JP2012508749A - 多発性骨髄腫治療のためのベンダムスチン、ドキソルビシンおよびボルテゾミブの併用 - Google Patents
多発性骨髄腫治療のためのベンダムスチン、ドキソルビシンおよびボルテゾミブの併用 Download PDFInfo
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- A—HUMAN NECESSITIES
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- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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- A—HUMAN NECESSITIES
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Abstract
【選択図】 なし
Description
対象における多発性骨髄腫を治療する方法を提供する。対象に、有効量の、プロテアソーム阻害剤、ベンダムスチンおよびドキソルビシンを含む組み合わせを投与する。驚いたことに、ベンダムスチンとドキソルビシンとの併用がリンパ腫細胞では拮抗的であることが知られているにもかかわらず、それらの併用には相乗効果が認められる。Chow et al.(2001)"In vitro induction of apoptosis of neoplastic cells in low−grade non−Hodgkin's lymphomas using combinations of established cytotoxic drugs with bendamustine."Haematologica 86:485−93。本発明の方法によれば、治療薬の有効量を減少させることができ、これは、治療を受ける対象の副作用を減少させることができることから、有利である。
H929およびMM1R骨髄腫細胞株をインビトロで培養し、細胞毒性をMTS([3−(4,5−ジメチルチアゾール−2−イル)−5−(3−カルボキシメトキシフェニる)−2−(4−スルフォフェニル)−2H−テトラゾリウム、内塩)試験により測定した。相加活性、拮抗活性、または相乗活性の観点から、併用の効果を、ValerioteおよびLinの方法(Valeriote and Lin,Cancer Chemother Rep 1975;59:895−900)により評価した。繰り返し実験で、ベンダムスチンは単独で時間と用量に依存してMM細胞死を誘起し、48時間後に細胞の50%が致死する濃度(LC50)は34.9±3.4μg/mlであった。また、ドキソルビシンを併用したとき、細胞が48時間薬剤に暴露された時点で、ベンダムスチンは拮抗作用を示さなかった。B+Dの併用で測定された細胞生存率は、個々の薬剤活性を基に算出した細胞生存率の予測値に類似しており、相加効果を示した(図1)。さらに、ベンダムスチンは、ボルテゾミブとの併用で相加効果を示し、そして既に述べたようにドキソルビシンとボルテゾミブは相乗効果を示した(図1)。3種の薬剤全ての併用による効果を試験するために、ベンダムスチン(15μg/ml)およびドキソルビシン(0.03μg/ml)で48時間、細胞を培養し、最後の24時間はボルテゾミブ(2.5mmol/L)を加え、細胞毒性を試験した。B+(D+V)の併用における細胞生存率の予測値は、BおよびD+Vの効果の積より低く(図1)、ベンダムスチンはドキソルビシンおよびボルテゾミブとの併用で相乗効果を示した。
Claims (30)
- 対象の多発性骨髄腫を治療する方法であって、前記対象に、有効量の、プロテアソーム阻害剤、ベンダムスチンおよびドキソルビシンを含む組み合わせを投与することを含む方法。
- 前記ベンダムスチンおよびドキソルビシンを、前記プロテアソーム阻害剤の投与の前に投与する、請求項1に記載の方法。
- 前記プロテアソーム阻害剤を、前記ベンダムスチンおよびドキソルビシンの投与の前に投与する、請求項1に記載の方法。
- 前記ベンダムスチンおよび前記プロテアソーム阻害剤を、前記ドキソルビシンの投与の前に投与する、請求項1に記載の方法。
- 前記ドキソルビシンを、前記ベンダムスチンおよび前記プロテアソーム阻害剤の投与の前に投与する、請求項1に記載の方法。
- 前記プロテアソーム阻害剤およびドキソルビシンを、前記ベンダムスチンの投与の前に投与する、請求項1に記載の方法。
- 前記ベンダムスチンを、前記プロテアソーム阻害剤およびドキソルビシンの投与の前に投与する、請求項1に記載の方法。
- ベンダムスチンを投与し、その後ドキソルビシンを投与し、その後前記プロテアソーム阻害剤を投与する、請求項1に記載の方法。
- ドキソルビシンを投与し、その後ベンダムスチンを投与し、その後前記プロテアソーム阻害剤を投与する、請求項1に記載の方法。
- 前記プロテアソーム阻害剤を投与し、その後ドキソルビシンを投与し、その後ベンダムスチンを投与する、請求項1に記載の方法。
- 前記プロテアソーム阻害剤を投与し、その後ベンダムスチンを投与し、その後ドキソルビシンを投与する、請求項1に記載の方法。
- 前記ドキソルビシンを投与し、その後ベンダムスチンを投与し、その後前記プロテアソーム阻害剤を投与する、請求項1に記載の方法。
- 前記ドキソルビシンを投与し、その後前記プロテアソーム阻害剤を投与し、その後ベンダムスチンを投与する、請求項1に記載の方法。
- 21日周期の4および5日目に前記ベンダムスチンを投与し、
21日周期の1、4、8、および11日目に前記プロテアソーム阻害剤を投与し、かつ21日周期の4日目に前記ドキソルビシンを投与する、請求項1に記載の方法。 - 前記ベンダムスチンを約75〜約250mg/m2/日の用量で投与する、請求項1〜14のいずれか一項に記載の方法。
- 前記プロテアソーム阻害剤を約1.0〜約1.5mg/m2の用量で投与する、請求項1〜15のいずれか一項に記載の方法。
- 前記プロテアソーム阻害剤を約2.0〜約2.5mg/m2の用量で投与する、請求項1〜15のいずれか一項に記載の方法。
- 前記ドキソルビシンはリポソームドキソルビシンの形態で、約20〜約40mg/m2の用量で投与する、請求項1〜17のいずれか一項に記載の方法。
- 前記ベンダムスチンを約90mg/m2/日の用量で投与し、前記プロテアソーム阻害剤を約1.3mg/m2の用量で投与し、かつ前記ドキソルビシンをリポソームドキソルビシンの形態で約30mg/m2の用量で投与する、請求項1〜18のいずれか一項に記載の方法。
- 前記ベンダムスチンを約120mg/m2/日の用量で投与し、プロテアソーム阻害剤を約1.3mg/m2の用量で投与し、かつ前記ドキソルビシンをリポソームドキソルビシンの形態で約30mg/m2の用量で投与する、請求項1〜18のいずれか一項に記載の方法。
- 前記ベンダムスチンを約150mg/m2/日の用量で投与し、プロテアソーム阻害剤を約1.3mg/m2の用量で投与し、かつ前記ドキソルビシンをリポソームドキソルビシンの形態で約30mg/m2の用量で投与する、請求項1〜18のいずれか一項に記載の方法。
- 前記ベンダムスチンを約180mg/m2/日の用量で投与し、プロテアソーム阻害剤を約1.3mg/m2の用量で投与し、かつ前記ドキソルビシンをリポソームドキソルビシンの形態で約30mg/m2の用量で投与する、請求項1〜18のいずれか一項に記載の方法。
- 前記ベンダムスチンを約210mg/m2/日の用量で投与し、プロテアソーム阻害剤を約1.3mg/m2の用量で投与し、かつ前記ドキソルビシンをリポソームドキソルビシンの形態で約30mg/m2の用量で投与する、請求項1〜18のいずれか一項に記載の方法。
- フィルグラスチムを投与することをさらに含む、請求項1〜23のいずれか一項に記載の方法。
- 前記フィルグラスチムを約5μg/kg/日の用量で6日目から開始して好中球がANC>1000に回復するまでSC投与する、請求項24に記載の方法。
- 前記プロテアソーム阻害剤、ドキソルビシンおよびベンダムスチンを静脈内投与する、請求項1〜25のいずれか一項に記載の方法。
- 前記プロテアソーム阻害剤、ドキソルビシンおよびベンダムスチンを腹腔内投与する、請求項1〜26のいずれか一項に記載の方法。
- 前記プロテアソーム阻害剤、ドキソルビシンおよびベンダムスチンを経口投与する、請求項1〜27のいずれか一項に記載の方法。
- 前記プロテアソーム阻害剤が、ボルテゾミブである、請求項1〜28のいずれか一項に記載の方法。
- 前記プロテアソーム阻害剤が、[(1R)−1−[[(2S,3R)−3−ヒドロキシ−2−[6−フェニル−ピリジン−2−カルボニル)アミノ]−1−オキソブチル]アミノ]−3−メチルブチルボロン酸である、請求項1〜28のいずれか一項に記載の方法。
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JPN6014002789; J. Cancer Res. Clin. Oncol.,2006,Vol.132,No.4,p.205-212 * |
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