JP4951194B2 - レオウイルスを用いる化学療法薬剤耐性新生物細胞の感作 - Google Patents
レオウイルスを用いる化学療法薬剤耐性新生物細胞の感作 Download PDFInfo
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Description
米国特許第6,136,307号
WO 94/18992(1994年9月1日発行)
WO 94/25627(1994年11月10日発行)
WO 99/18799(1994年4月22日発行)
癌は、死亡の主要な原因のうちの1つである。長期間医学的な研究に焦点が当てられてきたが、現在までの主要な癌治療は、手術、放射線治療および化学療法のままである。これらの治療の各々は、容易に克服できない制限に直面しており、改善された治療に対する研究は続いている。
本発明は、レオウイルスの使用によって、化学療法薬剤に対する薬物耐性細胞を感作する方法に関する。レオウイルスは、近年、活性化されたras経路を用いる細胞中でのレオウイルスの選択的複製に起因してras活性化新生物細胞を殺傷するが、正常細胞は殺傷しない、選択的抗癌剤として発見された(米国特許第6,136,307号;Coffeyら、1998;Strongら、1998)。予期せぬことに、本発明において、レオウイルスは、化学療法薬剤に対する細胞の感受性も同様に増加したことが、本発明においてさらに発見された。従って、シスプラチンに不応性である腫瘍は、シスプラチンとレオウイルスとの組合わせを用いて処置され、そしてその結果は、この組合わせがレオウイルス単独よりも効果的であったことを示した。シスプラチンは、レオウイルスの非存在下で投与された場合、腫瘍に対して何の効果も有さなかったので、この組合わせの効果は、単に個々の効果の相加効果でも相乗効果でもない。むしろ、レオウイルスは、腫瘍が通常不応性である化学療法薬剤に対して腫瘍を感作させた。
(a)有効量のレオウイルスを上記細胞に投与する工程;および
(b)有効量の化学療法薬剤を上記細胞に投与する工程、
を包含する。
(a)レオウイルスによって新生物細胞の感染が生じる条件下で、有効量のレオウイルスを被験体に投与する工程;および、
(b)有効量の化学療法薬剤を上記被験体に投与する工程、
を包含する。
(a)レオウイルスによって新生物の感染が生じる条件下で、有効量のレオウイルスを被験体に投与する工程;および、
(b)有効量の化学療法薬剤を上記被験体に投与する工程、
を包含する。
(a)レオウイルスによって新生物の感染が生じる条件下で、有効量のレオウイルスを上記被験体に投与する工程;および、
(b)有効量の化学療法薬剤を上記被験体に投与する工程
を包含する。
本発明は、レオウイルスを使用することによって、薬物耐性細胞を化学療法剤に対して感作させる方法に関する。レオウイルスは、活性化されたras経路を有する細胞におけるレオウイルスの選択的複製に起因して、ras活性化腫瘍性(neoplastic)細胞を殺傷するが正常細胞は殺傷しない選択的抗癌剤として近年発見されている(米国特許第6,136,307号;Coffeyら、1998;Strongら、1998)。予期せぬことに、レオウイルスが化学療法剤に対する細胞の感受性をなお増加させることが、本発明においてさらに発見された。よって、本発明は、癌化学療法の効率および選択性の両方を増強する方法を提供する。本発明はまた、進行性薬物耐性の発達を妨げるために使用され得る。
本明細書中で使用される場合、新生物細胞を化学療法剤に「感作する」は、化学療法剤に対する新生物細胞の感受性を増強させる作用をいう。
−ナイトロジェンマスタード(例えば、シクロホスファミド、トロフォスファミド、イホスファミドおよびクロラムブシル);
−ニトロソ尿素(例えば、カルムスチン(BCNU)、ロムスチン(CCNU)、セムスチン(メチルCCNU)およびニムスチン(ACNU));
−エチレンイミンおよびメチルメラミン(例えば、チオテーパ);
−葉酸アナログ(例えば、メトトキサレート);
−ピリミジンアナログ(例えば、5−フルオロウラシルおよびシタラビン);
−プリンアナログ(例えば、メルカプトプリンおよびアザチオプリン);
−ビンカアルカノイド(例えば、ビンブラスチン、ビンクリスチンおよびビンデシン);
−エピポドフィロトキシン(epipodophyllotoxin)(例えば、エトポシドおよびテニポシド);
−抗生物質(例えば、ダクチノマイシン、ダウノルビシン、ドキソルビシン、エピルビシン、ブレオマイシンa2、マイトマイシンcおよびミトザントロン);
−エストロゲン(例えば、エイエチルスチルベストロール(eiethyl stilbestrol));
−ゴナドトロピン放出ホルモンアナログ(例えば、ロイプロリド、ブセレリンおよびゴセレリン);
−抗エストロゲン(例えば、タモキシフェンおよびアミノグルテチミド);
−アンドロゲン(例えば、テストラクトンおよびデロスタノロンプロピオネート);
−プラチネート(例えば、シスプラチンおよびカルボプラチン)および
−インターフェロン(インターフェロンα、βおよびγを含む)。
レオウイルスは、ras活性化新生物に対する、有効な治療剤である。なぜならば、このウイルスは、活性化ras経路を用いて細胞内で選択的に複製するからである(米国特許第6,136,307号)。ras経路は、正常な細胞において活性化されず、従って、レオウイルスは、高い選択性で新生物細胞を殺す。理論には束縛されないが、正常な細胞中でのウイルス遺伝子の転写は、約65kDaの細胞タンパク質(二本鎖RNA活性化プロテインキナーゼ(PKR)であると決定された)のリン酸化と関係していると考えられる。PKRは、ras−活性化細胞においては観察されなかった。このPKRのリン酸化は、翻訳の阻害を導き、従って、ウイルス複製は完了され得ない。しかし、ras−活性化細胞において、rasまたはその下流の因子は、PKRのリン酸化をブロックし、それにより、ウイルスの翻訳および複製を開始させる。
℃=摂氏温度
hr=時間
min=分
μM=マイクロモル濃度
mM=ミリモル濃度
M=モル濃度
ml=ミリリットル
μl=マイクロリットル
mg=ミリグラム
μg=マイクログラム
PAGE=ポリアクリルアミドゲル電気泳動
rpm=1分あたりの回転
FBS=胎仔ウシ血清
DTT=ジチオトレイトール
SDS=ドデシル硫酸ナトリウム
PBS=リン酸緩衝化生理食塩水
DMEM=ダルベッコ改変イーグル培地
α−MEM=α−改変イーグル培地
β−ME=β−メルカプトエタノール
MOI=感染多重度
PFUまたはpfu=プラーク形成単位
PKR=二重鎖RNA活性化プロテインキナーゼ
EGF=上皮増殖因子
PDGF=血小板誘来増殖因子
DMSO=ジメチルスルホキシド
MDR=多剤耐性
MRP=多剤耐性関連タンパク質
HSV=単純疱疹ウイルス
(実施例1 レオウイルスによる、不応性腫瘍細胞のシスプラチンに対する感作)
C3Hマウス(Charles River)に、1.0×106PFUのras形質転換C3H細胞(D.Edwards,University of Calgaryの贈与物)を皮下的に移植し、腫瘍を発生させた。これらの研究で使用されたレオウイルス血清型3のDearing株を、L細胞の懸濁培養物中で増殖させ、β−メルカプトエタノール(β−ME)を抽出緩衝液から省いたほかは、Smith(Smithら、1969)に従って精製した。精製したレオウイルスについての粒子/PFU比は、代表的には100/1であった。
Claims (8)
- 化学療法薬剤に対して不応性であるras活性化新生物細胞を化学療法薬剤に対して感作するための組成物であって、該組成物が:
有効量のレオウイルス
を含み、
該化学療法薬剤は、シスプラチンおよびタキソールからなる群から選択される、組成物。 - 前記ras活性化新生物細胞が哺乳動物内に位置する、請求項1に記載の組成物。
- 前記哺乳動物が、イヌ、ネコ、ヒツジ、ヤギ、ウシ、ウマ、ブタ、ヒトおよび非ヒト霊長類からなる群から選択される、請求項2に記載の組成物。
- 前記化学療法薬剤がシスプラチンである、請求項1〜3のいずれか1項に記載の組成物。
- 前記レオウイルスが哺乳動物レオウイルスである、請求項1〜4のいずれか1項に記載の組成物。
- 前記哺乳動物レオウイルスがヒトレオウイルスである、請求項5に記載の組成物。
- 前記ヒトレオウイルスが血清型3レオウイルスである、請求項6に記載の組成物。
- 前記血清型3レオウイルスがDearing株レオウイルスである、請求項7に記載の組成物。
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PCT/CA2002/000201 WO2002066040A2 (en) | 2001-02-20 | 2002-02-19 | Sensitization of chemotherapeutic agent resistant neoplastic cells with reovirus |
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WO2013163724A1 (en) * | 2012-04-30 | 2013-11-07 | Oncolytics Biotech Inc. | Protecting modified viruses from neutralizing antibodies using the reovirus sigma 1 protein |
EP3209382B1 (en) | 2014-10-24 | 2020-11-25 | Calidi Biotherapeutics, Inc. | Combination immunotherapy approach for treatment of cancer |
CN104881181B (zh) * | 2015-05-27 | 2019-07-26 | 联想(北京)有限公司 | 显示方法及电子设备 |
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DK0931830T3 (da) | 1993-02-16 | 2001-06-11 | Onyx Pharma Inc | Cytopatiske vira til terapi og profylakse af neoplasi |
PT1314431E (pt) | 1993-04-30 | 2008-10-24 | Wellstat Biologics Corp | Composições purificadas de vírus da doença de newcastle |
US5776743A (en) | 1994-09-06 | 1998-07-07 | La Jolla Cancer Research Foundation | Method of sensitizing tumor cells with adenovirus E1A |
US6110461A (en) | 1997-08-13 | 2000-08-29 | Oncolytics Biotech Inc. | Reovirus for the treatment of neoplasia |
US6136307A (en) * | 1997-08-13 | 2000-10-24 | Oncolytics Biotech Inc. | Reovirus for the treatment of cellular proliferative disorders |
US6565831B1 (en) * | 1999-02-24 | 2003-05-20 | Oncolytics Biotech Inc. | Methods for preventing reovirus recognition for the treatment of cellular proliferative disorders |
ATE371372T1 (de) | 1997-10-09 | 2007-09-15 | Wellstat Biologics Corp | Behandlung von neoplasmen mit interferon- empfindlichen, klonalen viren |
US6428968B1 (en) * | 1999-03-15 | 2002-08-06 | The Trustees Of The University Of Pennsylvania | Combined therapy with a chemotherapeutic agent and an oncolytic virus for killing tumor cells in a subject |
EP1955703A1 (en) * | 1999-11-12 | 2008-08-13 | Oncolytics Biotech Inc. | Viruses for the treatment of cellular proliferative disorders |
AR035227A1 (es) * | 2001-02-20 | 2004-05-05 | Oncolytics Biotech Inc | Uso de un agente quimioterapeutico para la manufactura de un medicamento para la sensibilizacion de celulas neoplasicas resistentes a agentes quimioterapeuticos con reovirus |
US7163678B2 (en) * | 2002-11-07 | 2007-01-16 | Oncolytics Biotech Inc. | Reovirus for the treatment of ral-mediated cellular proliferative disorders |
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