JP5518062B2 - オーロラキナーゼ阻害剤および抗悪性腫瘍剤を含む治療用組み合わせ - Google Patents
オーロラキナーゼ阻害剤および抗悪性腫瘍剤を含む治療用組み合わせ Download PDFInfo
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- JP5518062B2 JP5518062B2 JP2011519103A JP2011519103A JP5518062B2 JP 5518062 B2 JP5518062 B2 JP 5518062B2 JP 2011519103 A JP2011519103 A JP 2011519103A JP 2011519103 A JP2011519103 A JP 2011519103A JP 5518062 B2 JP5518062 B2 JP 5518062B2
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Description
指数関数的に成長したヒト卵巣癌(A2780)および/またはヒト結腸癌(HCT−116)株化細胞を播種し、加湿した5%CO2雰囲気中にて37℃で温置した。薬物を実験培地に添加し、暗所中、37℃にて72時間温置した。上記で定義された式(A)の化合物1および抗悪性腫瘍剤のスカラー用量を、播種の24時間後に媒質に添加した。次の処置スケジュールの1つまたは両方を試験した:同時投与(両方の薬物を細胞に72時間投与する。)および連続的投与(他方の試薬の24時間後に化合物1を投与する。)。薬物溶液は、使用直前に調製した。処置の終わりに、読み取り機としてEnvision(PerkinElmer)を用いる細胞内のアデノシン三リン酸のモニタリングシステム(CellTiterGlo−Promega)によって細胞増殖を決定した。阻害活性を、Assay Explorer(MDL)プログラムを用いて、処置データとコントロールデータとを比較して評価した。細胞成長の50%を阻害する用量を、S字補間曲線を用いて計算した。組み合わせ指数(C.I.)は、相互に非排他的な薬物に関するChou−Talalayの式(Adv Enzyme Regul 1984;22:27−55)に基づく複数の薬剤作用分析に関するコンピュータプログラムを用いて計算したが、ここでC.I.<1は、追加作用よりも大きいことを示す(C.I.>3は強力な拮抗作用を示し;1.3<C.I.<3は拮抗作用;0.8<C.I.<1.3は加算性;0.3<C.I.<0.8は相乗作用;C.I.<0.3は強い相乗性)。
表1に示される結果は、ヒト卵巣癌A2780およびヒト結腸癌HCT−116株化細胞両方において、シスプラチンと組み合わせた化合物1の投与が相乗的な抗腫瘍作用をもたらしたことを示している。
表2に示される結果は、ヒト結腸癌HCT−116株化細胞において、オキサリプラチンと組み合わせた化合物1の投与が相乗的な抗腫瘍作用をもたらしたことを示している。
表3に示される結果は、ヒト結腸癌HCT−116株化細胞において、5−FUと組み合わせた化合物1の投与が相乗的な抗腫瘍作用をもたらしたことを示している。
表4に示される結果は、ヒト卵巣癌A2780において、トポイソメラーゼI阻害剤SN38と組み合わせた化合物1の投与が相乗的な抗腫瘍作用をもたらしたことを示している。
表5に示される結果は、ヒト結腸癌HCT−116株化細胞において、AraCと組み合わせた化合物1の投与が相乗的な抗腫瘍作用をもたらしたことを示している。
Harlan(イタリア)からのBalb,Nu/Nuオスマウスを、紙フィルターカバー、餌、滅菌された床および酸性化水を備えたケージ中に維持した。BX−PC3ヒト膵癌のフラグメントを胸腺欠損マウスに皮下移植した。この腫瘍モデルはゲムシタビンに対して感受性であることが以前から示されていたため、またゲムシタビンは膵癌のための標準的な処置であるため、この腫瘍モデルを選択した。ゲムシタビンを用いた処置は、腫瘍が触知可能となった腫瘍移植後9日目に開始した。化合物は、処置直前に調製した。
Harlan(イタリア)からのBalb,Nu/Nuオスマウスを、紙フィルターカバー、餌、滅菌された床および酸性化水を備えたケージ中に維持した。A2780ヒト卵巣癌細胞は、American Type Culture Collection(Rockville,MD)から得て、10%FBSで補完されたRPMI媒質中の連続培地として37℃、5%CO2にてインビトロで維持した。インビボ実験に関して、8×106A2780細胞を、胸腺欠損マウスにて皮下移植した。この腫瘍モデルは白金誘導体に対して感受性であるため、また卵巣癌におけるこの薬物の使用を基準にして選択された。
Harlan(イタリア)からのBalb,Nu/Nuオスマウスを、紙フィルターカバー、餌、滅菌された床および酸性化水を備えたケージ中に維持した。A2780ヒト卵巣癌細胞は、American Type Culture Collection(Rockville,MD)から得て、10%FBSで補完されたRPMI媒質中の連続培地として37℃、5%CO2にてインビトロで維持した。インビボ実験に関して、8×106A2780を、胸腺欠損マウスにて皮下移植した。この腫瘍モデルは白金誘導体に対して感受性であるため、また卵巣癌におけるこの薬物の使用を基準にして選択された。
Harlan(イタリア)からのBalb,Nu/Nuオスマウスを、紙フィルターカバー、餌、滅菌された床および酸性化水を備えたケージ中に維持した。2.5×106DU145前立腺癌細胞(American Type Culture Collection製)を、胸腺欠損マウスにて皮下注射した。この腫瘍モデルは、ドセタキセルがインビボモデルの成長を阻害することが以前に示されている(参考として:Cancer Res.2004 Oct 15,(64):7426−31を参照)ため、また前立腺癌におけるこの薬物の使用の基準(参考として:Approval summary:docetaxel in combination with prednisone for the treatment of androgen−independent hormone−refractory prostate cancer,Clin.Cancer Res.2004 Dec 15;10(24):8147−51を参照)により選択された。
Claims (6)
- 同時、別々または連続使用のための組み合わせた調製物である、請求項1に記載の腫瘍治療用組成物。
- 医薬的に許容される担体、希釈剤または賦形剤と混合する、請求項1に記載の組成物を含む腫瘍治療用医薬組成物。
- 増殖性障害を処置するまたはこの進行を遅延させるための薬剤の調製のための、請求項1または2に記載の組成物の使用。
- 治療が必要なヒトを含む哺乳類における抗悪性腫瘍剤を用いた抗悪性腫瘍治療によって生じる副作用を低下させるための薬剤の調製のための、請求項1または2に記載の組成物の使用。
- 好適な容器の手段において、(a)請求項1に記載の式(A)の化合物1と、(b)シスプラチン、オキサリプラチン、5−フルオロウラシル、ゲムシタビン、シトシンアラビノシド(Ara−C)、SN−38、イリノテカンおよびドセタキセルからなる群から選択される1つまたは複数の抗悪性腫瘍剤との組み合わせを含む腫瘍治療用組成物を含有する商業用のパッケージであって、活性成分が、いずれの場合も遊離の形態またはこれらの医薬的に許容される塩もしくはいずれかの水和物の形態にて存在し、同時、別々または連続的にそれを使用することに関する説明書も伴う、パッケージ。
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DE602007008949D1 (de) * | 2006-11-03 | 2010-10-14 | Nerviano Medical Sciences Srl | Verfahren zur verabreichung einer antitumoralen verbindung |
CN101589045A (zh) * | 2006-11-08 | 2009-11-25 | 先灵公司 | 作为蛋白质激酶抑制剂的咪唑并吡嗪 |
WO2008135232A1 (en) * | 2007-05-02 | 2008-11-13 | Riccardo Cortese | Use and compositions of purine derivatives for the treatment of proliferative disorders |
PL2187967T3 (pl) * | 2007-08-16 | 2013-09-30 | Irm Llc | Sposoby i kompozycje do leczenia raka |
US20110021524A1 (en) * | 2008-01-14 | 2011-01-27 | Irm Llc | Compositions and methods for treating cancers |
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2009
- 2009-07-03 US US13/054,646 patent/US20110117212A1/en not_active Abandoned
- 2009-07-03 WO PCT/EP2009/058413 patent/WO2010009967A1/en active Application Filing
- 2009-07-03 EP EP09780134.4A patent/EP2344156B1/en not_active Not-in-force
- 2009-07-03 ES ES09780134T patent/ES2703739T3/es active Active
- 2009-07-03 CN CN2009801286427A patent/CN102105147B/zh not_active Expired - Fee Related
- 2009-07-03 JP JP2011519103A patent/JP5518062B2/ja not_active Expired - Fee Related
- 2009-07-15 AR ARP090102681A patent/AR072871A1/es unknown
- 2009-07-23 TW TW098124835A patent/TW201008944A/zh unknown
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Also Published As
Publication number | Publication date |
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AR072871A1 (es) | 2010-09-29 |
TW201008944A (en) | 2010-03-01 |
CN102105147B (zh) | 2013-07-03 |
JP2011528680A (ja) | 2011-11-24 |
WO2010009967A1 (en) | 2010-01-28 |
EP2344156A1 (en) | 2011-07-20 |
HK1154344A1 (en) | 2012-04-20 |
ES2703739T3 (es) | 2019-03-12 |
EP2344156B1 (en) | 2018-10-17 |
US20110117212A1 (en) | 2011-05-19 |
CN102105147A (zh) | 2011-06-22 |
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