JP2012517427A - 5−アザシチジンを用いる、非小細胞肺癌の治療方法 - Google Patents
5−アザシチジンを用いる、非小細胞肺癌の治療方法 Download PDFInfo
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- JP2012517427A JP2012517427A JP2011549167A JP2011549167A JP2012517427A JP 2012517427 A JP2012517427 A JP 2012517427A JP 2011549167 A JP2011549167 A JP 2011549167A JP 2011549167 A JP2011549167 A JP 2011549167A JP 2012517427 A JP2012517427 A JP 2012517427A
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- azacytidine
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Abstract
【選択図】 図1
Description
本明細書においては、シチジン類似体、その塩、溶媒和物、水和物、前駆体及び/又は誘導体を用いる、非小細胞肺癌の治療方法が提供される。本明細書で提供する特定の方法は、5-アザシチジンを含む、2種以上の活性薬剤の組合せを用いる、非小細胞肺癌の治療方法を含む。
癌は、世界的な公衆衛生上の主要な問題であり;米国のみで、2006年に約560,000人が癌で死亡している。例えば、米国死亡データ2006、全米保険医療統計センター(National Center for Health Statistics)、米国疾病管理予防センター(Centers for Disease Control and Prevention)(2009)を参照されたい。医学文献には多くのタイプの癌が開示されている。具体例には、特に血液、骨、皮膚、肺、結腸、乳、前立腺、卵巣、脳、腎臓、膀胱、膵臓及び肝臓が含まれる。一般集団の老化として、及び癌の発生の新しい形態として、癌の発生率は上昇し続けている。癌を患っている患者を治療する有効な治療法を継続する必要がある。
特に定義しない限り、本明細書で用いられる全ての技術的及び科学的用語は、当業者に通常に理解されるのと同じ意味を有する。本明細書において言及される全ての出版物及び特許は引用により本明細書に組み込まれる。
本明細書及び添付する請求の範囲において用いられる場合、不定冠詞「a」及び「an」、並びに定冠詞「the」は、文脈が明らかに示さない限り、複数並びに単数を含む。
一実施態様においては、本明細書において提供される方法は、1種以上のシチジン類似体の投与又は同時投与を含む。特定の実施態様においては、シチジン類似体は5-アザシチジン(アザシチジン)である。特定の実施態様においては、シチジン類似体は5-アザ-2'-デオキシシチジン(デシタビン)である。特定の実施態様においては、シチジン類似体は、5-アザシチジン(アザシチジン)又は5-アザ-2'-デオキシシチジン(デシタビン)である。特定の実施態様においては、シチジン類似体は、例えば:1-β-D-アラビノフラノシルシトシン(シタラビン又はara-C);シュードイソ-シチジン(psi ICR);5-フルオロ-2’-デオキシシチジン(FCdR);2’-デオキシ-2’,2’-ジフルオロシチジン(ゲムシタビン);5-アザ-2’-デオキシ-2’,2’-ジフルオロシチジン;5-アザ-2’-デオキシ-2’-フルオロシチジン;l-β-D-リボフラノシル-2(lH)-ピリミジノン(ゼブラリン);2’,3’-ジデオキシ-5-フルオロ-3’-チアシチジン(エムトリバ);2’-シクロシチジン(アンシタビン);1-β-D-アラビノフラノシル-5-アザシトシン(ファザラビン又はara-AC);6-アザシチジン(6-aza-CR);5,6-ジヒドロ-5-アザシチジン(dH-aza-CR);N4-ペンチルオキシ-カルボニル-5’-デオキシ-5-フルオロシチジン(カペシタビン);N4-オクタデシル-シタラビン;又はエライジン酸シタラビンである。特定の実施態様においては、本明細書において提供されるシチジン類似体は、シチジン又はデオキシシチジンと構造的に関連し、シチジン又はデオキシシチジンの作用を機能的に模倣し、及び/又は拮抗する任意の化合物を含む。
一実施態様において、1種以上の医薬として許容し得る担体と組合せ、活性成分として、1種以上のシチジン類似体、又はその医薬として許容し得る塩若しくは溶媒和物を含む医薬組成物が本明細書中に提供される。一実施態様においては、医薬組成物は、少なくとも1種の非放出制御賦形剤又は担体を含む。一実施態様においては、医薬組成物は、少なくとも1種の放出制御、並びに少なくとも1種の非放出制御賦形剤又は担体を含む。
一実施態様においては、本明細書において提供される医薬組成物は、経口投与のために、固形、半固形、又は液状投与剤形で提供され得る。本明細書で用いられる場合、経口投与には、頬、舌及び舌下投与も含まれる。適切な経口投与剤形には、錠剤、カプセル、丸剤、トローチ、薬用キャンディー、芳香製剤、カシェ剤、ペレット剤、薬物添加チューインガム、顆粒剤、原末、発泡製剤、又は非発泡粉末若しくは顆粒剤、溶液、エマルション、懸濁液、溶液、ウェハ、スプリンクル(sprinkles)、エリキシル剤、及びシロップ剤が含まれるが、これらに限定されない。活性成分に加え、医薬組成物は、結合剤、充填材、希釈剤、崩壊剤、湿潤剤、滑沢剤、流動促進剤、着色剤、色素遊走阻止剤、甘味剤及び香味料を含むが、これらに限定されない1種以上の医薬として許容し得る担体又は賦形剤を含んでもよい。
一実施態様においては、本明細書において提供される医薬組成物は、局所又は全身投与のために、注射、輸液、又は移植により非経口的に投与することができる。本明細書で用いられる場合、非経口投与には、静脈内、動脈内、腹腔内、くも膜下腔内、脳室内、尿道内、嚢内、脳内、筋肉内、滑液嚢内、及び皮下投与が含まれる。
一実施態様においては、本明細書において提供される医薬組成物は、座剤、膣座薬、ブジー、湿布又はパップ剤、ペースト剤、粉末、包帯剤、クリーム、硬膏剤、避妊薬、軟膏剤、溶液、エマルション、懸濁液、タンポン、ゲル、泡、スプレー、又は浣腸剤の形状で、直腸、尿道、膣、又は膣周囲に投与することができる。これらの剤形は、例えば、Remingtonの文献、薬学の化学及び実践(The Science and Practice of Pharmacy)、前述、に開示されたような、従来の手段を用いて製造することができる。
一実施態様においては、本明細書において提供される活性成分は、同時に、又は同じ投与経路で患者に投与されない。他の実施態様においては、適量の活性成分の投与を簡略化することのできるキットが提供される。
本明細書においては、NSCLCを患っている被験者に1種以上のシチジン類似体を投与することにより、NSCLCを治療、予防又は管理する方法が提供される。一実施態様においては、該方法は、1種以上のシチジン類似体を用いてNSCLCを治療することを含む。一実施態様においては、該方法は、1種以上のシチジン類似体を用いてNSCLCを予防することを含む。一実施態様においては、該方法は、1種以上のシチジン類似体を用いてNSCLCを管理することを含む。特定の実施態様においては、シチジン類似体は5-アザシチジン(アザシチジン)である。特定の実施態様においては、シチジン類似体は5-アザ-2’-デオキシシチジン(デシタビン)である。特定の実施態様においては、前記方法は、2種以上の活性成分を同時投与することを含む。特定の実施態様においては、被験者は哺乳動物である。特定の実施態様においては、被験者はヒトである。
本明細書における特定の方法は、例えば、静脈注射(IV)、皮下注射(SC)又は経口投与によりシチジン類似体の投与を提供する。本明細書における特定の実施態様は、治療を必要とする被験者に相乗的治療効果を与えるように、1種以上の追加の活性薬剤と一緒に、シチジン類似体(例えば、5-アザシチジン)を同時投与することを提供する。同時に投与される薬剤は、本明細書に開示されるような、癌治療薬であってもよい。特定の実施態様においては、同時投与される薬剤は、経口的に、又は注射(例えば、IV又はSC)により投与することができる。
特定の実施態様においては、NSCLCを治療するための本明細書において提供される方法は、相乗的治療効果を得るために、シチジン類似体、例えば、5-アザシチジンを、1種以上の治療薬、例えば、癌治療薬と同時に投与する。同時投与される治療薬には、例えば、細胞毒性薬、代謝拮抗剤、葉酸拮抗剤、HDAC阻害剤、例えば、MGCDO103(N-(2-アミノフェニル)-4-((4-(ピリジン-3-イル)ピリミジン-2-イルアミノ)メチル)ベンズアミドとして知られる)、DNA挿入剤、 DNA架橋剤、DNAアルキル化剤、DNA開裂剤、トポイソメラーゼ阻害剤、CDK阻害剤、JAK阻害剤、抗血管新生剤、Bcr-AbI阻害剤、HER2阻害剤、EGFR阻害剤、VEGFR阻害剤、PDGFR阻害剤、HGFR阻害剤、IGFR阻害剤、c-Kit阻害剤、Ras経路阻害剤、PI3K阻害剤、多標的キナーゼ阻害剤、mTOR阻害剤、抗エストロゲン剤、抗アンドロゲン剤、アロマターゼ阻害剤、ソマトスタチン類似体、ERモジュレーター、抗チューブリン剤、ビンカアルカロイド、タキサン、HSP阻害剤、Smoothenedアンタゴニスト、テロメラーゼ阻害剤、COX-2阻害剤、抗転移剤、免疫抑制剤、生物学的薬剤(抗体等)、及びホルモン療法剤が含まれるが、これらに限定されない。特定の実施態様においては、同時に投与される治療薬は、サリドマイド、レナリドミド、又はポマリドマイドである。同時に投与される薬剤は、例えば、経口的に、又は注射により投与することができる。
特定の実施態様においては、病状における本明細書において提供される方法の効果を判定又は予測し、投与計画に関するガイダンスを提供するために、適切な生物マーカーを用いることができる。例えば、本明細書における特定の実施態様は、患者の核酸のメチル化の状態を評価することによって、NSCLCであると診断された患者が、シチジン類似体を含む医薬組成物による治療からの大きな効果を得る可能性が増大しているかどうかを判定するための方法が提供される。特定の実施態様においては、シチジン類似体は5-アザシチジンである。特定の実施態様においては、核酸はDNA又はRNAである。特定の実施態様においては、大きな利益は全体的な生存利益である。特定の実施態様においては、メチル化状態は、1種以上の遺伝子、例えば、NSCLCと関連する遺伝子において分析される。特定の実施態様は、基準DNAメチル化レベルが、5-アザシチジンで治療したNSCLCを患っている患者における、全体的な生存に影響を与えるかどうかを判定するための方法を含む。特定の実施態様は、遺伝子プロモーターのメチル化レベルが、NSCLCを患っている患者の全体的な生存に影響を与えるかどうかを判定するための方法を提供する。
(6.1 実施例1)
特定の細胞タイプのNSCLCの生存能力におけるアザシチジン(AZA)及びデシタビン(DAC)の効果を判定するために試験を実施した。以下の6種の細胞系:A549(表1及び図1)、H1975(表2及び図2)、H23(表3及び図3)、H460(表4及び図4)、及びH1299(表5及び図5)を試験した。
種々のNSCLC細胞タイプにおける、2種の異なるアザシチジン類似体、アザシチジン(AZA)及びデシタビン(DAC)の効果を区別するため、及びこれら2種のシチジン類似体の作用機構を試験するために、細胞周期分布の試験を実施した。これらの試験は、NIM-DAPI分析を用い、AZA又はDACで処理したNSCLC細胞の細胞周期分布を調べた。
種々のNSCLC細胞タイプにおける、2種の異なるアザシチジン類似体、アザシチジン(AZA)及びデシタビン(DAC)の効果を区別するため、及びこれら2種のシチジン類似体の作用機構を試験するために、アポトーシスの試験を実施した。これらの試験は、アネキシンV-FITC/7-AADを用い、AZA又はDACで処理したNSCLC細胞のアポトーシス効果を調べた。
種々のNSCLC細胞タイプにおける、2種の異なるアザシチジン類似体、アザシチジン(AZA)及びデシタビン(DAC)の効果を試験するため、及びこれら2種のシチジン類似体の作用機構を試験するために、メチル化アッセイを実施した。これらの試験は、LINE-1メチル化アッセイを用い、AZA又はDACで処理したNSCLC細胞のメチル化効果を調べた。
種々のNSCLC細胞タイプにおける、2種の異なるアザシチジン類似体、アザシチジン(AZA)及びデシタビン(DAC)の効果を区別するため、及びこれら2種のシチジン類似体の作用機構を試験するために、DNA損傷及びアポトーシス試験を実施した。これらの試験は、0.3 μM、1μM、3μM、又は10μMの濃度で、24時間、48時間、72時間、又は144時間、AZA又はDACで処理したNSCLC細胞のDNA損傷を、ヒストンH2AX(Ser139)リン酸化のためのアッセイを用いて調べた(図10〜12及び14)。これらの試験は、PARP開裂のためのアッセイを用いてアポトーシスをも調べた。試験を行った細胞は、H460、A549及びH1299細胞を含む。
種々のNSCLC細胞タイプにおける、2種の異なるアザシチジン類似体、アザシチジン(AZA)及びデシタビン(DAC)の効果を区別するため、及びこれら2種のシチジン類似体の作用機構を試験するために、NSCLC細胞内の遺伝子発現を分析した。これらの試験は、AZA又はDACで処理したNSCLC細胞内における遺伝子発現の影響を調べた。
実施例5に示すように、AZAによる48時間の処理は、A549、H460、及びH1299細胞において、二重鎖DNA損傷(ヒストン-H2AXリン酸化)を誘発したが、DACは誘発しなかった(図10〜12)。AZA及びDACで処理したNSCLC細胞系のDNA損傷応答を、より明確にするために、NSCLC細胞系を、AZA又はDACで長時間処理した。
細胞生存能力アッセイにおいて、DACと比較してAZAに対するNSCLC細胞系の異なる感受性が、各薬剤のDNAへの取り込みにおける相違に反映しているかどうかを判定するため、DNMT1タンパク質枯渇及びDNA低メチル化を、薬剤のDNAへの取り込みの間接的測定として評価した。A549、H460、及びH1229 NSCLC細胞系を、ある濃度範囲のAZA又はDACで20時間処理した。DNMT1タンパク質濃度は、AZA及びDACの両者により有意に減少した(図15)。DNMT1濃度の濃度依存的減少は、DACで処理したA549細胞を除いて全てのケースで観察され、最も低濃度(0.05μM)で最大の減少が観察された。A549及びH1299細胞において、DNMT1濃度の減少についてDACはAZAよりも強力であった。H460細胞においては、DNMT1濃度の減少について、AZA及びDACは等しい力を有していた(図15)。減少したDNMT1濃度は、早ければ薬剤処理の4時間後に、これらの細胞系内で検出された(図17)。AZA及びDACは、H23細胞系において、DNMT1の時間及び濃度依存的な枯渇をも引き起こした。
シチジン類似体、例えば、5-アザシチジンの、NSCLCを患っている患者を治療する能力(例えば、NSCLCを患っている患者における、特定の細胞タイプのNSCLCの成長を停止又は逆転させる能力を含む)を評価するために臨床試験を実施する。特定の臨床試験においては、5-アザシチジンの投与前に、特定の細胞タイプのNSCLC、例えば、A549、H1975、H23、H460、及びH1299についての試験が患者に行われる。このような試験においては、5-アザシチジンの投与から選択的に利益を得ることが知られている細胞タイプを有する患者が登録される。他の臨床試験においては、特定のNSCLC細胞タイプの分析をしていない、NSCLCを患っている患者が登録される。このような試験においては、任意のNSCLC細胞タイプを患っている患者は、5-アザシチジンを用いる治療の候補者である。
Claims (47)
- 5-アザシチジン、又はその医薬として許容し得る塩、溶媒和物若しくは水和物を被験者に投与することにより、非小細胞肺癌を患っている被験者を治療する方法。
- 前記5-アザシチジン、又はその医薬として許容される塩、溶媒和物若しくは水和物を経口的に投与する、請求項1記載の方法。
- 前記5-アザシチジン、又はその医薬として許容される塩、溶媒和物若しくは水和物を非経口的に投与する、請求項1記載の方法。
- 前記5-アザシチジン、又はその医薬として許容される塩、溶媒和物若しくは水和物を局所に投与する、請求項1記載の方法。
- 前記5-アザシチジンが、約500mg/m2以下の1日投与量をもたらすのに十分な量で存在する、請求項1〜4のいずれか1項記載の方法。
- 5-アザシチジン、又はその医薬として許容し得る塩、溶媒和物若しくは水和物を含む医薬組成物を被験者に投与することにより、非小細胞肺癌を患っている被験者を治療する方法。
- 前記医薬組成物を経口的に投与する、請求項6記載の方法。
- 前記医薬組成物を非経口的に投与する、請求項6記載の方法。
- 前記医薬組成物を局所に投与する、請求項6記載の方法。
- 前記医薬組成物が、約500mg/m2以下の1日投与量をもたらすのに十分な量の5-アザシチジンを含む、請求項6〜9のいずれか1項記載の方法。
- 追加の癌治療薬を被験者に投与することを更に含む、請求項1又は6記載の方法。
- 前記被験者がヒトである、請求項1又は6記載の方法。
- 前記非小細胞肺癌が、ある種の非小細胞肺癌細胞タイプを含む、請求項1〜12のいずれか1項記載の方法。
- 前記細胞タイプがA549である、請求項13記載の方法。
- 前記細胞タイプがH1975である、請求項13記載の方法。
- 前記細胞タイプがH23である、請求項13記載の方法。
- 前記細胞タイプがH460である、請求項13記載の方法。
- 前記細胞タイプがH1299である、請求項13記載の方法。
- 被験者における非小細胞肺癌の細胞タイプの存在を特定し、5-アザシチジンを被験者に投与することを含む、請求項1〜12のいずれか1項記載の方法。
- 前記細胞タイプがA549である、請求項19記載の方法。
- 前記細胞タイプがH1975である、請求項19記載の方法。
- 前記細胞タイプがH23である、請求項19記載の方法。
- 前記細胞タイプがH460である、請求項19記載の方法。
- 前記細胞タイプがH1299である、請求項19記載の方法。
- 前記非小細胞肺癌が、5-アザシチジンに対して感受性である細胞タイプを含む、請求項1〜13及び19のいずれか1項記載の方法。
- 前記非小細胞肺癌が、5-アザシチジンがヒストンH2AXのリン酸化を誘発する細胞タイプを含む、請求項1〜13及び19のいずれか1項記載の方法。
- 前記非小細胞肺癌が、5-アザシチジンがDNAの損傷を誘発する細胞タイプを含む、請求項1〜13及び19のいずれか1項記載の方法。
- 前記非小細胞肺癌が、5-アザシチジンがPARPの開裂を誘発する細胞タイプを含む、請求項1〜13及び19のいずれか1項記載の方法。
- 前記非小細胞肺癌が、5-アザシチジンが細胞死を誘発する細胞タイプを含む、請求項1〜13及び19のいずれか1項記載の方法。
- 前記非小細胞肺癌が、5-アザシチジンがアネキシンV染色に陽性である細胞を誘発する細胞タイプを含む、請求項1〜13及び19のいずれか1項記載の方法。
- 前記非小細胞肺癌が、5-アザシチジンがsub-G1期において細胞の蓄積を誘発する細胞タイプを含む、請求項1〜13及び19のいずれか1項記載の方法。
- 前記非小細胞肺癌が、5-アザシチジンが差次的遺伝子発現を誘発する細胞タイプを含む、請求項1〜13及び19のいずれか1項記載の方法。
- 5-アザシチジン、又はその医薬として許容し得る塩、溶媒和物若しくは水和物を含む医薬組成物を含む、非小細胞肺癌治療用キット。
- 前記医薬組成物が少なくとも1種の医薬として許容し得る担体又は賦形剤を更に含む、請求項33記載のキット。
- 癌治療薬を含む第二の医薬組成物を更に含む、請求項33記載のキット。
- 非小細胞肺癌の治療、予防又は管理のための薬剤の製造における、5-アザシチジン、又はその医薬として許容し得る塩、溶媒和物若しくは水和物の使用。
- 非小細胞肺癌の治療、予防又は管理のための薬剤の製造における、5-アザシチジン、又はその医薬として許容し得る塩、溶媒和物若しくは水和物を含む医薬組成物の使用。
- 前記非小細胞肺癌が、ある種の非小細胞肺癌細胞タイプを含む、請求項36又は37の使用。
- 前記非小細胞肺癌の細胞タイプが、A549、H1975、H23、H460及びH1299から選択される、請求項38記載の使用。
- 前記非小細胞肺癌が、5-アザシチジンに感受性である細胞タイプを含む、請求項36〜39のいずれか1項記載の使用。
- 前記非小細胞肺癌が、5-アザシチジンがヒストン52AXのリン酸化を誘発する細胞タイプを含む、請求項36〜39のいずれか1項記載の使用。
- 前記非小細胞肺癌が、5-アザシチジンがDNAの損傷を誘発する細胞タイプを含む、請求項36〜39のいずれか1項記載の使用。
- 前記非小細胞肺癌が、5-アザシチジンがPARPの開裂を誘発する細胞タイプを含む、請求項36〜39のいずれか1項記載の使用。
- 前記非小細胞肺癌が、5-アザシチジンが細胞死を誘発する細胞タイプを含む、請求項36〜39のいずれか1項記載の使用。
- 前記非小細胞肺癌が、5-アザシチジンがアネキシンV染色に陽性である細胞を誘発する細胞タイプを含む、請求項36〜39のいずれか1項記載の使用。
- 前記非小細胞肺癌が、5-アザシチジンがsub-G1期において細胞の蓄積を誘発する細胞タイプを含む、請求項36〜39のいずれか1項記載の使用。
- 前記非小細胞肺癌が、5-アザシチジンが差次的遺伝子発現を誘発する細胞タイプを含む、請求項36〜39のいずれか1項記載の使用。
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