいずれか1項に記載の医薬組成物。
- 該分子が、一又は複数の2’−リボヌクレオチドを含む、請求項1〜9のいずれか1項に記載の医薬組成物。
- 該主鎖が、メチルホスホネート、ホスホルアミデート、ホスホロチオエート、モルホリノ核酸、2’−O,4’−C メチレン/エチレン橋かけされたロックされた核酸、ペプチド核酸(PNA)、短鎖アルキル、あるいは可変長さのシクロアルキル糖間結合又は短鎖ヘテロ原子若しくは複素環糖内結合を含む、請求項9又は10に記載の医薬組成物。
- 核酸が、各ストランドの端部又は少なくとも3’端部ストランドに一又は複数の化学的基を含む、請求項1〜11のいずれか1項に記載の医薬組成物。
- 核酸が、各ストランドの端部又は少なくとも3’端部ストランドに一又は複数のホスホロチオエートを含む、請求項12に記載の医薬組成物。
- 核酸が、DNA複製、DNA修復又は損傷シグナリングプロセスを妨害する少なくとも1つの埋め込まれたエレメントを更に含み、該少なくとも1つのエレメントは、二本鎖分子の中心又は端部で組み込まれている、請求項1〜13のいずれか1項に記載の医薬組成物。
- 核酸が、a)ヘキサエチレングリコール鎖、b)3’−修飾されたヌクレオチド、
c)テトラデオキシチミジレート(T4)を含む、請求項14に記載の医薬組成物。 - 該分子が、化学合成、半生合成又は生合成により製造される、請求項1〜15のいずれか1項に記載の医薬組成物。
- DNA損傷抗がん性治療が、放射線治療及び化学療法から選択される、請求項1〜16のいずれか1項に記載の医薬組成物。
- がんが、グリオブラストーマ又は咽頭がんである、請求項1〜17のいずれか1項に記載の医薬組成物。
- がんが、放射線及び/又は化学療法に高耐性である、請求項1〜18のいずれか1項に記載の医薬組成物。
- 分子が、静脈内、腫瘍内若しくは皮下注射により、又は経口経路により投与される、請求項1〜19のいずれか1項に記載の医薬組成物。
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JP2021515580A (ja) | 2018-03-13 | 2021-06-24 | オンクセオOnxeo | がんの治療における獲得耐性に対抗するdbait分子 |
CN112313241A (zh) | 2018-04-17 | 2021-02-02 | 总医院公司 | 核酸结合、修饰、和切割试剂的底物偏好和位点的灵敏体外试验 |
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TW202214857A (zh) | 2020-06-19 | 2022-04-16 | 法商昂席歐公司 | 新型結合核酸分子及其用途 |
WO2023111203A1 (en) | 2021-12-16 | 2023-06-22 | Onxeo | New conjugated nucleic acid molecules and their uses |
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EP0649467B1 (en) * | 1992-07-02 | 1998-09-16 | HYBRIDON, Inc. | Self-stabilized oligonucleotides as therapeutic agents |
US6441158B1 (en) * | 1997-12-31 | 2002-08-27 | Medical College Of Georgia Research Institute, Inc. | Oligomers that bind to ku protein |
EP0978561A1 (en) * | 1998-08-07 | 2000-02-09 | Hoechst Marion Roussel Deutschland GmbH | Antisense oligonucleotides for the inhibition of VEGF expression |
US7060690B2 (en) * | 2001-01-22 | 2006-06-13 | Genta Incorporated | Methods and compositions for treating a cell-proliferative disorder using CRE decoy oligomers, BCL-2 antisense oligomers, and hybrid oligomers thereof |
CA2476468A1 (en) | 2002-02-13 | 2003-08-21 | Medbridge, Inc. | Protein carrier system for therapeutic oligonucleotides |
AU2003207708A1 (en) | 2002-02-20 | 2003-09-09 | Sirna Therapeutics, Inc. | Rna interference mediated inhibition of map kinase genes |
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EP1675954B1 (en) | 2010-10-20 |
ATE485375T1 (de) | 2010-11-15 |
CY1111060T1 (el) | 2015-06-11 |
JP2007510405A (ja) | 2007-04-26 |
CA2542942C (en) | 2014-04-29 |
JP4743789B2 (ja) | 2011-08-10 |
PL1675954T3 (pl) | 2011-04-29 |
WO2005040378A1 (en) | 2005-05-06 |
US7595302B2 (en) | 2009-09-29 |
US20070197458A1 (en) | 2007-08-23 |
AU2004284228B2 (en) | 2010-04-08 |
SI1675954T1 (sl) | 2011-01-31 |
AU2004284228A1 (en) | 2005-05-06 |
CN1871350B (zh) | 2014-10-15 |
PT1675954E (pt) | 2010-12-27 |
CN1871350A (zh) | 2006-11-29 |
DK1675954T3 (da) | 2011-01-10 |
DE602004029699D1 (de) | 2010-12-02 |
ES2354359T3 (es) | 2011-03-14 |
CA2542942A1 (en) | 2005-05-06 |
EP1526177A1 (en) | 2005-04-27 |
EP1675954A1 (en) | 2006-07-05 |
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