JP5841938B2 - 治療効能のある変形核酸及びグアノシンを含有するオリゴヌクレオチド変形体 - Google Patents
治療効能のある変形核酸及びグアノシンを含有するオリゴヌクレオチド変形体 Download PDFInfo
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- JP5841938B2 JP5841938B2 JP2012518491A JP2012518491A JP5841938B2 JP 5841938 B2 JP5841938 B2 JP 5841938B2 JP 2012518491 A JP2012518491 A JP 2012518491A JP 2012518491 A JP2012518491 A JP 2012518491A JP 5841938 B2 JP5841938 B2 JP 5841938B2
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- oligonucleotide
- guanosine
- acid
- cancer
- modified nucleic
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Description
通常、抗癌剤として用いている物質は相当な毒性を持っており、癌細胞のみ選択的に除去できないため、癌が発生した後、その治療だけでなく、癌の発生を予防するための毒性が少なく、効果的な抗癌剤の開発が切実に求められている。
このようなグアニン四重鎖を形成するオリゴヌクレオチドは、米国特許第7314926、米国特許公開第2007−105805号に記載したように、癌細胞の表面にたくさん発現している特定のタンパク質と結合した後、エンドサイトーシスにより癌細胞に浸透し、細胞死滅に関連したタンパク質と結合して細胞成長を阻害すると知られており、細胞毒性効果(cytotoxic effect)よりも細胞成長静止効果(cytostatic effect)により細胞死滅を誘導すると報告されている[Paula J. Bates et al., The journal of Biological Chemistry 1999 26369-26377; Bruna et al., FEBS journal 2006 1350-1361]。
このようにグアニン四重鎖構造を形成するオリゴヌクレオチドが多様な疾患に対して効果的であるため、研究者らがこれに対する研究を行い、現在、抗癌剤として臨床試験中である[Paula J. Bates et al., Experimental and Molecular Pathology (2009) 151-164]。
臨床薬品のAS−1411は、グアニン四重鎖を形成するオリゴヌクレオチドとして癌細胞に過剰発現しているヌクレオリン(nucleolin)と結合することにより、優れた細胞成長阻害効果があると報告された。また、生体内で正常細胞に及ぼす影響を最小化し、薬剤耐性を有する癌細胞腫に対しても複合的に死滅率を増大させると判断されるため、新しい抗癌剤として期待されている[Christopher R. Ireson et al., Mol Cancer Ther. 2006 Dec;5(12) :2957-62]。
代表的な治療用変形核酸は5−フルオロウラシル(5−fluorouracil、5−FU)が挙げられる。5−FUは、1950年代末に代謝拮抗物質系の抗癌剤として開発され、チミジル酸生成酵素(thymidylate synthase)を遮断して抗癌効果を現した[Piedo et al., J Clin Oncol 1988, 1953-1664]。また、5−フルオロデオキシウリジン(5−flurorodeoxyuridine、5−FdU)、5−フルオロデオキシシチジン(5−flurorodeoxycytidine、5−FdC)、5−フルオロウリジン(5−fluorouridine)のような5−フルオロピリミジン(5−fluoropyrimidine)系のヌクレオシド(nucleoside)形態のプロドラッグ(prodrug)が広範囲に大腸、乳房、頭頸部などに対して癌治療を目的として40年以上使用され、現在臨床で用いられている[Thomas et al., Clin Exp Pharmacol Physiol. 1998 887-895; Heidelberger et al., Nature 1957 179:663-666; Longley et al., Nat Rev Cancer 2003 330-338; Beumer et al., Cancer Chemother Pharmacol 2008 363-368; Song et al., Clinical cancer research. 1997, 901-909]。
このような5−フルオロデオキシウリジン(5−flurorodeoxyuridine)、5−フルオロデオキシシチジン(5−flurorodeoxycytidine)、5−フルオロウリジン(5−fluorouridine)ヌクレオシドがオリゴヌクレオチドに含まれるようにするホスホラミダイト(phosphoramidite)製剤が合成され、固相DNA合成機で治療的ヌクレオシドが含まれたオリゴヌクレオチドの合成が可能になった[Gmeiner et al., J. Org. Chem. 1994, 5779-5783; Schmidit et al., Nucleic Acids Research, 1992, 2421-2426; Stolarski et al., Biochemistry 1992, 31, 7027-7042]。
従って、本発明は、1つ以上の治療効能のある変形核酸と豊富なグアノシンが含まれた新規なオリゴヌクレオチド変形体を提供することにその目的がある。
また、本発明は、前記オリゴヌクレオチド変形体又はその薬学的に許容可能な塩を有効性分として含有する癌予防及び治療用組成物を提供することに他の目的がある。
また、本発明は、前記オリゴヌクレオチド変形体又はその薬学的に許容可能な塩を有効性分として含有する癌予防及び治療用組成物を他の特徴とする。
本発明は、グアノシンに富み、グアニン四重鎖(G−quardruplex)を形成するオリゴヌクレオチドが細胞毒性を有する変形核酸を含むように製造したオリゴヌクレオチドに関する。
本発明に用いられるグアニン四重鎖(G−quardruplex)は、グアノシン(G)として代表的に言及される2’−デオキシグアノシン(2−deoxy−guanosine)、グアノシン(guanosine)、2’−O−メチル−グアノシン(2’−O−methyl−guanosine)、2’−フルオロ−グアノシン(2’−F−guanosine)、LNA(Locked Nucleic Acid)−グアノシン、D−デオキシグアノシン、及びD−グアノシンから選択された1種又は2種以上(図1参照)などに富み、特定配列の場合、4つのグアノシンが1平面に位置してフーグステン(hoogsten)型の水素結合を形成して四重螺旋構造を有するオリゴヌクレオチドをいい、これに治療的効果を有する変形核酸を導入するように合成される。
グアノシンに富み、グアニン四重鎖(G−quardruplex)構造を形成するオリゴヌクレオチドは、癌細胞に選択的に結合し、細胞内で様々な機序により癌細胞の成長を阻害すると知らされている。
具体的に、本発明に用いられるウリジン又はシチジン由来の治療用変形核酸(N)は、次の式(1)のウリジン又は式(2)のシチジンのようなピリミジン系のヌクレオチドが好ましく、前記ヌクレオチドを通常の方法[Oligonucleotides and Analogues: A Practical Approach 1991 Fritz Eckstein et al., IRL Press: Oxford]によりホスホラミダイト形態に製造してもよく、ヌクレオチドホスホラミダイトを、グレンリサーチ(glenresearch)社、ベリー・アンド・アソシエイツ(Berry and Associates)社、オキノス(Okeanos Tech)社、ケムジーンズ(Chemgenes)社、プロリゴ(Proligo)社などから購入して既知の方法によりDNA合成機を用いた固相合成法によりグアノシンに富んだオリゴヌクレオチドに含まれるように生産してもよい。
本発明は、「GxHyNz」配列で表されるオリゴヌクレオチド変形体をその特徴とする。(配列において、Gはグアノシン又はグアノシン誘導体、Hはグアノシンでない核酸、Nはウリジン又はシチジン由来の治療的効能を有する変形核酸であり、G、H、Nは順列により無作為に配列され、xは1〜30の整数、yは0〜30の整数、zは1〜30の整数であり、ただし、x、y、zの和は60を超えない。)
前記Gはグアノシンであり、好ましくは2’−デオキシグアノシン(2−deoxy−guanosine)、グアノシン(guanosine)、2’−O−メチル−グアノシン(2’−O−methyl−guanosine)、2’−フルオロ−グアノシン(2’−F−guanosine)、LNA(Locked Nucleic Acid)−グアノシン、D−デオキシグアノシン、D−グアノシンから選択された1種又は2種以上であり、Nはシチジン又はウリジン由来の変形核酸であって、好ましくは5−フルオロデオキシウリジン(5−fluorodeoxyuridine)、5−フルオロウリジン(5−fluorouridine)、5−フルオロデオキシシチジン(5−fluorodeoxycytidine)、5−フルオロシチジン(5−fluorocytidine)、5−ヨードデオキシウリジン(5−iododeoxyuridine)、5−ヨードウリジン(5−iodouridine)、5−ヨードデオキシシチジン(5−iododeoxycytidine)、5−ヨードシチジン(5−iododeoxycytidine)、シトシンアラビノシド(Cytosine arabinoside/Ara−C)、2’,2’−ジフルオロデオキシシチジン(Gemcitabine)、カペシタビン(Capecitabine)、及びブロモビニル−デオキシウリジン(bromovinyl−deoxyuridine)から選択された1種又は2種以上であり、これと類似の構造を有する変形核酸を含んでもよい。
本発明による新規なオリゴヌクレオチド変形体は、既存の治療効果を有するヌクレオシド含有治療剤に比べて、著しく向上した癌細胞の細胞死滅効果を有する。
好ましい有機酸との塩として、例えば、ギ酸、酢酸、トリフルオロ酢酸、フタル酸、フマル酸、シュウ酸、酒石酸、マレイン酸、クエン酸、コハク酸、メタンスルホン酸、ベンゼンスルホン酸、p−トルエンスルホン酸などとの塩がある。
本発明の組成物の剤形は、薬剤学的に許容される担体と混合して多様に製造される。また、組成物の剤形は注射剤の場合は単位投薬アンプル又は多数回投薬形態に製造し、経口投与時には錠剤、エリキシル剤、カプセル、懸濁液、トローチ、ウエハー、及びシロップなどの形態に製造し、懸濁液、錠剤、丸薬、カプセル、及び徐放性製剤などに剤形化することができる。
以下、本発明は、次の実施例に基づいて具体的に説明するが、本発明がこれに限定されることはない。
DNA合成は、一般的なDNA固相合成機を用いて1μmoleスケールの合成を実施した。合成に用いられるホスホラミダイトは、グレンリサーチ(Glen research)社のデオキシグアノシン、チミジン、デオキシシチジン、5−フルオロ−デオキシウリジン、Ara−C、TMP−5−フルオロ−デオキシウリジンホスホラミダイトを乾燥したアセトニトリルを用いて0.067M濃度に溶かし、ポリジーン(Polygene)社のDNA固相合成機に装着する。次の表1に提示された配列により合成が行われ、一般的に3’→5’方向に進行するが、最初のヌクレオチドの3’水酸基を樹脂に付着し、1つの塩基が添加される間、大きく4段階の化学反応、すなわち、5’−末端の脱トリチル反応(detritylation)、新たな塩基の付加反応(coupling)、付加反応しないDNA鎖のキャッピング(capping)反応、リン酸基の酸化反応(oxidation)を繰り返し行った。反応が終了すると、保護装置を除去し、合成されたCPGレジンをアンモニア水に入れて55℃で5時間放置し、アンモニア水を乾燥して白色パウダーを得た。ウォーターズ(Waters)の陰イオン交換HPLCコラムを用いてHPLCシステムで1M NaCl溶液を5〜70%に増加して精製を実施した。メインピークを収集し、これに100%エタノールを入れてオリゴヌクレオチドを沈殿させて乾燥した。HPLCを用いた測定結果、純度85%以上のオリゴヌクレオチドが得られ、ESI−LC−MS(Q−TRAP 2000 ESI−MS)を用いて分子量を測定して合成が成功したか否かを把握した。
次の表1の配列以外に、既に治療を目的に報告されたオリゴヌクレオチド配列又はグアニン四重鎖を形成して生理的活性を有する様々な配列に対して上述した方法によりオリゴヌクレオチド変形体を製造することができる。
それぞれのオリゴヌクレオチドを10mM Tris−HCl(pH7.4)溶液に希釈して最終濃度を100μMにした。希釈した溶液を94℃で5分間放置し、氷にチューブを放置した。2M KCl溶液を添加して最終濃度を50mMのKCl溶液にした後、3時間の間60℃で放置し、室温までゆっくり冷やした。それぞれのオリゴヌクレオチドを10mM Tris−HCl(pH7.4)溶液に希釈して10μM濃度にした後、94℃で5分間放置し、氷にチューブを放置した溶液と2M KCl溶液を添加して最終濃度を50mMのKCl溶液にした後、3時間の間60℃で放置し、室温までゆっくり冷やした。
実験前日、96ウェルプレートに1ml当たり103〜104個の前立腺癌細胞のPC−3細胞株が懸濁されている培養液190μlを接種した後、翌日、前記実施例1により製造されたオリゴヌクレオチド溶液10μlを添加して6日間培養した。接種6日後、一般的なXTT方法で細胞死滅を測定した[JBC 1999、26369参考]。
APT−2001、APT−2002、及びAPT−2003に対する細胞死滅率の測定結果、図2に示すように、陽性対照群のAPT−4001と陰性対照群のAPT−4002よりも本発明の新規なオリゴヌクレオチド変形体のAPT−2001、APT−2002、及びAPT−2003のIC50又はIC90が3〜10倍程度優れた細胞死滅効果を確認した(図2)。
前記実施例1により製造されたオリゴヌクレオチドのグアニン四重鎖構造の形成を測定するために、CD(Circular dichroism)分析技術を用いた。
前記実施例1により製造されたオリゴヌクレオチド溶液を1μMにするために、リン酸カリウム緩衝剤に希釈して冷凍保管した。各オリゴヌクレオチドを100μMにするために、10mMリン酸カリウム緩衝剤に希釈して2mlの溶液を製造した後、円偏光二色性(CD、circular dichroism)分析に用いた。CDスペクトルはJARSCO J−810分光偏光計(spectropolarimeter)を用い、20℃で100nm/min走査速度(scan speed)、0.5s反応時間(response time)、2nm帯域幅(band width)、1cm経路長(path length)をもって320nm〜220nm波長まで観察した。
その結果、264nmで最大ピークを示しており、グアニン四重鎖を形成すると知られた対照物質(APT−4001)と同じCDスペクトルを有することを確認した。すなわち、このような結果は、グアニン四重鎖を形成することが文献(M. Lu, Q. Guo, N. R. Kallenback, Biochemistry, 1992, 31, 2455; P. Balagurumoorthy, S. K. Brahmachari, Nucleic Acids Res., 1992, 20, 4061; Proc. Natl. Acad. Sci. U.S.A. 91, 1994, 7658-7662; Biochemistry. 1997, 36, 12498; Biochemistry. 2002, 41, 3676)に報告されており、本発明のオリゴヌクレオチド変形体は、グアニン四重鎖を形成することを確認することができた(図6〜7)。
本発明の有効性分に対して毒性実験を次の通り行った。
APT−2001、APT−2002、及びAPT−2003をそれぞれジメチルスルホキシド(dimethylsulfoxide、DMSO)に溶解して水で希釈し、これをマウス(1群当たり10匹)にそれぞれ1g/kgを投与し、7日間観察したが、死亡したマウスはいなかった。
APT−2001 10mgを含有する注射液剤は次のような方法で製造した。
APT−2001 1g、塩化ナトリウム0.6g、及びアスコルビン酸0.1gを蒸溜水に溶解して100mlを作った。この溶液を容器に入れて20℃で30分間加熱して滅菌させた。
前記注射液剤の構成成分は次の通りである。
有効性分 1g
塩化ナトリウム 0.6g
アスコルビン酸 0.1g
蒸溜水 適量
Claims (2)
- ヌクレオチド配列「GxHyNz」で表される、グアニン四重鎖構造を有するオリゴヌクレオチド変形体であって、配列番号1〜47のいずれかで表されることを特徴とするオリゴヌクレオチド変形体。
- 請求項1に記載のオリゴヌクレオチド変形体又はその薬学的に許容可能な塩を有効成分として含有することを特徴とする癌予防又は治療用医薬組成物。
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