JP6920337B2 - 神経膠腫の治療用の薬剤の調製における化合物の使用 - Google Patents
神経膠腫の治療用の薬剤の調製における化合物の使用 Download PDFInfo
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- JP6920337B2 JP6920337B2 JP2018553286A JP2018553286A JP6920337B2 JP 6920337 B2 JP6920337 B2 JP 6920337B2 JP 2018553286 A JP2018553286 A JP 2018553286A JP 2018553286 A JP2018553286 A JP 2018553286A JP 6920337 B2 JP6920337 B2 JP 6920337B2
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Description
神経膠芽腫のRNA及びcDNAを得る
80個の神経膠芽腫試料を医薬品倫理委員会の基準に従った手術により収集した。各試料は、試料を提供した患者及びその患者の医師から同意書を得て収集した。試料の性別、年齢、及び疾患のタイプを表1に示す。
神経膠芽腫中における本発明の融合タンパク質の検出
実施例1で調製した各試料の二本鎖cDNAを鋳型とし、以下のプライマー配列を使用して増幅させた。
順方向プライマー:
配列番号11 ATGCGAATCCTAAAGCGTTTCCTCG
逆方向プライマー:
配列番号12 CTATGATGTCTCCCAGAAGGAGGCT
神経膠芽腫中の融合タンパク質のイムノブロッティングによる確認
実施例1で収集した80個の神経膠芽腫試料の全タンパク質を、融合タンパク質のイムノブロッティングによる確認に供した。
神経膠芽腫細胞の増殖に対する式Aで表される化合物の阻害活性の決定
式Aで表される化合物及びクリゾチニブ、並びに式Aの構造と同様の構造をそれぞれ有する式B〜Hで表される化合物を使用して、神経膠芽腫細胞の増殖に対する阻害活性を試験する実験を行った。
神経膠芽腫のin−vivoでの腫瘍形成に対する式Aで表される化合物の阻害活性の決定
神経膠芽腫のin−vivoでの腫瘍形成の阻害についての実験を、式Aで表される化合物及びクリゾチニブを用いて実施した。
最初に、腫瘍を保有するマウスモデルを確立した。約16〜18gの体重の6〜8週齢の、母系BALB/c(nu/nu)ヌードマウスをVital River社から購入した。実施例4で調製した「PCDH−blank発現細胞」及び「PCDH−ZM2−2発現細胞」をそれぞれPBSで107細胞/mlの懸濁液になるように調製した。75%のエタノールで消毒したヌードマウスに、右の肩甲骨領域に100μlの細胞懸濁液を皮下注射した。ここでは、PCDH−blank発現細胞を7匹のヌードマウスに注射し、PCDH−ZM2−2発現細胞を21匹のヌードマウスに注射した。皮下接種後、約2〜3日で、固形腫瘍の形成が観察され始め、約15日後に腫瘍が形成されたことが分かった。腫瘍の大きさ及びマウスの体重の変化を1週間に2回測定した。「PCDH−blank発現細胞」の注射により得た腫瘍を保有するマウスを「ベクターマウス(1)」と命名し、「PCDH−ZM2−2発現細胞」の注射により得た腫瘍を保有するマウスを「ZM2−2マウス(1)」と命名した。
最初に、腫瘍を保有するマウスモデルを確立した。実施例4で調製した「PCDH−blank発現細胞」及び「PCDH−ZM2−2発現細胞」をそれぞれ、PBSで105細胞/5μlの懸濁液になるように調製した。75%のエタノールで消毒したヌードマウスに100μlの細胞懸濁液を接種した。(大泉門の右側に2mm、後ろ側に2mm離れた)細胞接種位置をマウス用の脳の定位固定装置を用いて決定した。注射の深さは3.5mmであり、その後0.6mm上昇させた。5μlの細胞溶液をそれぞれ、各マウスに注射した。注射後、マウスを更に1時間そのまま維持し、次に、従来の皮膚閉鎖を行った。頭蓋内腫瘍を観察した後、「PCDH−blank発現細胞」を用いて得た腫瘍を保有するマウスを「ベクターマウス(2)」と命名し、「PCDH−ZM2−2発現細胞」を用いて得た腫瘍を保有するマウスを「ZM2−2マウス(2)」と命名した。
Claims (12)
- 式A:
前記神経膠腫は、融合タンパク質を発現する神経膠芽腫であり、前記融合タンパク質は、PTPRZ1のエキソン1、エキソン1〜2、エキソン1〜3、又はエキソン1〜8から翻訳されるタンパク質部分を、c−Metのエキソン2〜24から翻訳されるタンパク質部分に対して融合することにより形成され、
PTPRZ1の前記タンパク質部分は、c−Metの前記タンパク質部分のN末端に配置される;または
前記神経膠腫は、融合転写物を含有する神経膠芽腫であり、前記融合転写物は、PTPRZ1のエキソン1、エキソン1〜2、エキソン1〜3、又はエキソン1〜8から転写される1つのRNA部分と、c−Metのエキソン2〜24から転写される1つのRNA部分とを連結することにより形成され、
PTPRZ1の前記RNA部分は、c−Metの前記RNA部分の5’末端に配置される
ことを特徴とする使用。 - 前記神経膠腫は二次性神経膠芽腫であることを特徴とする、請求項1に記載の使用。
- 前記融合タンパク質は、配列番号1で示されるアミノ酸配列を含むことを特徴とする、請求項1に記載の使用。
- 前記融合タンパク質は、配列番号2で示されるアミノ酸配列を更に含むことを特徴とする、請求項3に記載の使用。
- 前記融合タンパク質はN末端に、配列番号1で示されるアミノ酸配列及び配列番号2で示されるアミノ酸配列を含む
ことを特徴とする、請求項3に記載の使用。 - 前記融合タンパク質は、配列番号3、配列番号4、配列番号5、又は配列番号6で示されるアミノ酸配列を含む
ことを特徴とする、請求項3から5のいずれか一項に記載の使用。 - 前記融合タンパク質の前記アミノ酸配列は、配列番号3、配列番号4、配列番号5、又は配列番号6で示されるものである
ことを特徴とする、請求項6に記載の使用。 - 前記融合転写物は、配列番号1で示されるアミノ酸配列をコードするRNA配列を含む
ことを特徴とする、請求項1に記載の使用。 - 前記融合転写物は、配列番号2で示されるアミノ酸配列をコードするRNA配列を更に含む
ことを特徴とする、請求項8に記載の使用。 - 前記融合転写物は5’末端に、配列番号1で示されるアミノ酸配列をコードする1つのRNA配列、及び配列番号2で示されるアミノ酸配列をコードする1つのRNA配列を含む
ことを特徴とする、請求項8に記載の使用。 - 前記融合転写物は、配列番号3、配列番号4、配列番号5、又は配列番号6で示されるアミノ酸配列をコードする1つのRNA配列を含む
ことを特徴とする、請求項8から10のいずれか一項に記載の使用。 - 前記融合転写物のヌクレオチド配列は、配列番号3、配列番号4、配列番号5、又は配列番号6で示されるアミノ酸配列をコードする1つのRNA配列からなる
ことを特徴とする、請求項11に記載の使用。
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