JP6899201B2 - 細胞死誘導剤、細胞増殖抑制剤及び細胞の増殖異常に起因する疾患の治療用医薬組成物 - Google Patents
細胞死誘導剤、細胞増殖抑制剤及び細胞の増殖異常に起因する疾患の治療用医薬組成物 Download PDFInfo
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Description
(2)GST−π及びMRPL17を抑制する薬物を有効成分として含む;又はGST−πを抑制する薬物と、MRPL17を抑制する薬物とを有効成分として含む、がん細胞の細胞増殖抑制剤。
(3)上記薬物が、RNAi分子、リボザイム、アンチセンス核酸、DNA/RNAキメラポリヌクレオチド及びこれらのうち少なくとも1種を発現するベクターからなる群から選択される物質であることを特徴とする(1)又は(2)記載の剤。
(4)上記MRPL17を抑制する薬物が、当該MRPL17に作用する化合物であることを特徴とする(1)又は(2)記載の剤。
(5)アポトーシスを誘導することを特徴とする(1)記載の剤。
(6)上記がん細胞は、GST−πを高発現するがん細胞であることを特徴とする(1)又は(2)記載の剤。
(7)上記(1)〜(6)のいずれかに記載の剤を含む、細胞の増殖異常に起因する疾患の治療用医薬組成物。
(8)GST−πを抑制する薬物と組み合わせて投与されることを特徴とする、MRPL17を抑制する薬物を有効成分として含有する、細胞の増殖異常に起因する疾患の治療用医薬組成物。
(9)MRPL17を抑制する薬物と組み合わせて投与されることを特徴とする、GST−πを抑制する薬物を有効成分として含有する、細胞の増殖異常に起因する疾患の治療用医薬組成物。
(10)上記疾患ががんであることを特徴とする(7)乃至(9)いずれか記載の医薬組成物。
(11)上記がんはGST−πを高発現するがんであることを特徴とする(10)記載の医薬組成物。
(12)MRPL17を抑制する薬物を選択することを含む、GST−πを抑制する薬物とともに使用される、がん細胞の細胞死誘導剤及び/又は細胞増殖抑制剤のスクリーニング方法。
(13)がん細胞に対して被検物質を接触させる工程と、上記細胞におけるMRPL17の発現量を測定する工程と、被検物質の非存在下において測定した場合と比較して、当該発現量が低下した場合にMRPL17を抑制する薬物として選択する工程とを含む(12)記載のスクリーニング方法。
(14)GST−πを抑制する薬物を選択することを含む、MRPL17を抑制する薬物とともに使用される、がん細胞の細胞死誘導剤及び/又は細胞増殖抑制剤のスクリーニング方法。
(15)がん細胞に対して被検物質を接触させる工程と、上記細胞におけるGST−πの発現量を測定する工程と、被検物質の非存在下において測定した場合と比較して、当該発現量が低下した場合にGST−πを抑制する薬物として選択する工程とを含む(14)記載のスクリーニング方法。
(16)GST−π及びMRPL17を抑制する薬物を選択することを含む、細胞死誘導剤及び/又は細胞増殖抑制剤のスクリーニング方法。
(17)がん細胞に対して被検物質を接触させる工程と、上記細胞におけるGST−πの発現量及びMRPL17の発現量を測定する工程と、被検物質の非存在下において測定した場合と比較して、GST−πの発現量及びMRPL17の発現量がともに低下した場合にGST−π及びMRPL17を抑制する薬物として選択する工程とを含む(16)記載のスクリーニング方法。
NA(short hairpin RNA)、ddRNA(DNA-directed RNA)、piRNA(Piwi-interacting RNA)、rasiRNA(repeat associated siRNA)などの二重鎖RNA及びこれらの改変体などを含む。これらのRNAi分子は市販されているか、公知の配列情報、すなわち、配列番号1乃至4に示した塩基配列及び/又はアミノ酸配列に基づいて設計、作製することが可能である。
ン、塩酸ミトキサントロン、マイトマイシンC等の抗腫瘍性抗生物質、エトポシド、塩酸イリノテカン、酒石酸ビノレルビン、ドセタキセル水和物、パクリタキセル、硫酸ビンクリスチン、硫酸ビンデシン、硫酸ビンブラスチン等のアルカロイド、アナストロゾール、クエン酸タモキシフェン、クエン酸トレミフェン、ビカルタミド、フルタミド、リン酸エストラムスチン等のホルモン療法剤、カルボプラチン、シスプラチン(CDDP)、ネダプラチン等の白金錯体、サリドマイド、ネオバスタット、ベバシズマブ等の血管新生阻害剤、L−アスパラギナーゼなどを挙げることができる。
がん細胞の例として、0.5×105個のA549細胞(KRAS変異ヒト肺がん細胞)を6cmシャーレに播種し、10%ウシ胎児血清(Fetal bovine serum、FBS)と1%L-グルタミン及び1% L-Glutamine-Penicillin streptomycin(Sigma社)を添加したDulbecco’s modified Eagle’s medium(DMEM、Sigma社)で18時間培養した。培養条件は、特に別記しない限り37℃、5%CO2で行った。
センス鎖:CCUUUUGAGACCCUGCUGUtt(配列番号5)
アンチセンス鎖:ACAGCAGGGUCUCAAAAGGct(配列番号6)
MRPL17 siRNA:
センス鎖:UGGCAGUGAUCGAGUAUAAtt(配列番号7)
アンチセンス鎖:UUAUACUCGAUCACUGCCAtt(配列番号8)
Control siRNA:
センス鎖:ACGUGACACGUUCGGAGAAtt(配列番号9)
アンチセンス鎖:UUCUCCGAACGUGUCACGUtt(配列番号10)
Claims (12)
- GST−πの発現を抑制する薬物と、MRPL17の発現を抑制する薬物とを有効成分として含み、
前記GST−πの発現を抑制する薬物及び前記MRPL17の発現を抑制する薬物が、それぞれ、GST−π又はMRPL17をコードするDNAに対するRNAi分子、リボザイム、アンチセンス核酸、DNA/RNAキメラポリヌクレオチド及びこれらのうち少なくとも1種を発現するベクターからなる群から選択される物質である、
がん細胞の細胞増殖抑制剤。 - 上記がん細胞は、GST−πを高発現するがん細胞であることを特徴とする請求項1記載の剤。
- 請求項1又は2記載の剤を含む、がんの治療用医薬組成物。
- GST−πの発現を抑制する薬物と組み合わせて投与されることを特徴とする、MRPL17の発現を抑制する薬物を有効成分として含有する、がんの治療用医薬組成物であって、
前記GST−πの発現を抑制する薬物及び前記MRPL17の発現を抑制する薬物が、それぞれ、GST−π又はMRPL17をコードするDNAに対するRNAi分子、リボザイム、アンチセンス核酸、DNA/RNAキメラポリヌクレオチド及びこれらのうち少なくとも1種を発現するベクターからなる群から選択される物質である、
がんの治療用医薬組成物。 - MRPL17の発現を抑制する薬物と組み合わせて投与されることを特徴とする、GST−πの発現を抑制する薬物を有効成分として含有する、がんの治療用医薬組成物であって、
前記GST−πの発現を抑制する薬物及び前記MRPL17の発現を抑制する薬物が、それぞれ、GST−π又はMRPL17をコードするDNAに対するRNAi分子、リボザイム、アンチセンス核酸、DNA/RNAキメラポリヌクレオチド及びこれらのうち少なくとも1種を発現するベクターからなる群から選択される物質である、
がんの治療用医薬組成物。 - 上記がんはGST−πを高発現するがんであることを特徴とする請求項3乃至5のいずれか一項記載の医薬組成物。
- MRPL17を抑制する薬物を選択することを含む、GST−πを抑制する薬物とともに使用される、がん細胞の細胞増殖抑制剤のスクリーニング方法。
- がん細胞に対して被検物質を接触させる工程と、上記細胞におけるMRPL17の発現量を測定する工程と、被検物質の非存在下において測定した場合と比較して、当該発現量が低下した場合にMRPL17を抑制する薬物として選択する工程とを含む請求項7記載のスクリーニング方法。
- GST−πを抑制する薬物を選択することを含む、MRPL17を抑制する薬物とともに使用される、がん細胞の細胞増殖抑制剤のスクリーニング方法。
- がん細胞に対して被検物質を接触させる工程と、上記細胞におけるGST−πの発現量を測定する工程と、被検物質の非存在下において測定した場合と比較して、当該発現量が低下した場合にGST−πを抑制する薬物として選択する工程とを含む請求項9記載のスクリーニング方法。
- GST−π及びMRPL17を抑制する薬物を選択することを含む、がん細胞の細胞増殖抑制剤のスクリーニング方法。
- がん細胞に対して被検物質を接触させる工程と、上記細胞におけるGST−πの発現量及びMRPL17の発現量を測定する工程と、被検物質の非存在下において測定した場合と比較して、GST−πの発現量及びMRPL17の発現量がともに低下した場合にGST−π及びMRPL17を抑制する薬物として選択する工程とを含む請求項11記載のスクリーニング方法。
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US10780107B2 (en) | 2020-09-22 |
CA3028934C (en) | 2021-06-08 |
WO2017222035A1 (ja) | 2017-12-28 |
EP3476401A4 (en) | 2020-03-11 |
CA3028934A1 (en) | 2017-12-28 |
CN109328072B (zh) | 2021-11-23 |
TWI812591B (zh) | 2023-08-21 |
US20190151344A1 (en) | 2019-05-23 |
CN109328072A (zh) | 2019-02-12 |
TW201803596A (zh) | 2018-02-01 |
JP2017226626A (ja) | 2017-12-28 |
EP3476401A1 (en) | 2019-05-01 |
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