JPWO2017175827A1 - 合成アミノ酸の癌細胞内取り込みを保持する修飾法と正常細胞を保護する中性子捕捉療法 - Google Patents
合成アミノ酸の癌細胞内取り込みを保持する修飾法と正常細胞を保護する中性子捕捉療法 Download PDFInfo
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Abstract
Description
[1] 癌細胞における含ホウ素化合物の蓄積量を選択的に向上させるために用いられる、少なくとも1種のアミノ酸及び/又は少なくとも1種のアミノ酸輸送系阻害剤を含む組成物又はキット。
[2] 含ホウ素化合物が、含ホウ素置換基を含む芳香族アミノ酸、又は標識された含ホウ素置換基を含む芳香族アミノ酸である、[1]の組成物又はキット。
[3] 少なくとも1種のアミノ酸が芳香族アミノ酸を含む、[1]又は[2]の組成物又はキット。
[4] 少なくとも1種のアミノ酸輸送系阻害剤がL型アミノ酸トランスポーター−1(LAT−1)阻害剤を含む、[1]〜[3]のいずれかの組成物又はキット。
[5] 含ホウ素化合物と、少なくとも1種のアミノ酸及び/又は少なくとも1種のアミノ酸輸送系阻害剤とを含む、癌を中性子捕捉療法(BNCT)により治療するための治療剤又はキット。
[6] 含ホウ素化合物が含ホウ素置換基を含む芳香族アミノ酸である、[5]の治療剤又はキット。
[7] さらに、メルカプトウンデカハイドロドデカボレート(BSH)、ホウ素10を含むリポソーム、ガドリニウム、又はポルフィリン化合物を含む、[5]又は[6]の治療剤又はキット。
[8] 標識された含ホウ素化合物と、少なくとも1種のアミノ酸及び/又は少なくとも1種のアミノ酸輸送系阻害剤を含む、ポジトロン断層法(PET)又は核磁気共鳴画像法(MRI)により癌を診断するための診断剤又はキット。
[9] 標識された含ホウ素化合物が標識された含ホウ素置換基を含む芳香族アミノ酸である、[8]の診断剤又はキット。
[10] 含ホウ素化合物、並びに、少なくとも1種のアミノ酸及び/又は少なくとも1種のアミノ酸輸送系阻害剤を癌細胞における含ホウ素化合物の蓄積量を選択的に向上させる有効量で投与し、癌細胞における該含ホウ素化合物の蓄積量を選択的に向上させた後、該癌細胞に熱中性子又は熱外中性子あるいは混合ビームを照射して該癌細胞を殺傷する工程を含む、中性子捕捉療法(BNCT)により癌を治療するための方法。
[11] 少なくとも1種のアミノ酸輸送系阻害剤が、L型アミノ酸トランスポーター−1(LAT−1)阻害剤であり、有効量の含ホウ素化合物を投与した後で、有効量の少なくとも1種のアミノ酸輸送系阻害剤を投与する、[10]の方法。
[12] 標識された含ホウ素化合物、並びに、少なくとも1種のアミノ酸及び/又は少なくとも1種のアミノ酸輸送系阻害剤を癌細胞における標識された含ホウ素化合物の蓄積量を選択的に向上させる有効量で投与し、癌細胞における該標識された含ホウ素化合物の蓄積量を選択的に向上させた後、該標識された含ホウ素化合物を検出する工程を含む、ポジトロン断層法(PET)又は核磁気共鳴画像法(MRI)により癌を診断するための方法。
[13] 少なくとも1種のアミノ酸輸送系阻害剤が、L型アミノ酸トランスポーター−1(LAT−1)阻害剤であり、有効量の標識された含ホウ素化合物を投与した後で、有効量の少なくとも1種のアミノ酸輸送系阻害剤を投与する、[12]の方法。
本発明は、少なくとも1種のアミノ酸及び/又は少なくとも1種のアミノ酸輸送系阻害剤を含み、癌細胞における含ホウ素化合物の蓄積量を選択的に向上させるために用いられる、組成物又はキットに関する。
本発明は、含ホウ素化合物と、癌細胞における当該含ホウ素化合物の蓄積量を選択的に向上させるために用いられる、少なくとも1種のアミノ酸及び/又は少なくとも1種のアミノ酸輸送系阻害剤を含む、癌をBNCTにより治療するための治療剤又は治療キットに関する。
本方法において、含ホウ素化合物としてBPAを使用し、BPAを投与する0〜30分前からフェニルアラニン及び/又はチロシンを含むアミノ酸輸液の静脈内投与を開始する。BPA投与後20分〜1時間安静にし、BPAを癌細胞に取り込ませる。アミノ酸輸液の静脈内投与に加えて、又は代えて、癌細胞又は癌組織に取り込まれた含ホウ素化合物の量が最大又はその付近となる段階に(例えば、BPA投与終了後から0〜90分後、好ましくは0〜60分後、より好ましくは20〜40分後)、LAT−1に対するアミノ酸輸送系阻害剤の静脈内投与を開始する。その後(例えば、アミノ酸輸送系阻害剤を投与してから10〜20分後)、熱中性子又は熱外中性子あるいは混合ビームを照射する。熱中性子線を照射するときは、前記アミノ酸輸液及び/又は前記アミノ酸輸送系阻害剤の投与を継続していてもよいし、中止してもよい。
本発明は、標識された含ホウ素化合物と、癌細胞における当該標識された含ホウ素化合物の蓄積量を選択的に向上させるために用いられる、少なくとも1種のアミノ酸及び/又は少なくとも1種のアミノ酸輸送系阻害剤を含む、PET又はMRIにより癌を診断するための診断剤又は診断キットに関する。
本方法において、標識された含ホウ素化合物としてFBPAを使用し、FBPAを投与する0〜30分前からフェニルアラニン及び/又はチロシンを含むアミノ酸輸液の静脈内投与を開始する。FBPA投与後20分〜1時間安静にし、FBPAを癌細胞に取り込ませる。アミノ酸輸液の静脈内投与に加えて、又は代えて、癌細胞又は癌組織に取り込まれたFBPAの量が最大又はその付近となる段階に(例えば、FBPA投与終了後から0〜90分後、好ましくは0〜60分後、より好ましくは20〜40分後)、LAT−1に対するアミノ酸輸送系阻害剤の静脈内投与を開始する。その後、FBPAの検出を行い、当該FBPAの集積の有無を指標にして癌の検出を行い、あるいは/並びに、当該FBPAの蓄積量を評価する。FBPAの検出に際しては、前記アミノ酸輸液及び/又は前記アミノ酸輸送系阻害剤の投与を継続していてもよいし、中止してもよい。
悪性黒色腫の転移性脳腫瘍(脳下垂体及び側脳室壁)を発症した24歳の男性に対して、表2に示した組成の総合アミノ酸製剤注射液(200ml)の点滴投与(約4ml/min)を開始した。点滴開始から5分後にFBPA 5ml(158MBq)を静脈注射し、30分間暗室にて安静にした。その後、PETを実施した。なお、アミノ酸輸液の点滴はPETが終了するまで行い、160ml投与した。
アミノ酸輸液の点滴投与を行わなかった以外は、実施例1と同様にしてFBPA(155MBq)を投与し、PETを実施した。18Fで標識されたFBPAをアミノ酸の存在下(実施例1)及び非存在下(比較例1)に投与したときの脳腫瘍組織及びその周辺部におけるPET画像を図1に示す。
癌細胞実験系における集積された10BPAのLAT−1阻害剤による細胞外流出阻害効果の検討
ヒトバーキットリンパ腫細胞(JCRB9119、Ramos(RA1))を、1×107個の細胞数となるように細胞培養フラスコに播種した。10BPAを含む溶液を細胞に添加し、1.5時間インキュベートした。次いで、LAT−1阻害剤であるBCHを含むPBS溶液を上記の細胞に添加し、全体の溶液の最終濃度が5mMとなるように調整して、20分間インキュベートした。対照群では、BCHを含むPBS溶液に代えて、同量のPBSを細胞に添加し、同条件でインキュベートした。細胞をPBSで洗浄した。洗浄した細胞を、過酸化水素及び過塩素酸を用いて灰化処理した。灰化処理した試料に含まれる10Bを、ICP−AESを用いて定量した。Ramos(RA1)細胞を灰化処理した試料に含まれる10Bの定量結果を図2に示す。
Claims (13)
- 癌細胞における含ホウ素化合物の蓄積量を選択的に向上させるために用いられる、少なくとも1種のアミノ酸及び/又は少なくとも1種のアミノ酸輸送系阻害剤を含む組成物又はキット。
- 含ホウ素化合物が、含ホウ素置換基を含む芳香族アミノ酸、又は標識された含ホウ素置換基を含む芳香族アミノ酸である、請求項1に記載の組成物又はキット。
- 少なくとも1種のアミノ酸が芳香族アミノ酸を含む、請求項1又は2に記載の組成物又はキット。
- 少なくとも1種のアミノ酸輸送系阻害剤がL型アミノ酸トランスポーター−1(LAT−1)阻害剤を含む、請求項1〜3のいずれか1項に記載の組成物又はキット。
- 含ホウ素化合物と、少なくとも1種のアミノ酸及び/又は少なくとも1種のアミノ酸輸送系阻害剤とを含む、癌を中性子捕捉療法(BNCT)により治療するための治療剤又はキット。
- 含ホウ素化合物が含ホウ素置換基を含む芳香族アミノ酸である、請求項5に記載の治療剤又はキット。
- さらに、メルカプトウンデカハイドロドデカボレート(BSH)、ホウ素10を含むリポソーム、ガドリニウム、又はポルフィリン化合物を含む、請求項5又は6に記載の治療剤又はキット。
- 標識された含ホウ素化合物と、少なくとも1種のアミノ酸及び/又は少なくとも1種のアミノ酸輸送系阻害剤を含む、ポジトロン断層法(PET)又は核磁気共鳴画像法(MRI)により癌を診断するための診断剤又はキット。
- 標識された含ホウ素化合物が標識された含ホウ素置換基を含む芳香族アミノ酸である、請求項8に記載の診断剤又はキット。
- 含ホウ素化合物、並びに、少なくとも1種のアミノ酸及び/又は少なくとも1種のアミノ酸輸送系阻害剤を癌細胞における含ホウ素化合物の蓄積量を選択的に向上させる有効量で投与し、癌細胞における該含ホウ素化合物の蓄積量を選択的に向上させた後、該癌細胞に熱中性子又は熱外中性子あるいは混合ビームを照射して該癌細胞を殺傷する工程を含む、中性子捕捉療法(BNCT)により癌を治療するための方法。
- 少なくとも1種のアミノ酸輸送系阻害剤が、L型アミノ酸トランスポーター−1(LAT−1)阻害剤であり、有効量の含ホウ素化合物を投与した後で、有効量の少なくとも1種のアミノ酸輸送系阻害剤を投与する、請求項10に記載の方法。
- 標識された含ホウ素化合物、並びに、少なくとも1種のアミノ酸及び/又は少なくとも1種のアミノ酸輸送系阻害剤を癌細胞における標識された含ホウ素化合物の蓄積量を選択的に向上させる有効量で投与し、癌細胞における該標識された含ホウ素化合物の蓄積量を選択的に向上させた後、該標識された含ホウ素化合物を検出する工程を含む、ポジトロン断層法(PET)又は核磁気共鳴画像法(MRI)により癌を診断するための方法。
- 少なくとも1種のアミノ酸輸送系阻害剤が、L型アミノ酸トランスポーター−1(LAT−1)阻害剤であり、有効量の標識された含ホウ素化合物を投与した後で、有効量の少なくとも1種のアミノ酸輸送系阻害剤を投与する、請求項12に記載の方法。
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