JP6224597B2 - グリオーマを処置するための組成物及び方法 - Google Patents
グリオーマを処置するための組成物及び方法 Download PDFInfo
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- JP6224597B2 JP6224597B2 JP2014533645A JP2014533645A JP6224597B2 JP 6224597 B2 JP6224597 B2 JP 6224597B2 JP 2014533645 A JP2014533645 A JP 2014533645A JP 2014533645 A JP2014533645 A JP 2014533645A JP 6224597 B2 JP6224597 B2 JP 6224597B2
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- temozolomide
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Description
本発明は、2011年9月27日に出願された米国特許仮出願第61/539、779号に対する利益を主張する。上記出願の全内容は、参照により組み込まれる。
本発明者等は、本明細書において開示される特定の化合物が、テモゾロマイド等の従来型の化学療法剤との組み合わせにおいて使用される場合、従来型の化学療法剤が単独で使用される場合と比べて、グリオーマのげっ歯類モデルにおいて相乗的な抗腫瘍反応を提供することを発見した。これらの発見は、癌、特に切除不能及び処置不能のグリア芽腫の処置の新規のアプローチを提案する。
本発明の1つの実施形態は、グリオーマの効果を処置または改善するための方法である。本方法は、アンジオテンシン受容体遮断剤、抗真菌薬、ビスホスホネート、オキシトシン阻害剤、インターロイキン1(IL−1)阻害剤、シクロオキシゲナーゼ阻害剤、α2δ電位依存性カルシウムチャネル(VDCC)阻害剤、ジヒドロオロト酸デヒドロゲナーゼ阻害剤、カルシウムチャネル遮断剤、腎塩化ナトリウム共輸送体阻害剤、α2アドレナリンアゴニスト、フェノチアジン系抗精神病薬、カルシニューリン阻害剤、5−HTアゴニスト、アンジオテンシン−変換酵素(ACE)阻害剤、直接的レニン阻害剤、及びそれらの組み合わせから成る群から選択される第一の活性剤の有効量、並びに化学療法剤である第二の活性剤の有効量を、それを必要とする対象に投与することをを含んで成る。
雌性無胸腺ヌードマウス(nu/nu、Harlan)は、8〜12週齢であった。これらのマウスにおいて、一連の皮下移植により、U87MGヒトグリア芽腫(Piedmont Research Center、Morrisville、NC)での異種移植を開始した。それぞれの検定マウスは、大きさ1mm3のU87MG腫瘍フラグメントを受けた。腫瘍の平均の大きさが、80〜120mm3の標的範囲に近づいた時に、テモゾロマイド単独、またはテモゾロマイド及びカンデサルタン・シレキセチル(本実施例では、カンデサルタンと略される)の組み合わせによる処置を開始した。体重及び腫瘍の大きさを監視した。
実験は、1日目の皮下U87MG異種移植片(75〜144mm3)を有する雌性無胸腺ヌードマウスの群(n=10)から成る。1、5、10及び50mg/kgの投与量を、1日1回、21日間(qd×21)、腹腔内(i.p.)に投与するスケジュールで、単剤療法として、カンデサルタンを評価した。テモゾロマイド(5mg/kg p.o.qd×5)及びカンデサルタン(10mg/kg i.p.qd×21)またはバルサルタン(150もしくは30mg/kg i.p.qd×21)の組み合わせも、テモゾロマイド単独(5mg/kg p.o.qd×5)との比較において評価した。試験は、未処置の腫瘍成長コントロール群、及び100mg/kg p.o.qd×5でテモゾロマイドを受けたポジティブコントロール群を含めた。投与は1日目から開始し、そして試験が49日目で終了するまで、腫瘍を毎週2回ずつ測定した。動物を個別に監視し、そしてその腫瘍が2000mm3の体積(約2グラム)に到達した時、または最終日(49日目)に到達した時に、どちらが先に来るとしても、それぞれのマウスをエンドポイントのために安楽死させた。腫瘍サンプルをエンドポイントで収集し、そして組織病理学的分析を行った。
マウス
雌性無胸腺ヌードマウス(nu/nu、Harlan)は、8〜9週齢であり、且つ試験の1日目で、16.7〜25.6グラムの範囲の体重を有した。動物には、自由に飲める水(逆浸透、1ppm Cl)、並びに自由に食せる18.0%の粗タンパク質、5.0%の粗脂肪、及び5.0%の粗繊維から成るNIH 31 Modified and Irradiated Lab Diet(登録商標)を与えた。マウスは、21〜22℃(70〜72°F)及び40〜60%の湿度での12時間光サイクルで固定されたマイクロアイソレーターにおいて放射線を照射したEnrich−o’cobs(商標)実験動物床で飼育した。拘束、畜産、外科手術、餌及び液体調節、及び獣医ケアに関する実験動物のケア及び使用のための指針の提言を順守した。
異種移植は、U87MGヒトグリア芽腫(Piedmont Research Center、Morrisville、NC)により、無胸腺ヌードマウスにおける連続皮下移植により開始した。それぞれの試験マウスは、右脇腹中に皮下生着させるU87MG腫瘍フラグメント(1mm3)を受け、また腫瘍の成長は、80〜120mm3の標的範囲に近づいた平均サイズを監視した。9日後に、1日目の試験に指定された動物を、個々に75〜144mm3の範囲の腫瘍体積及び111〜113mm3の群平均腫瘍体積を有するそれぞれ10匹のマウスから成る15群に対対応させた。腫瘍体積は、以下の式:
を用いて計算した。腫瘍重量は、1mgが1mm3の腫瘍体積と同等であると仮定して推定され得る。
バルサルタン及びカンデサルタンは、乾燥粉末として供給され、それを室温で貯蔵した。さらにバルサルタン及びカンデサルタン乾燥粉末及び投与分を光から保護した。
試験の1日目に、マウスをそれぞれ10匹のマウスから成る15群に分類し、そして表3に要約した処置計画に従い投与を開始した。テモゾロマイド投与は、経口(p.o.)で、1日1回、5日間(qd×5)投与した。他に断りのない限り、それぞれの検定薬剤は、腹腔内(i.p.)に、1日1回、21日間(qd×21)投与した。
キャリパーを用いて週に2回ずつ腫瘍を測定した。動物を個々に監視し、そしてその腫瘍が2000mm3のエンドポイントサイズに達した時、または試験終了時(49日目)に、どちらが先に来るとしても、それぞれのマウスを安楽死させた。それぞれのマウスのエンドポイントまでの時間(TTE)は、以下の方程式:
から計算した。データセットは、試験エンドポイント体積を超える最初の観察、及びエンドポイント体積に速やかに達成した先行する3つの連続的な観察を含んで成った。エンドポイントに到達しない動物は、試験最終日と等しいTTE値を与えられる。事故(NTRa)のせいで、または原因不明(NTRu)で、NTR(処置に関連しない)死に分類される動物は、TTE計算(及び全てのさらなる分析)から排除される。TR(処置に関連した)死、またはNTRm(転移による非処置関連死)と分類される動物は、死亡日と同等のTTE値を与えられる。
により評価されるか、または、コントロール群の中央値TTEのパーセンテージとして表された:
エンドポイントで、コントロール群(群1)中、2匹の動物、並びに群3(5mg/kgのテモゾロマイド)、群8(5mg/kgのテモゾロマイド / 10 mg/kgのカンデサルタン)、及び群9(5mg/kgのテモゾロマイド/150mg/kgのバルサルタン)中、群ごとに3匹の動物から腫瘍サンプルを収集した。それぞれの腫瘍サンプルを10%の中性緩衝ホルマリン中で、16〜24時間保存し、その後に70%のエタノールに移した。保存した腫瘍サンプルを、ヘマトキシリン及びエオシン(H&E)染色、並びにKDR、CD−31、Ki−67及び開裂カスパーゼ−3分析のためにBiotechnics、Inc.(Hillsborough、NC)に輸送した。
1〜5日目までに毎日動物の体重を測定し、その後、試験が終了するまでに週2回動物の体重を測定した。任意の有害事象の明白な兆候についてマウスを頻繁に観察し、観察時に処置に関連した副作用、及び毒性の臨床的兆候を記録した。許容され得る毒性は、試験期間中で20%未満の群平均体重損失、及び10匹の処置動物の中で多くても1匹の処置関連(TR)死、として定義した。より甚大な毒性をもたらす任意の投薬計画は、最大耐性用量(MTD)を上回ると見なされる。死亡が、臨床兆候及び/または剖検から明らかにされたような処置副作用に起因するならばTRと分類され、或いはさらに投与期間の間に、または最終投与の14日以内に起こる未知の事象のせいであるならば、TRと分類され得る。死亡が処置副作用に関連したという証拠が存在しないならば、死亡はNTRと分類される。
全体の生存経験を評価するログランク検定は、選択された群のTTE値間の有意差を分析するために用いた。ログランク検定は、NTR死により試験に属さないものを除き、群中の全ての動物についての個々のTTEを分析する。2匹を追跡した統計的分析を、有意性レベルP=0.05で行った。処置がMTDを上回ると見なされるものの任意の群についての統計的分析は、行わなかった。Kaplan−Meierプロットを構築し、時間の関数として、試験に残っている動物のパーセンテージを示した。これらのプロットは、ログランク検定と同一のデータセットを用いた。
本実施例では、テモゾロマイドとの組み合わせにおいて多様なスケジュールで投与されたカンデサルタンを、皮下U87MGヒトグリア芽腫異種移植片を有するnu/nuマウスにおいて有効性を評価した。
マウス
雌性無胸腺ヌードマウス(nu/nu、Harlan)は、7〜8週齢であり、且つ試験1日目で、20.4〜26.3グラムの範囲の体重を有した。動物のケアは、前述の実施例1に発表した通りである。
異種移植は、Piedmontで維持されたU87MGヒトグリア芽腫で、無胸腺ヌードマウスにおける連続皮下移植により開始した。それぞれの試験マウスは、右脇腹中に皮下生着させるU87MG腫瘍フラグメント(1mm3)を受け、また腫瘍成長は、80〜120mm3の標的範囲に近づいた平均サイズとして監視した。9日後に、個々に63〜144mm3の範囲の腫瘍体積及び101〜103mm3の群平均腫瘍体積を有する1日目の試験として指定された動物を、それぞれ10匹のマウスから成る6群に対応させた。腫瘍体積は、式:
を用いて計算した。腫瘍重量は、1mgが1mm3の腫瘍体積と同等であると仮定して推定され得る。
試験の1日目に、マウスをそれぞれ10匹のマウスから成る6群に分類し、そして表1に要約した処置計画に従い投与を開始した。群1のマウスは処置されず、且つ%TGDの計算のためのコントロールとしての役割を果たした。群2は、経口的に(p.o.)、1日1回、5日間(qd×5)投与される5mg/kgのテモゾロマイドを受け、且つ組み合わせ処置に対する単独療法コントロールとしての役割を果たした。群3〜5は、腹腔内(i.p.)に与えられる10mg/kgのカンデサルタンとの組み合わせにあるテモゾロマイド(5mg/kg p.o.qd×5)を、3つの異なるスケジュール:それぞれ1日1回、35日間(qd×35)、1日1回、5日間(qd×5)、及び1日1回、30日間、6日目に開始(qd×30、6日目開始)において受けた。群6は、100mg/kgのテモゾロマイド p.o. qd×5を受け、且つモデルのためのポジティブコントロールとしての役割を果たした。全ての投与は、個々の動物の体重に対して見積もられた。
キャリパーを用いて週に2回ずつ腫瘍を測定した。動物を個々に監視し、そしてその腫瘍が2000mm3のエンドポイントサイズに達した時、または試験終了時(46日目)に、どちらが先に来るとしても、それぞれのマウスを安楽死させた。それぞれのマウスのエンドポイントまでの時間(TTE)は、上記の実施例2において開示したように計算した。
1〜5日目までに毎日動物の体重を測定し、その後、試験が終了するまでに週2回、動物の体重を測定した。任意の有害事象の明白な兆候についてマウスを頻繁に観察し、観察時に処置に関連した副作用、及び毒性の臨床的兆候を記録した。許容され得る毒性は、試験の間に20%未満の群平均体重損失、及び10匹の処置動物の中で多くても1匹の処置関連(TR)死、として定義した。より甚大な毒性をもたらす任意の投薬計画は、最大耐性用量(MTD)を上回ると見なされる。死亡が、臨床兆候及び/または剖検から明らかにされたような処置副作用に起因するならばTRと分類され、或いはさらに投与期間の間、または最終投与の14日以内に起こる未知の事象のせいであるならば、TRと分類され得る。死亡が処置副作用に関連したという証拠が存在しないならば、死亡はNTRと分類される。NTR死は、死因に基づきさらに特徴化され得る。死亡が事故または人為的ミスからもたらされた場合、NTRaとして分類され得る。剖検が浸潤及び/または転移による腫瘍播種から死亡がもたらされ得たと示したならば、死亡はNTRmとして分類され得る。死因が不明であり、且つ処置副作用、転移、事故または人為的ミスに関連した入手可能な死亡の証拠が存在しない場合、処置副作用のための死亡が排除され得るにも関わらず、死亡はNTRuとして分類され得る。
全体の生存経験を評価するログランク検定は、選択された群のTTE値間の有意差を分析するために用いた。ログランク検定は、NTR死により試験に属さないものを除き、群中の全ての動物についての個々のTTEを分析する。2匹を追跡した統計的分析を、有意性レベルP=0.05で行った。処置がMTDを上回ると見なされるものの任意の群についての統計的分析は、Kaplan−Meierプロットを構築し、時間の関数として、試験で残っている動物のパーセンテージを示した。これらのプロットは、ログランク検定と同一のデータセットを用いた。
一般的に入手可能なU87MGグリオーマヒト腫瘍細胞株の連続継代により作り出した腫瘍フラグメント異種移植モデルにおける組み合わせ有効性について、化合物を評価する。実験群は、8〜12週齢、雌性HRLN nu/nuマウスに生きている異種移植片における連続継代を通して維持された1mm3の腫瘍のサブフラグメントを播種することにより導いた。異種移植されたマウスは、80〜120mgの範囲の腫瘍組織量に達するように(典型的に播種後、5〜10日以内)、それらを化学療法処置のための群に無作為化する。その後マウスにサブ有効用量のテモゾロマイドを投与する。投与は、典型的に5mg/kgで、水ビヒクル中の経口強制補給を介して10mL/kgの用量体積において、1日1回、5日間送達される。組み合せ薬物療法の効果を検定するための実験薬剤は、5mg/kgのテモゾロマイドと同時に投与し、そしてその後に試験が終了するまでの全ての日(典型的に少なくとも20日、後述の表7における「スケジュール」列を参照)において実験化合物単独での投与を継続する。実験化合物は、変化するビヒクル再懸濁中で、且つ多様な経路において、1日1回、10mL/kg以下の用量体積において投与する(後述の表7を参照)。定期的に体重、及び腫瘍組織量について、機械的なキャリパーを有する標準的なプロトコールを用いて全ての動物を評価する。2000mm3超の腫瘍組織量を有する動物は安楽死させ;実験化合物に曝された全てのこれらの動物が、腫瘍組織量閾値に達するまで、全てのマウスについてプロトコールにおける投与及び評価を継続する。
HRLN雌性nu/nuマウスの脇腹中に、1mm3のU87MG腫瘍フラグメントを皮下的に播種した。試験最終日に、最終のキャリパー及び体重測定を行った。
Claims (10)
- 第一の活性剤、及び第二の活性剤を含んで成る、グリオーマを処置または改善するための組み合わせ医薬であって、
前記第一の活性剤が、カンデサルタン、ロサルタン、それらのプロドラッグ及び医薬的に許容され得るそれらの塩から成る群から選択され、
前記第二の活性剤が、テモゾロマイド、そのプロドラッグ、または医薬的に許容され得るそれらの塩である、組み合わせ医薬。 - 前記第一の活性剤が、カンデサルタン・シレキセチルである、請求項1に記載の組み合わせ医薬。
- 前記カンデサルタン・シレキセチルが、1日あたり、約2〜32mgで投与される、請求項2に記載の組み合わせ医薬。
- 前記テモゾロマイドが、1日あたり、約50〜200mg/m2で投与される、請求項1に記載の組み合わせ医薬。
- 前記グリオーマが星状細胞腫である、請求項1に記載の組み合わせ医薬。
- 前記星状細胞腫がグリア芽腫である、請求項5に記載の組み合わせ医薬。
- 前記第一の活性剤及び第二の活性剤が、医薬組成物の一部として投与される、請求項1に記載の組み合わせ医薬。
- 医薬的に許容され得る担体、第一の活性剤、及び第二の活性剤を含んで成る、グリオーマを処置または改善するための組成物であって、
前記第一の活性剤が、カンデサルタン、ロサルタン、それらのプロドラッグ又は医薬的に許容され得るそれらの塩であり、
前記第二の活性剤が、テモゾロマイド、そのプロドラッグ、または医薬的に許容され得るそれらの塩である、組成物。 - 単位剤形である、請求項8に記載の医薬組成物。
- カンデサルタン、そのプロドラッグ、医薬的に許容され得るそれらの塩、及びそれらの組み合わせから成る群から選択される第一の活性剤、並びに
テモゾロマイド、そのプロドラッグ、または医薬的に許容され得るそれらの塩である第二の活性剤
を含んで成る、グリア芽腫を処置または改善するための組み合わせ医薬であって、
前記第一の活性剤及び第二の活性剤は共投与される、組み合わせ医薬。
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