JP2015231978A - 癌治療用医薬組成物 - Google Patents
癌治療用医薬組成物 Download PDFInfo
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- JP2015231978A JP2015231978A JP2014190619A JP2014190619A JP2015231978A JP 2015231978 A JP2015231978 A JP 2015231978A JP 2014190619 A JP2014190619 A JP 2014190619A JP 2014190619 A JP2014190619 A JP 2014190619A JP 2015231978 A JP2015231978 A JP 2015231978A
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Abstract
Description
〔1〕 Arl4c遺伝子の発現を抑制する物質又はArl4cタンパク質の活性を抑制する物質を含む、癌の治療のための医薬組成物。
〔2〕 Arl4c遺伝子の発現を抑制する物質及びArl4cタンパク質の活性を抑制する物質からなる群より選ばれる少なくとも1つが、核酸である、請求項1記載の医薬組成物。
〔3〕 遺伝子の発現を抑制する物質が、siRNA、アンチセンスオリゴヌクレオチド若しくはリボザイム又はこれらの発現ベクターである、〔1〕又は〔2〕に記載の医薬組成物。
〔4〕 遺伝子の発現を抑制する物質が、siRNA又はsiRNAの発現ベクターである、〔1〕〜〔3〕いずれかに記載の医薬組成物。
〔5〕 siRNAの一方又は両方の鎖に3’末端のオーバーハングを含む、〔3〕又は〔4〕に記載の医薬組成物。
〔6〕 癌が大腸癌又は肺癌である、〔1〕〜〔5〕いずれかに記載の医薬組成物。
〔7〕 Arl4c遺伝子の発現を抑制する物質又はArl4cタンパク質の活性を抑制する物質を投与する工程を有する、癌を治療する方法。
〔8〕 遺伝子の発現を抑制する物質が、siRNA又はsiRNAの発現ベクターである〔7〕に記載の方法。
〔9〕 癌の治療するための、Arl4c遺伝子の発現を抑制する物質又はArl4cタンパク質の活性を抑制する物質。
〔10〕 遺伝子の発現を抑制する物質がsiRNA又はsiRNAの発現ベクターである、〔9〕に記載の物質。
〔11〕 癌の治療するための、Arl4c遺伝子の発現を抑制する物質又はArl4cタンパク質の活性を抑制する物質の使用。
〔12〕 遺伝子の発現を抑制する物質がsiRNA又はsiRNAの発現ベクターである、〔11〕に記載の使用。
〔13〕 癌の治療剤の調製における、Arl4c遺伝子の発現を抑制する物質又はArl4cタンパク質の活性を抑制する物質の使用。
〔14〕 遺伝子の発現を抑制する物質がsiRNA又はsiRNAの発現ベクターである、〔13〕に記載の使用。
〔15〕下記の工程(a)〜(c)を含む、癌の治療用物質をスクリーニングする方法:
(a)Arl4c遺伝子の発現又はArl4cタンパク質の活性を測定可能な細胞と被験物質とを接触させる工程;
(b)被験物質を接触させた細胞における前記遺伝子の発現量又はタンパク質の活性を測定し、該測定値を、被験物質を接触させない対照細胞における前記遺伝子の発現量又はタンパク質の活性と比較する工程;
次いで
(c)被験物質を与えられた細胞における前記遺伝子の発現量又はタンパク質の活性が、被験物質を与えられていない細胞における前記遺伝子の発現量又はタンパク質の活性よりも低下している場合に、被験物質を癌の治療物質として選択する工程。
(i)Arl4c遺伝子の発現を抑制する物質又はArl4cタンパク質の活性を抑制する物質を投与する工程を有する、癌を治療する方法、
(ii)癌の治療に用いられる、Arl4c遺伝子の発現を抑制する物質又はArl4cタンパク質の活性を抑制する物質、ならびに
(iii)癌の治療剤の調製における、Arl4c遺伝子の発現を抑制する物質又はArl4cタンパク質の活性を抑制する物質の使用
を提供する。
上記「遺伝子の発現を抑制する物質」又は「タンパク質の活性を抑制する物質」については、上で説明したとおりである。また、「遺伝子の発現を抑制する物質」として、siRNAが用いられる場合、好ましいsiRNAについては上述したとおりである。
(a)Arl4c遺伝子の発現又はArl4cタンパク質の活性を測定可能な細胞と被験物質とを接触させる工程;
(b)被験物質を接触させた細胞における前記遺伝子の発現量又はタンパク質の活性を測定し、該測定値を、被験物質を接触させない対照細胞における前記遺伝子の発現量又はタンパク質の活性と比較する工程;
次いで
(c)被験物質を与えられた細胞における前記遺伝子の発現量又はタンパク質の活性が、被験物質を与えられていない細胞における前記遺伝子の発現量又はタンパク質の活性よりも低下している場合に、被験物質を癌の治療物質として選択する工程。
2007年1月から2013年3月の期間、阪大病院において、28歳から86歳(中央値は68歳)の大腸癌患者(118名)と肺腺癌患者(68名)から組織を採取した。組織は10%ホルマリンにて固定化し、パラフィン処理した後、厚さ4μmの切片試料を作製した。
大腸癌と肺癌由来の種々の細胞株においてArl4c mRNAの発現を調べ、β−カテニンとRasに遺伝子変異のある大腸癌細胞株のHCT116細胞とRasに遺伝子変異を持っている肺腺癌細胞株のA549細胞がArl4cを高発現していることから、癌細胞におけるArl4cの役割を調べた。
Randomized control:5’-CAGTCGCGTTTGCGACTGG-3’(配列番号5)
human Arl4c :5’-CCTCTAACATCTCGGCCTT-3’(配列番号6)
上記で得られたHCT116細胞とA549細胞に、RNAiMAX(Invitrogen社製)を用いて、上記配列に対するsiRNAの混合物(20nMずつ)をトランスフェクトして、細胞(SiControl、SiArl4c)を得た。得られた細胞はトランスフェクトして36〜48時間後に以下の評価を行った。
先ず、Arl4c shRNAを安定発現する細胞を作製するためのプラスミドを作製した。具体的には、Gateway technology(Invitrogen社製)を用いて、以下の配列をH1プロモーターと共にCS−RfA−EVBsd内に組み込んで、レンチウイルスベクターを作製した。
Control shRNA targeting luciferase:5’-GTGCGTTGCTAGTACCAAC-3’(配列番号7)
human Arl4c #1:5’-GGCTGTGAAGCTGAGTAAT-3’(配列番号8)
human Arl4c #2:5’-GATGATCCTGAAACGCAGGAA-3’(配列番号9)
これらのベクターをX293T細胞にパッケージングベクターと共にトランスフェクトし、得られたレンチウイルス上清を用いてプラスミドをHCT116細胞とA549細胞に導入して、Arl4c shRNAを安定発現する細胞(shControl、shArl4c #1、shArl4c #2)を調製した。これらの細胞における二次元シャーレと3Dマトリゲルでの増殖程度を調べた。
5週齢の雄性BALB/cAnNCrj-nuヌードマウス(チャールスリバー研究所)にメデトミジン(0.3mg/kg 体重)とミダゾラム(4mg/kg 体重)で麻酔した後、実施例2で調製したHCT116細胞(5×106細胞)又はA549細胞(5×106細胞)を100μLのPBSに懸濁したものを背面に皮下投与した。移植後、14日後(HCT116)又は38日後(A549)に移植サンプルを摘出し、径及び重量を測定し、実施例1と同様にして組織学的検査を行った。
5週齢の雄性BALB/cAnNCrj-nuヌードマウス(チャールスリバー研究所)を実施例4と同様にして麻酔した後、HCT116細胞(1×106細胞)を100μLのPBSに懸濁したものを背面に皮下投与した。移植後3日後に、腫瘍部(径4mm以下)に、コントロールのsiRNA又はArl4c siRNAを0.5%(v/v)アテロコラーゲン(AteloGene(登録商標)、高研社製)に30μmol/Lで調製した溶液200μLを直接注入して投与した。本実施例内のsiRNAとしては、実施例3で用いたhuman Arl4c #1配列をCUGA(登録商標) 7 in vitro Transcription Kit(ニッポン・ジーン)を用いて、研究室内で合成したものを使用した。siRNA投与後10日後に、ヌードマウスから移植サンプルを摘出し、径及び重量を測定し、実施例1及び実施例4と同様にして組織学的検査を行った。
配列表の配列番号2は、ヒトArl4c アイソフォーム1のポリペプチドである。
配列表の配列番号3は、ヒトArl4c アイソフォーム2のmRNAの塩基配列である。
配列表の配列番号4は、ヒトArl4c アイソフォーム2のポリペプチドである。
配列表の配列番号5は、Arl4c siRNAの実験で標的としたコントロール配列である。
配列表の配列番号6は、Arl4c siRNAの実験で標的とした配列である。
配列表の配列番号7は、Controlベクター内に導入された配列である。
配列表の配列番号8は、ヒトArl4c #1ベクター内に導入された配列である。
配列表の配列番号9は、ヒトArl4c #2ベクター内に導入された配列である。
Claims (4)
- Arl4c遺伝子の発現を抑制する物質又はArl4cタンパク質の活性を抑制する物質を含む、癌の治療のための医薬組成物。
- Arl4c遺伝子の発現を抑制する物質及びArl4cタンパク質の活性を抑制する物質からなる群より選ばれる少なくとも1つが、核酸である、請求項1記載の医薬組成物。
- 癌が大腸癌又は肺癌である、請求項1又は2に記載の医薬組成物。
- Arl4c遺伝子の発現又はArl4cタンパク質の活性を指標とし、発現の抑制又は活性の抑制をする物質を候補化合物とする、癌の治療のための物質のスクリーニング方法。
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WO2024071099A1 (ja) * | 2022-09-29 | 2024-04-04 | 国立大学法人東京医科歯科大学 | 5'-シクロプロピレン修飾を含む核酸分子 |
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JP7396577B2 (ja) | 2018-09-05 | 2023-12-12 | 国立大学法人大阪大学 | Arl4cを標的分子とするアンチセンスオリゴヌクレオチド、及び当該アンチセンスオリゴヌクレオチドを使用した核酸医薬 |
WO2024071099A1 (ja) * | 2022-09-29 | 2024-04-04 | 国立大学法人東京医科歯科大学 | 5'-シクロプロピレン修飾を含む核酸分子 |
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