JP2023506609A - 血液がんを治療するための組成物および方法 - Google Patents
血液がんを治療するための組成物および方法 Download PDFInfo
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Abstract
Description
PV-10で処理を行った、原発性または再発小児白血病患者由来の市販の白血病細胞株11種(表1)と、原発性白血病サンプル2種(表2)とからなるパネルを用いて実施された、予備的なインビトロ細胞培養生存率アッセイの結果を示す。
原発性または再発小児白血病患者由来の細胞株11種(CEM-C1、CCRF-SB、Kasumi-1、KOPN8、Molm-13、Molt-3、Molt-4、MV4-11、SEM、SUP-B15、およびTIB-202)と、原発性白血病患者検体3種の細胞(T-ALL、AML、乳児AML)とからなるパネルに対し、濃度を高めながらPV-10での処理を行い、処理の96時間後にアラマーブルーアッセイで細胞生存率を測定した。標的の調節と細胞死経路の誘導については、ウェスタンブロット、位相差顕微鏡法、およびタイムラプスビデオ顕微鏡法にて調査を行った。
先行研究により、先に述べたハロゲン化キサンテン化合物は、がん性腫瘍細胞に対して、RBと同様の結果をもたらすことが示されている。
A.1×104細胞/mLをBALB/cヌードマウスに皮下注射した。腫瘍が治療可能な体積まで増殖するのに2~3週間を要した。
B.20μLから40μLのハロゲン化キサンテン溶液(0.01、0.001、または0.1%w/v)を、腫瘍に完全に浸潤するまで注射した。薬剤が注入されるにつれて腫瘍が赤色に変化していくのを確認することができた。
C.注射の24時間後、腫瘍にレーザを照射した。レーザ:Coherent社製、Verdi 5W、532nm CWレーザ、200mW/cm2、100J/cm2、処理領域:4cm2。
E.蛍光による特異性の確認:CWレーザで励起された腫瘍内のハロゲン化キサンテン剤の蛍光を目視で観察することにより、腫瘍内送達から24時間後の腫瘍内における化合物の保持を確認した。532nmの励起波長は、メレスグリオ社製フィルタ(部品番号:03 FIM 008)を用いて除去した。化合物の蛍光は、オリンパス株式会社(登録商標)製デジタルカメラ(型番:0-300-L)を用いて記録した。
Claims (37)
- (A)白血病細胞を有する哺乳動物対象に、治療有効量のハロゲン化キサンテン、その薬学的に許容可能な塩またはそのC1-C4アルキルエステルを、薬学的に許容可能な水性媒体に溶解または分散された第1のがん細胞毒性剤として投与するステップと、
(B)前記哺乳動物対象を、前記白血病細胞の死を誘導するのに十分な期間維持するステップと、
を含む、白血病細胞を有する哺乳動物対象を治療する方法。 - 前記ステップは繰り返し行われる、請求項1に記載の方法。
- 前記白血病細胞は、急性B細胞またはT細胞リンパ芽球性白血病、あるいは急性骨髄性白血病である、請求項1に記載の方法。
- 前記接触は、前記哺乳動物対象においてインビボで行われる、請求項1に記載の方法。
- 前記哺乳動物対象は、ヒト、類人猿、サル、実験動物、コンパニオンアニマル、および食用動物からなる群から選択される、請求項4に記載の方法。
- 前記第1のがん細胞毒性剤であるハロゲン化キサンテン、その薬学的に許容可能な塩またはそのC1-C4アルキルエステルは、ローズベンガル、その薬学的に許容可能な塩またはそのC1-C4アルキルエステルである、請求項1に記載の方法。
- 前記ローズベンガル、その薬学的に許容可能な塩またはそのC1-C4アルキルエステルは、ローズベンガル二ナトリウム塩である、請求項6に記載の方法。
- 前記薬学的に許容可能な水性媒体は、ほぼ等張性の水溶液である、請求項1に記載の方法。
- 前記ステップ(A)の投与は、薬学的に許容可能な媒体に溶解または分散された、第2の治療有効量の第2の異なる作用のがん細胞毒性剤の前記哺乳動物対象への投与と併せて実施される、請求項1に記載の方法。
- 前記第2のがん細胞毒性剤は、薬学的に許容可能な固体媒体に溶解または分散されている、請求項9に記載の方法。
- 前記第2のがん細胞毒性剤を含有する前記薬学的に許容可能な固体媒体は、経口投与される、請求項10に記載の方法。
- 前記第2のがん細胞毒性剤は、分子量が約200~約1000Daの低分子である、請求項9に記載の方法。
- 前記低分子は、前記第1のがん細胞毒性剤との相乗効果を示す、請求項9に記載の方法。
- 前記第2のがん細胞毒性剤は、薬学的に許容可能な水性媒体に溶解または分散されている、請求項9に記載の方法。
- 前記第2のがん細胞毒性剤を含有する前記薬学的に許容可能な水性媒体は、静脈内投与される、請求項14に記載の方法。
- 前記第2のがん細胞毒性剤は、無傷モノクローナル抗体またはそのパラトープ含有部分を含む、請求項15に記載の方法。
- 前記無傷モノクローナル抗体またはそのパラトープ含有部分は、免疫チェックポイントタンパク質阻害剤である、請求項16に記載の方法。
- 前記免疫チェックポイントタンパク質阻害剤は、CTLA-4、PD-1、PD-L1、PD-L2、およびOX40からなる群のうちの1つまたは複数から選択される1つまたは複数のタンパク質性物質に結合する、請求項17に記載の方法。
- 前記第1のがん細胞毒性剤および前記第2のがん細胞毒性剤は、同時に、または互いに約3時間以内に投与される、請求項9に記載の方法。
- 白血病細胞を有する哺乳動物対象の治療のための、薬学的に許容可能な水性媒体に溶解または分散された第1のがん細胞毒性剤としての治療有効量のハロゲン化キサンテン、その薬学的に許容可能な塩またはそのC1-C4アルキルエステルの使用であって、前記ハロゲン化キサンテンは、前記白血病細胞の死を誘導するのに十分な期間、前記哺乳動物対象において維持される、使用。
- 前記白血病細胞は、急性B細胞またはT細胞リンパ芽球性白血病、あるいは急性骨髄性白血病である、請求項20に記載の使用。
- 前記使用は、前記哺乳動物対象においてインビボで行われる、請求項20に記載の使用。
- 前記哺乳動物対象は、ヒト、類人猿、サル、実験動物、コンパニオンアニマル、および食用動物からなる群から選択される、請求項20~22に記載の使用。
- 前記第1のがん細胞毒性剤であるハロゲン化キサンテン、その薬学的に許容可能な塩またはそのC1-C4アルキルエステルは、ローズベンガル、その薬学的に許容可能な塩またはそのC1-C4アルキルエステルである、請求項20~23に記載の使用。
- 前記ローズベンガル、その薬学的に許容可能な塩またはそのC1-C4アルキルエステルは、ローズベンガル二ナトリウム塩である、請求項20~24に記載の使用。
- 前記薬学的に許容可能な水性媒体は、ほぼ等張性の水溶液である、請求項20~25に記載の使用。
- 前記白血病細胞を有する哺乳動物対象の治療のための、薬学的に許容可能な媒体に溶解または分散された、第2の治療有効量の第2の異なる作用のがん細胞毒性剤の使用を更に含む、請求項20に記載の使用。
- 前記第2のがん細胞毒性剤は、薬学的に許容可能な固体媒体に溶解または分散されている、請求項27に記載の使用。
- 前記第2のがん細胞毒性剤を含有する前記薬学的に許容可能な固体媒体は、経口投与される、請求項28に記載の使用。
- 前記第2のがん細胞毒性剤は、分子量が約200~約1000Daの低分子である、請求項27に記載の使用。
- 前記低分子は、前記第1のがん細胞毒性剤との相乗効果を示す、請求項28に記載の使用。
- 前記第2のがん細胞毒性剤は、薬学的に許容可能な水性媒体に溶解または分散されている、請求項28に記載の使用。
- 前記第2のがん細胞毒性剤を含有する前記薬学的に許容可能な水性媒体は、静脈内投与される、請求項32に記載の使用。
- 前記第2のがん細胞毒性剤は、無傷モノクローナル抗体またはそのパラトープ含有部分を含む、請求項33に記載の使用。
- 前記無傷モノクローナル抗体またはそのパラトープ含有部分は、免疫チェックポイントタンパク質阻害剤である、請求項34に記載の使用。
- 前記免疫チェックポイントタンパク質阻害剤は、CTLA-4、PD-1、PD-L1、PD-L2、およびOX40からなる群のうちの1つまたは複数から選択される1つまたは複数のタンパク質性物質に結合する、請求項35に記載の使用。
- 前記第1のがん細胞毒性剤および前記第2のがん細胞毒性剤は、同時に、または互いに約3時間以内に投与される、請求項27に記載の使用。
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