JPH09500023A - レセプターでトランスフェクションされた細胞の選択増幅によるリガンドの同定 - Google Patents
レセプターでトランスフェクションされた細胞の選択増幅によるリガンドの同定Info
- Publication number
- JPH09500023A JPH09500023A JP7504713A JP50471395A JPH09500023A JP H09500023 A JPH09500023 A JP H09500023A JP 7504713 A JP7504713 A JP 7504713A JP 50471395 A JP50471395 A JP 50471395A JP H09500023 A JPH09500023 A JP H09500023A
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- ligand
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- Granted
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Abstract
Description
Claims (1)
- 【特許請求の範囲】 1.リガンドとして働くことのできる物質を検出する方法であって、 (a)細胞増幅が可能となる条件下で、リガンドに応答して細胞増幅に影響を及 ぼすことのできるレセプターをコードするDNA でトランスフェクションされた細 胞を、このレセプターの潜在的な作動因子又は拮抗因子である試験物質と共にイ ンキュベートする、ここでこの細胞は細胞増幅のマーカーを含んで成る、そして (b)細胞増幅が可能となるのに十分な期間を経た後、このマーカーを含まない 細胞に比してのこのマーカーを含む細胞の増幅の有無を決定する、 ことを含んで成る方法。 2.前記細胞を単独のレセプターをコードするDNA でトランスフェクションす る、請求項1記載の方法。 3.前記DNA が、チロシンキナーゼレセプター、G−タンパク質複合型レセプ ター、チロシンキナーゼ活性化性レセプター、チロシンホスファターゼレセプタ ー、転写因子、ステロイドレセプター、オンコジーン又はリガンドもしくはボル テージ依存性イオンチャンネル、又は一のレセプターのリガンド結合性領域と別 のレセプターのシグナル変換領域とより成るキメラレセプターをコードする、請 求項2記載の方法。 4.一又は複数種の試験物質の任意の作動活性を、前記レセプターによりトラ ンスフェクションされていない細胞のバックグランドに対する、トランスフェク ションされた細胞の増幅に及ぼす前記レセプターの高揚効果により決定する、請 求項1記載の方法。 5.試験物質の任意の拮抗活性を、前記レセプターによりトラン スフェクションされていない細胞のバックグランドに対する、トランスフェクシ ョンされた細胞の増幅に及ぼす前記レセプターの阻害効果により決定する、請求 項1記載の方法。 6.前記試験物質を、細胞増幅のレセプター剌激の作動因子の存在下で、前記 トランスフェクションされた細胞とインキュベートする、請求項5記載の方法。 7.前記マーカーが、トランスフェクションされたレセプターDNA 、転写され たレセプターmRNA、酵素、結合性タンパク質又は抗原である、請求項1記載の方 法。 8.前記マーカーがレセプターDNA 又はmRNAであり、そしてその存在をDNA 増 幅及び/又はハイブリダイゼーション技術により決定する、請求項7記載の方法 。 9.前記マーカーが、ホスファターゼ(例えば酸性又はアルカリ性ホスファタ ーゼ)、β−ガラクトシダーゼ、ウレアーゼ、グルコースオキシダーゼ、カルボ ニックアンヒドラーゼ、アセチルコリンエステラーゼ、グルコアミラーゼ、マレ イン酸デヒドロゲナーゼ、グルコース−6−リン酸デヒドロゲナーゼ、β−グル コシダーゼ、プロテアーゼ、ピルビン酸デカルボキシラーゼ、エステラーゼ、ル シフェラーゼ、アルコールデヒドロゲナーゼ又はペリオキシダーゼ(例えば西洋 ワサビペルオキシダーゼ)より成る群から選ばれる酵素である、請求項7記載の 方法。 10.前記方法であって、 (a)細胞を、レセプターをコードするDNA 及びマーカー酵素をコードするDNA でトランスフェクションする、 (b)トランスフェクションした細胞を数等分のアリコートに分ける、 (c)各アリコートを1又は複数の試験物質と、剌激されたレセプ ター及び非剌激レセプターとが区別できるようになるのに十分な時間インキュベ ートする、そして (d)各アリコートにおけるマーカー酵素活性を測定することにより細胞増殖の 任意の変化を決定する、 ことを含んで成る、請求項1〜9のいづれか1項記載の方法。 11.前記細胞を2種以上のレセプターをコードするDNA でトランスフェクショ ンし、ここでこのトランスフェクションされた細胞は個々のレセプターを発現す る、請求項1記載の方法。 12.前記DNA が、チロシンキナーゼレセプター、G−タンパク質複合型レセプ ター、チロシンキナーゼ活性化性レセプター、チロシンホスファターゼレセプタ ー、転写因子、ステロイドレセプター、オンコジーン又はリガンドもしくはボル テージ依存性イオンチャンネル、又は一のレセプターのリガンド結合性領域と別 のレセプターのシグナル変換領域とより成るキメラレセプターをコードする、請 求項11記載の方法。 13.一又は複数種の試験物質の任意の作動活性を、前記レセプターによりトラ ンスフェクションされていない細胞のバックグランドに対する、トランスフェク ションされた細胞の増幅に及ぼす一又は複数種の前記レセプターの高揚効果によ り決定する、請求項11記載の方法。 14.一又は複数種の試験物質の任意の拮抗活性を、前記レセプターによりトラ ンスフェクションされていない細胞のバックグランドに対する、トランスフェク ションされた細胞の増幅に及ぼす一又は複数種の前記レセプターの阻害効果によ り決定する、請求項11記載の方法。 15.前記一又は複数種の試験物質を、細胞増幅のレセプター剌激の作動因子の 存在下で、前記トランスフェクションされた細胞とイ ンキュベートする、請求項14記載の方法。 16.前記マーカーが、トランスフェクションされたレセプターDNA 、転写され たレセプターmRNA、酵素、結合性タンパク質又は抗原である、請求項11記載の方 法。 17.前記マーカーがレセプターDNA 又はmRNAであり、そしてその存在をDNA 増 幅及び/又はハイブリダイゼーション技術により決定する、請求項16記載の方法 。 18.前記マーカーがβ−ガラクトシダーゼ、アルカリ性ホスファターゼ、ホタ ルルシフェラーゼ、アルコールデヒドロゲナーゼより成る群から選ばれる、請求 項16記載の方法。 19.一定のレセプターを発現する細胞が、別のレセプターによりトランスフェ クションされた細胞により発現されたマーカーから区別できるマーカーを発現す る、請求項11記載の方法。 20.前記方法であって、 (a)2種以上の異なるレセプターをコードするDNA と、マーカー酵素をコード するDNA とで細胞をトランスフェクションする、ここで各トランスフェクション された細胞は個々のレセプターを発現する、 (b)このトランスフェクションされた細胞を数等分のアリコートに分ける、 (c)各アリコートを1又は複数の試験物質と、剌激されたレセプター及び非剌 激レセプターが区別できるようになるのに十分な時間インキュベートする、 (d)各アリコートにおけるマーカー酵素活性を測定することにより細胞増殖の 任意の変化を決定し、細胞増殖特性を改変するその能力により活性リガンドを同 定する、そして (e)請求項10記載の工程(a)−(d)において上記した方法に 各レセプターを委ねることによりこのリガンドによりどのレセプターが活性化さ れるかを同定する、 ことを含んで成る、請求項11〜19のいづれか1項記載の方法。 21.前記方法であって、 (a)2種以上の異なるレセプターをコードするDNA と、マーカー酵素をコード するDNA とで細胞をトランスフェクションする、ここで各トランスフェクション された細胞は個々のレセプターを発現する、 (b)このトランスフェクションされた細胞を数等分のアリコートに分ける、 (c)各アリコートを1又は複数の試験物質と、剌激されたレセプター及び非剌 激レセプターが区別できるようになるのに十分な時間インキュベートする、 (d)各アリコートにおけるマーカー酵素活性を測定することにより細胞増殖の 任意の変化を決定し、細胞増殖特性を改変するその能力により活性リガンドを同 定する、そして (e)DNA 増幅及び/又はハイブリダイゼーション技術によりレセブターDNA 及 び/又はmRNAをアッセイすることにより、このリガンドによりどのレセプターが 活性化されるかを同定する、 ことを含んで成る、請求項11〜19のいづれか1項記載の方法。 22.前記方法であって、 (a)2種以上の異なるレセプターをコードするDNA と、2種以上のマーカー酵 素をコードする複数のDNA とで細胞をトランスフェクションする、これにより各 トランスフェクションされた細胞は個々のレセプターを発現し、一定のレセプタ ーを発現する細胞は、別のレセプターによりトランスフェクションされた細胞に より発現されるマーカーから区別できるマーカーを発現するようになる、 (b)このトランスフェクションされた細胞は数等分のアリコートに分ける、 (c)各アリコートを1又は複数の試験物質と、剌激されたレセプター及び非剌 激レセプターが区別できるようになるのに十分な時間インキュベートする、 (d)各アリコートにおけるマーカー酵素活性を測定することにより細胞増殖の 任意の変化を決定し、細胞増殖特性を改変するその能力により活性リガンドを同 定する、そして (e)各個別のマーカー酵素にとっての基質を加え、次いでアッセイすることに より、このリガンドによりどのレセプターが活性化されるかを同定する、 ことを含んで成る、請求項11〜19のいづれか1項記載の方法。 23.リガンドとして働くことのできる物質を検出するための試験キットであっ て、 (a)リガンドに応答して細胞増幅に影響を及ぼすことのできるレセプターをコ ードするDNA でトランスフェクションされている凍結細胞、ここでこの細胞は細 胞増幅のマーカーを含んで成る、 (b)細胞の増殖のための培地、 (c)マーカーの存在及び量を検出するための試薬、 を含んで成る試験キット。 24.前記DNA が、チロシンキナーゼレセプター、G−タンパク質複合型レセプ ター、チロシンキナーゼ活性化性レセプター、チロシンホスファターゼレセプタ ー、転写因子、ステロイドレセプター、オンコジーン又はリガンドもしくはボル テージ依存性イオンチャンネル、又は一のレセプターのリガンド結合性領域と別 のレセプターのシグナル変換領域とより成るキメラレセプターをコードする、請 求項23記載の試験キット。 25.細胞増幅のレセプター剌激の作動因子を更に含んで成る、請求項23記載の 試験キット。 26.前記マーカーが、トランスフェクションされたレセプターDNA 、転写され たレセプターmRNA、酵素、結合性タンパク質又は抗原である、請求項23記載の試 験キット。 27.前記マーカーが、ホスファターゼ(例えば酸性又はアルカリ性ホスファタ ーゼ)、β−ガラクトシダーゼ、ウレアーゼ、グルコースオキシダーゼ、カルボ ニックアンヒドラーゼ、アセチルコリンエステラーゼ、グルコアミラーゼ、マレ イン酸デヒドロゲナーゼ、グルコース−6−リン酸デヒドロゲナーゼ、β−グル コシダーゼ、プロテアーゼ、ピルビン酸デカルボキシラーゼ、エステラーゼ、ル シフェラーゼ、アルコールデヒドロゲナーゼ又はペリオキシダーゼ(例えば西洋 ワサビペルオキシダーゼ)より成る群から選ばれる酵素である、請求項26記載の 試験キット。 28.前記マーカーの存在及び量を検出するための試薬が、o−ニトロフェニル −β−D−ガラクトピラノシド、5−ブロモ−4−クロロ−3−インドリル−β −D−ガラクトピラノシド、クロロナフトール、o−フェニレンジアミン、3− (p−ヒドロキシフェニル)プロピオン酸、ルミノール、インドキシルホスフェ ート、p−ニトロフェニルホスフェート、ニトロフェニルガラクトース、4−メ チルウンベリフェリル−D−ガラクトピラノシド、H2O2/テトラメチルベンジジ ン又はルシフェリンより成る群から選ばれる、請求項27記載の試験キット。 29.リガンドとして働くことのできる物質を検出するための試験キットであっ て、 (a)リガンドに応答して細胞増幅に影響を及ぼすことのできる第一レセプター をコードするDNA でトランスフェクションされた凍結 細胞、ここでこの細胞は細胞増幅のマーカーを含んで成る、 (b)リガンドに応答して細胞増幅に影響を及ぼすことのできる第二レセプター をコードするDNA でトランスフェクションされた凍結細胞、ここでこの細胞は細 胞増幅のマーカーを含んで成る、 (c)細胞の増殖のための培地、 (d)このマーカーの存在及び量を検出するための試薬、 を含んで成る試験キット。 30.更なる個別のレセプターをコードするDNA でトランスフェクションされた 凍結細胞を更に含んで成り、各後続レセプターは各先行レセプターとは異なる、 請求項29記載の試験キット。 31.前記細胞が2種以上のマーカーをコードするDNA でトランスフェクション されており、これにより一定のレセプターを発現する細胞は別のレセプターによ りトランスフェクションされた細胞により発現されるマーカーから区別できるマ ーカーを発現し、ここでこのキットは更に各マーカーを検出するための試薬を更 に含んで成る、請求項29記載の試験キット。 32.前記DNA が、チロシンキナーゼレセプター、G−タンパク質複合型レセプ ター、チロシンキナーゼ活性化性レセプター、チロシンホスファターゼレセプタ ー、転写因子、ステロイドレセプター、オンコジーン又はリガンドもしくはボル テージ依存性イオンチャンネル、又は一のレセプターのリガンド結合性領域と別 のレセプターのシグナル変換領域とより成るキメラレセプターをコードする、請 求項29記載の試験キット。 33.細胞増幅のレセプター剌激の作動因子を更に含んで成る、請求項29記載の 試験キット。 34.前記マーカーが、トランスフェクションされたレセプターDNA 、転写され たレセプターmRNA、酵素、結合性タンパク質又は抗原 である、請求項29記載の試験キット。 35.前記マーカーが、ホスファターゼ(例えば酸性又はアルカリ性ホスファタ ーゼ)、β−ガラクトシダーゼ、ウレアーゼ、グルコースオキシダーゼ、カルボ ニックアンヒドラーゼ、アセチルコリンエステラーゼ、グルコアミラーゼ、マレ イン酸デヒドロゲナーゼ、グルコース−6−リン酸デヒドロゲナーゼ、β−グル コシダーゼ、プロテアーゼ、ピルビン酸デカルボキシラーゼ、エステラーゼ、ル シフェラーゼ、アルコールデヒドロゲナーゼ又はペリオキシダーゼ(例えば西洋 ワサビペルオキシダーゼ)より成る群から選ばれる酵素である、請求項29記載の 試験キット。 36.前記マーカーの存在及び量を検出するための試薬が、o−ニトロフェニル −β−D−ガラクトピラノシド、5−ブロモ−4−-クロロ−3−インドリル− β−D−ガラクトピラノシド、クロロナフトール、o−フェニレンジアミン、3 −(p−ヒドロキシフェニル)プロピオン酸、ルミノール、インドキシルホスフ ェート、p−ニトロフェニルホスフェート、ニトロフェニルガラクトース、4− メチルウンベリフェリル−D−ガラクトピラノシド、H2O2/テトラメチルベンジ ジン又はルシフェリンより成る群から選ばれる、請求項35記載の試験キット。 37.リガンドの非存在下では細胞増幅を媒介することのできない野生型遺伝子 の突然変異形態を検出する方法であって、 (a)細胞増幅の可能な条件下で、この遺伝子の突然変異形態のコード領域を含 むと予測されるDNA でトランスフェクションされた細胞を、リガンドの非存在下 で、又は不適切な量のリガンドの存在下でインキュベートする、ここでこの細胞 は細胞増幅のマーカーを含んで成る、そして (b)細胞増幅が可能な十分な時間の後、前記マーカーを含まない 細胞に対するこのマーカーを含む細胞の増幅の有無を決定する、 ことを含んで成る方法。 38.前記突然変異形態が疾病症状に係っている、請求項37記載の方法。 39.前記突然変異形態がオンコジーンである、請求項38記載の方法。
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US4859609A (en) * | 1986-04-30 | 1989-08-22 | Genentech, Inc. | Novel receptors for efficient determination of ligands and their antagonists or agonists |
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US5912132A (en) | 1999-06-15 |
EP0708922A1 (en) | 1996-05-01 |
WO1995002823A1 (en) | 1995-01-26 |
US5955281A (en) | 1999-09-21 |
DE69417037D1 (de) | 1999-04-15 |
AU7333094A (en) | 1995-02-13 |
ES2129658T3 (es) | 1999-06-16 |
JP3102571B2 (ja) | 2000-10-23 |
CA2167048A1 (en) | 1995-01-26 |
IL110298A (en) | 1999-04-11 |
IL110298A0 (en) | 1994-10-21 |
DE69417037T2 (de) | 1999-10-21 |
CA2167048C (en) | 2001-09-25 |
AU679253B2 (en) | 1997-06-26 |
ATE177535T1 (de) | 1999-03-15 |
EP0708922B1 (en) | 1999-03-10 |
KR100272459B1 (ko) | 2000-11-15 |
NZ269442A (en) | 1997-06-24 |
DK0708922T3 (da) | 1999-09-27 |
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