JP2010095547A - 固形腫瘍を予防および治療するための方法および組成物 - Google Patents
固形腫瘍を予防および治療するための方法および組成物 Download PDFInfo
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Abstract
【解決手段】 エンドセリンBアゴニストおよび化学療法薬を有効成分として利用して、ヒトを含む哺乳動物での固形腫瘍を治療する。
【選択図】 なし
Description
動 物
体重180〜200gのメスのSprague Dawley系ラット(Harlan社、マディソン、ウィスコンシン州)を使用した。 すべての動物は、温度(23±1℃)および湿度(50±10%)が調節され、人工照明(6時〜18時)が装備された室内で、個別のかごに、3匹ずつ収容した。 動物には、餌料および水を自由に摂取させた。少なくとも4日間かけて動物を飼育環境へ順化させた後に、実験を行った。
N-メチルニトロソ尿素(MNU)は、Ash Stevens社(デトロイト、ミシガン州)から購入した。 BQ788(N-シス-2,6-ジメチルピペリジノカルボニルL-γ-メチル-ロイシル-D-1-メトキシカルボニルトリプトファニル-D-Nle)、IRL1620、およびエンドセリン-1(ET-1)は、American Peptide社(サニーベール、カリフォルニア州)から入手した。 BQ788は、生理食塩水に溶解し、また、ET-1は0.1%アルブミンに溶解した。
メスのSprague Dawley系ラットに、MNU(50mg/kg、腹腔内)または生理食塩水(1ml/kg、腹腔内)を投与した。 腫瘍が、直径2〜4cmに達した後、血流量実験を実施した。 動物は、以下のグループに分けた。
(ii) IRL1620(3nmol/kg)を注射して15分後に、タキソール(3mg/kg)を注射した、正常ラット(N=4);
(iii) 生理食塩水を注射して15分後に、タキソール(3mg/kg)を注射した、腫瘍を有するラット(N=4);および
(iv) IRL1620(3nmol/kg)を注射して15分後に、タキソール(3mg/kg)を注射した、腫瘍を有するラット(N=4)
外科的準備
ウレタン(1.5g/kg、腹腔内)(Sigma Chemicals社、セントルイス、ミズーリ州)で、ラットを麻酔状態にした。 薬物投与のために、左大腿静脈にカニューレ(PE 50チュービング、Clay Adams社、パーシパニー、ニュージャージー州)を穿刺した。 参照血液試料を採取するために、左大腿動脈にカニューレを穿刺した。 右大腿動脈をカニューレを穿刺し、そして、7PIプリアンプを介して、Grass P7Dポリグラフ(Grass Instrument社、クインシー、マサチューセッツ州、米国)で血圧を記録するために、Gould P23 ID圧トランスデューサーへ接続した。 心拍数(HR)は、血圧信号に反応する7P4B Grassタコグラフ(Grass Instrument社、クインシー、マサチューセッツ州)で記録した。
ラットの乳腺への血液潅流を、レーザードップラー流速計で測定した。 動物の乳頭周囲を剃毛し、乳腺周囲の皮膚を切開した。 標準的モデルの光ファイバープローブを乳腺動脈へ固定し、Periflux PF2b 4000レーザードップラー流速計(Perimed KB、ストックホルム、スウェーデン国)へ接続した。 時定数を1.5秒に設定し、帯域幅を4KHzに設定した。
すべてのデータは、平均値±SEMとして表示した。 データは、分散分析を用いて分析し、その後にDuncan検定を実施した。 p<0.05のレベルを、統計的な有意差とみなした。
IRL1620およびタキソールが乳房腫瘍の潅流に及ぼす作用
生理食塩水またはIRL1620およびタキソールの投与後に、正常ラットの乳房組織への血流量の変化は、観察されなかった。 ベースラインからのIRL1620注射(36.3%、p<0.05)後の血流量とタキソール投与(51.9%、p<0.0-5)後の血流量との間で、有意差が観察された(図5を参照)。
正常ラットおよび腫瘍を有するラットにおいて、生理食塩水またはIRL1620およびタキソールの投与後に、血圧の変化は観察されなかった。
全身性血行動態ならびに正常ラットおよび腫瘍を有するラットでの乳房組織への血流量に関して、ET-1の注入が及ぼす作用を評価するために、以下の動物グループについて試験を行った。
(ii) 30分かけてET-1(50ng/kg/分)を注入したMNU(50mg/kg、腹腔内)処置ラットグループ(N=6)。
(ii)20分かけてBQ788(0.5μmol/kg)を注入した後に、30分かけてET-1(50ng/kg/分)を注入したMNU(50mg/kg、腹腔内)処置ラットグループ(N=5)。
ウレタン(1.5g/kg、腹腔内)(Sigma Chemicals社、セントルイス、ミズーリ州)で、ラットを麻酔状態にした。 手術領域すべてを剃毛し、アルコール綿で消毒した。 薬物投与のために、左大腿静脈にカニューレ(PE 50チュービング、Clay Adams社、パーシパニー、ニュージャージー州)を穿刺した。 血液採取用ポンプ(モデル22、Harvard Apparatus社、サウスナティック、マサチューセッツ州)を使用してミクロスフェア試験用の参照血液試料を採取するために、左大腿動脈にカニューレ(PE 50チュービング)を穿刺した。 右大腿動脈をカニューレ(PE 50チュービング)を穿刺し、そして、7PIプリアンプを介して、Grass P7Dポリグラフ(Grass Instrument社、クインシー、マサチューセッツ州、米国)で血圧を記録するために、Gould P23 ID圧トランスデューサーへ接続した。 心拍数(HR)は、血圧信号に反応する7P4B Grassタコグラフ(Grass Instrument社、クインシー、マサチューセッツ州)で記録した。 右頸動脈を露出せしめ、次いで、PE 50チュービングを総頸動脈に通して左室内へ誘導した。 左室内のカニューレの存在は、Statham P23 DC圧トランスデューサー(Grass Instrument社、クインシー、マサチューセッツ州)を用いて、Grassポリグラフ上で血圧を記録することによって確認した。 カニューレが左室に到達すると、拡張期圧がゼロへ低下した。 血中pO2、pCO2、およびpH定数を維持するために、また、呼吸が血圧およびHRに及ぼす作用を回避するために、齧歯類用ベンチレーター(683型、Harvard Apparatus社、サウスナティック、マサチューセッツ州)に接続した気管内カニューレを挿入することで、動物の定速人工換気を維持した。
全身性血行動態および局所血液循環は、文献(13、16、47)に記載の方法に従って測定した。 各測定では、46Sc(スカンジウム)、113Sn(錫)、141Ce(セリウム)または95Nb(ニオブ)で標識した約100,000個のマイクロスフェア(直径15±1μm)(New England Nuclear社、ボストン、マサチューセッツ州、米国)を生理食塩水0.2mlで完全に混合して得た懸濁液を左室内に注入し、15秒間にわたって、生理食塩水0.3mlでフラッシュ洗浄した。 血流量を計算するために、0.5 mL/分の速度で右大腿動脈から動脈血を採取した。 血液の採取は、マイクロスフェア注射の約5〜10秒間前に開始し、90秒間継続した。 実験終了時に、過剰量のペントバルビタールナトリウムで、動物を致死せしめた。 全組織および器官を切除し、計量し、バイアルに入れた。 標準物質、血液試料および組織試料での放射能は、放射性同位体エネルギーを識別するための、プリセットウィンドウを装備したPackard Minaxi Auto-Gamma 5000シリーズのγ線カウンター(Packard Instruments社、ダウナーズグローブ、イリノイ州)で計数した。 次のパラメーターを、計算した。 (1)心拍出量(CO)((注射された放射能×動脈血の採取速度)/採取した動脈血液での放射能)、(2)一回拍出量(SV)(CO/HR)、(3)全末梢血管抵抗(TPR)(平均動脈圧(MAP)/CO)、(4)局所血流量((組織内の放射能×動脈血の採取速度)/採取した動脈血液での放射能)、および(5)局所血管抵抗(MAP/局所血流量)。 データは、文献(45)に記載されたコンピュータプログラムを使用して計算処理した。
ラット乳腺への血液潅流は、文献(50、51)に記載の方法に従って、レーザードップラー流速計を用いて測定した。 動物の乳頭周囲を剃毛した。 乳腺周囲の皮膚は、幅約6cmおよび長さ4cmの皮弁となるよう切開した。 標準モデルの光ファイバープローブを、切開皮膚の表面へ適用し、両面接着テープで組織へ固定した。 切開皮膚を、金属製ホルダー内に置き、テープで固定し、次いで、Periflux PF2b 4000レーザードップラー流速計(Perimed KB社、ストックホルム、スウェーデン)に接続した。 時定数を1.5秒に設定し、また、帯域幅を4KHzに設定した。
すべてのデータは、平均値±SEMとして表示した。 データは、分散分析を用いて分析し、その後にDuncan検定を実施した。 p<0.05のレベルを、統計的な有意差とみなした。
正常ラットおよび腫瘍を有するラットの全身性血行動態に対するET-1の効果
正常(生理食塩水処置)ラットでのベースライン時の全身性血行動態パラメーターは、MAP:111.1±4.8mmHg;CO:268.6±17.6ml/分;SV:0.87±0.06ml;TPR:419.6±24.37mmHg.分/ml;およびHR:312.5±20.2回/分であった。 正常ラットでは、MAPにおける有意な増加は、ET-1注入の30分後(14.5%;p<0.05)に、また、減少は、120分後(17.8%;p<0.05)に認められた。 TPRは、120分後に増加した(49.2%;p<0.05)。 COは、ET-1注入の60分後および120分後(各々、22.9%および42.5%;p<0.05)に低下した。 SVは、60分後および120分後(各々、20.9%および36%;p<0.05)に低下した。 HRにおける有意な変化は、観察されなかった(図1)。
ET-1の投与後に、生理食塩水で処置した正常ラットの乳房組織での血流量の変化は観察されなかった。 60分後には血管抵抗にて有意な減少(18.61%;p<0.05)が観察されたが、この現象は、正常ラットの乳房組織においてはET-1注入の30分後で認められた(図2)。
腫瘍を有するラットおよび正常ラットの乳房組織での潅流、移動性血球濃度(CMBC)および赤血球(RBC)の速度変化を、図3に示している。 ET-1を投与した後は、正常ラットの乳房組織での血液潅流に変化は認められなかった。 ET-1を投与して30分後に、腫瘍を有するラットの乳房組織での潅流は、正常ラットのそれと比較して、有意に増加した(176%;p<0.05)。 ET-1を投与して60分後および120分後に、腫瘍を有するラットでの潅流は、ベースライン時のレベルにまで回復した。
腫瘍を有するラットおよび正常ラットでの血液潅流、CMBCおよびRBCの速度の各々におけるET-1で誘導された変化に対するBQ788の効果を、図4に示している。 正常ラットの乳房組織での血液潅流は、BQ788投与後またはET-1注入後において有意な変化を示さなかった。 しかし、腫瘍を有するラットの乳房腫瘍組織での潅流は、BQ788前処置ラットにET-1を注入して30分後(25.25±5.7%;p<0.05)および60分後(25.17±2.8%;p<0.05)に有意に減少した。 BQ788を用いた前処置は、腫瘍を有するラットにおいて、ET-1が誘導した潅流の増加を後退せしめた。 BQ788前処置ラットにET-1を注入した後では、腫瘍を有するラットの乳房組織での潅流と、正常ラットの乳房組織での潅流との間での差異は全く認められなかった。
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上記した本願発明の修正および変更は、本願発明の趣旨および範囲から逸脱せずに行うことができるので、添付の特許請求の範囲の記載の限定事項のみが、本願発明に付加されるべきである。
Claims (17)
- 治療有効量のエンドセリンBアゴニスト、および、治療有効量の化学療法薬を、治療を必要とする哺乳動物に投与する工程を含む、固形腫瘍を治療する方法。
- 前記固形腫瘍が、卵巣腫瘍、結腸腫瘍、カポジ肉腫、乳房腫瘍、黒色腫、前立腺腫瘍、髄膜腫、肝腫瘍、および、乳腺葉状腫瘍からなるグループから選択される請求項1に記載の方法。
- 前記固形腫瘍が、乳房腫瘍である請求項2に記載の方法。
- 前記エンドセリンアゴニストが、ET-1、ET-2、ET-3、BQ3020、IRL1620、サラフォトキシン56c、[Ala1、3、11、15]ET-1、および、これらの混合物からなるグループから選択される請求項1に記載の方法。
- 前記エンドセリンBアゴニストが、IRL1620を含む請求項4に記載の方法。
- 前記化学療法薬が、アドリアマイシン、カンプトテシン、カルボプラチン、シスプラチン、ダウノルビシン、ドキソルビシン、α-、β-またはγ-インターフェロン、インターロイキン2、イリノテカン、ドセタキセル、パクリタキセル、トポテカン、および、これらの混合物からなるグループから選択される請求項1に記載の方法。
- 前記エンドセリンBアゴニスト、および、前記化学療法薬が、同時に投与される請求項1に記載の方法。
- 前記エンドセリンBアゴニスト、および、前記化学療法薬が、単一組成物で投与される請求項7に記載の方法。
- 前記エンドセリンBアゴニスト、および、前記化学療法薬が、別個の組成物で投与される請求項7に記載の方法。
- 前記エンドセリンBアゴニスト、および、前記化学療法薬が、連続して投与される請求項1に記載の方法。
- 前記化学療法薬が、前記エンドセリンBアゴニストに先駆けて投与される請求項10に記載の方法。
- 前記エンドセリンBアゴニストが、前記化学療法薬に先駆けて投与される請求項10に記載の方法。
- 前記哺乳動物が、ヒトである請求項1に記載の方法。
- 化学療法薬、エンドセリンBアゴニスト、および、任意の賦形剤を含む組成物。
- (a) エンドセリンBアゴニストを含む包装済組成物、
(b) 哺乳動物の固形腫瘍を治療するために(a)を投与する際の指示事項を含む添付文書、および
(c) (a)および(b)を収容するための容器、を含む製品。 - (a) エンドセリンBアゴニストを含む包装済組成物、
(b) 化学療法薬を含む包装済組成物、
(c) 哺乳動物の固形腫瘍を治療するために(a)および(b)を同時または連続的に投与する際の指示事項を含む添付文書、および
(d) (a)、(b)および(c)を収容するための容器、を含む製品。 - (a) エンドセリンBアゴニストおよび化学療法薬を含む包装済組成物、
(b) 哺乳動物の固形腫瘍を治療するために(a)を投与する際の指示事項を含む添付文書、および
(c) (a)および(b)を収容するための容器、を含む製品。
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CN105315318B (zh) * | 2015-11-06 | 2019-04-19 | 山东大学 | 一种α‐L‐鼠李糖苷酶在制备5-氟-2’-脱氧脲苷衍生物中的应用 |
WO2019140324A1 (en) | 2018-01-12 | 2019-07-18 | Enb Therapeutics, Inc. | Deuterated compounds, compositions, and methods for treating cancers associated with etbr activation |
CN110179806B (zh) * | 2019-06-12 | 2022-11-22 | 首都医科大学 | 磺胺类药物在制备抗肿瘤药物中的应用 |
EP4087661A4 (en) * | 2020-01-06 | 2024-04-10 | Lassogen Inc | LASSO PEPTIDES FOR THE TREATMENT OF CANCER |
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US5550110A (en) * | 1992-04-22 | 1996-08-27 | Warner-Lambert Company | Endothelin Antagonists II |
CA2135151A1 (en) * | 1993-11-08 | 1995-05-09 | Mitsuhiro Wakimasu | Cyclic hexapeptides, their production and use |
US5811416A (en) * | 1994-06-06 | 1998-09-22 | Board Of Regents The University Of Texas System | Endothelin antagonist and/or endothelin synthase inhibitor in combination with a progestin, an estrogen, a cyclooxygenase inhibitor, or a nitric acid donor or substrate |
US5612359A (en) * | 1994-08-26 | 1997-03-18 | Bristol-Myers Squibb Company | Substituted biphenyl isoxazole sulfonamides |
CA2206119C (en) | 1994-12-12 | 2008-05-13 | Omeros Medical Systems, Inc. | Irrigation solution and method for inhibition of pain, inflammation and spasm |
EP0815870A3 (en) | 1996-06-27 | 2000-05-03 | Takeda Chemical Industries, Ltd. | Composition for prohylaxis or treatment of cerebral infarction |
CA2268640A1 (en) * | 1998-04-14 | 1999-10-14 | Mitsuru Shiraishi | Composition for preventing or treating ischemic disease |
US7566452B1 (en) * | 1999-05-04 | 2009-07-28 | New York University | Cancer treatment with endothelin receptor antagonists |
US6545048B1 (en) * | 1999-06-29 | 2003-04-08 | California Institute Of Technology | Compositions and methods of treating cancer using compositions comprising an inhibitor or endothelin receptor activity |
AU2001264570A1 (en) | 2000-05-31 | 2001-12-11 | Warner Lambert Company | Combinations of an endothelin receptor antagonist and an antiepileptic compound having pain alleviating properties or analgesic |
AU2002241736A1 (en) * | 2000-12-21 | 2002-07-01 | Bristol-Myers Squibb Company | Method for preventing or treating pain by administering an endothelin antagonist |
US20030104976A1 (en) * | 2001-07-23 | 2003-06-05 | Gudarz Davar | Analgesic methods using endothelin receptor ligands |
US7973064B2 (en) | 2001-11-27 | 2011-07-05 | The Board Of Trustees Of The University Of Illinois | Method and composition for potentiating an opiate analgesic |
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US20040138121A1 (en) | 2004-07-15 |
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EP1556073B1 (en) | 2016-01-06 |
AU2003286647A1 (en) | 2004-05-13 |
CA2502848C (en) | 2012-10-02 |
CN1729012A (zh) | 2006-02-01 |
EP1556073A2 (en) | 2005-07-27 |
CN1729012B (zh) | 2013-05-22 |
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