JP2017516751A - 薬剤誘導性性腺毒性または子宮毒性の治療および防止のための色素上皮由来因子(pedf)の使用方法 - Google Patents
薬剤誘導性性腺毒性または子宮毒性の治療および防止のための色素上皮由来因子(pedf)の使用方法 Download PDFInfo
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Abstract
Description
(a)前記対象における性腺機能を決定し、そして
(b)前記対象に、治療有効量の色素上皮由来因子(PEDF)を投与して、前記対象において薬剤により誘導される性腺毒性を治療または防止する
ことを含む、方法が提供される。
(i)IVFにおける使用のためのIVFグレードの培地;および
(ii)PEDF
を含むキットが提供される。
(a)前記対象における性腺機能を決定し、そして
(b)前記対象に、治療有効量の色素上皮由来因子(PEDF)を投与して、前記対象において薬剤により誘導される性腺毒性を治療または防止する
ことを含む、方法が提供される。
0.02〜0.4mg/kg/日、0.162〜0.32mg/kg/日、0.01〜0.2mg/kg/日、0.1〜0.4mg/kg/日、0.2〜0.4mg/kg/日または0.05〜0.1mg/kg/日などである。
(i)IVFにおける使用のためのIVFグレードの培地;および
(ii)PEDF
を含むキットも提供される。
試薬−H2O2、Dulbeccoの改変Eagle培地/Ham F12 1:1(DMEM−F12)、Dulbeccoのリン酸緩衝生理食塩水(DPBS)、ペニシリンおよびストレプトマイシン(Biological Industries、イスラエル国、ベイト ハメニク)、活性炭処理済みウシ胎仔血清(CS−FBS;Invitrogen、米国、ニューヨーク州、グランドアイランド)、ドキソルビシン(DXR、Teva イスラエル国)。
DXRはマウス卵巣中のPEDF mRNAレベルを低下させる
マウス卵巣に対してDXRが与える損傷を評価するために、標準的なPMSG/hCGプロトコール[非特許文献53]を用いて過剰排卵処理し、次いで、DXRで処理したマウスから回収したマウス卵巣において、PEDF mRNAレベルを評価した(図1のA)。図1のBに示されるように、DXRはPEDF mRNAレベルを有意に(P<0.05)低下させた。
PEDF mRNAレベルに対するDXRの負の作用に基づいて、外因性組換えPEDF(rPEDF)による、排卵に対するDXRの破壊作用を克服する作用について検討した。この目的のために、雌のマウスをDXRで処理し、次の日にrPEDFを投与した。実験の4日目に、標準的なPMSG/hCGプロトコール[非特許文献53]を用いてマウスに過剰排卵を誘導した。hCG投与の16〜17時間後にマウスを屠殺した(図2のA)。図2のBに示されるように、rPEDFは、DXR誘導性の排卵された卵母細胞数の低下を有意に(P<0.05)減少させた。
H2O2はLH−15細胞の生存率およびこれら細胞中のPEDF mRNAレベルに影響を及ぼす
顆粒膜細胞に対して酸化ストレス(OS)が与える損傷を評価するために、MTTアッセイを用いて、細胞の生存率を追跡した。24時間にわたる、段階的に濃度を高めた(100〜500μMの)H2O2へのラット顆粒膜細胞株(「LH−15細胞」と呼ぶ)の曝露は、統計的に有意な(P<0.05)、用量依存的な、細胞生存率の低下を引き起こした(図3のA)。さらにH2O2は、100μM濃度で既にPEDF mRNAレベルを有意に(P<0.01)低下させた(図3のB)。
LH−15細胞の生存率およびPEDF mRNAのレベルに対するH2O2の負の作用に基づいて、外因性組換えPEDF(rPEDF)による、顆粒膜細胞におけるH2O2の破壊作用を克服する作用について検討した。この目的のために、LH−15細胞を、rPEDF(1nMまたは5nM)の存在下または非存在下で、24時間にわたって100μMまたは200μMのH2O2と共にインキュベートし、MTTアッセイで細胞生存率を評価した。図4のAに示されるように、rPEDFは、H2O2誘導性の細胞生存率の低下を有意に(P<0.05)減少させた。さらに、同じ刺激条件下における、LH−15細胞内における、アポトーシス促進タンパク質BAXの発現ならびに抗酸化酵素であるSOD−1およびGPX−1のmRNAレベルを追跡した。その結果、BAXレベルはH2O2処理後に上昇するが、rPEDFの外部添加によって、その発現は減少したことがわかる(図4のB〜C;P<0.05)。対照的に、SOD−1およびGPX−1のmRNAレベルは、H2O2処理後に低下したが、rPEDFを外部添加によってそれらの発現は上昇した(図5のA〜B)。
PEDF受容体であるPNPLA2は、マウス卵巣中で発現される
生存促進性PEDF−Rである、パタチン様ホスホリパーゼドメイン含有タンパク質2(PNPLA2)のマウス卵巣における発現を、タンパク質レベルおよびmRNAレベルで評価した。マウス卵巣の免疫染色により、生存促進性PEDF−RであるPNPLA2は、顆粒膜細胞、莢膜細胞および卵母細胞中で発現されることがわかる(図6のA)。さらに、マウス卵巣は、PEDF−RのmRNA(図6のB)およびタンパク質(図6のC)を発現する。
これまでに観察された、LH−15細胞に対するrPEDFの効果から、顆粒膜細胞はPEDF受容体(PEDF−R)を発現することを示唆している。図3のB〜Cに示されるように、顆粒膜細胞は、生存促進性PEDF−RであるPNPLA2のmRNA(図6のB)およびタンパク質(図6のC)を発現する。
顆粒膜細胞が、PEDF生存促進機能を仲介するPNPLA2を発現することが示されたので、生存促進シグナル伝達経路における既知の因子であるAKT(非特許文献54)に対する、rPEDFによる活性化作用を調べた。この目的のために、血清飢餓条件に置いたLH−15細胞を、様々な期間にわたって1nMのrPEDFで刺激した。その結果、rPEDF刺激は、AKTに対して長期的な、時間依存的なリン酸化を刺激期間5分から誘導することが示された(図7のA〜B;P<0.05)。
亜急性タモキシフェン処理は子宮重量ならびにVEGFおよびPEDFの発現に影響を及ぼす
閉経後の子宮組織に対するタモキシフェンの亜急性投与の作用を評価するために、卵巣切除(OVX)マウスを、様々な濃度のタモキシフェンで7日間にわたって毎日処理した。図8に示されるように、亜急性タモキシフェン投与後に子宮重量の用量依存的増加が観察された。さらに、子宮のVEGFタンパク質レベルは、用量依存的に上方調節され(図9のA〜B)、子宮重量と正に相関していた。一方、PEDFタンパク質の発現は、タモキシフェン用量が増加するにつれて下方調節された(図9のAおよび図9のC)。亜急性タモキシフェン投与後の子宮におけるVEGFタンパク質レベルとPEDFタンパク質レベルの相互的な変化は、VEGF/PEDFタンパク質レベル比の劇的で有意な用量依存的上昇をもたらした(図9のD)。
子宮重量およびVEGF発現に対するタモキシフェンの破壊作用を克服する外因性組換えPEDF(rPEDF)の作用について検討した。マウスにおけるrPEDF処理の確立されたレジメン[非特許文献55および非特許文献56]に基づいて、7日間にわたり、1日用量のタモキシフェンで処理した卵巣切除マウスに、10mg/kgの用量でrPEDFを投与した。図11および図12のA〜Bに示されるように、タモキシフェンのみの場合と比較して、タモキシフェン+rPEDFで処理したマウスにおいて、子宮重量および子宮VEGFタンパク質レベルの有意な減少が観察され、これは、rPEDFが、おそらくタモキシフェン誘導性VEGF上昇に抵抗することによって、タモキシフェン誘導性の子宮に対する副作用を無効化したことを示唆している。
亜急性タモキシフェンモデルにおける、AKTおよびJNKのリン酸化レベルに対するrPEDFの投与の効果の分析によって、タモキシフェンのみで処理したマウスと比べて、タモキシフェン+rPEDFで処理したマウスにおいて、AKTのリン酸化の有意な減少(図13のA〜B)およびJNKのリン酸化の有意な増加(図14のA〜B)が明らかとなった。このように、rPEDFによる処理は、がん関連シグナル伝達経路の活性化を低下させる可能性がある。
がん患者は、長期間(最大10年)にわたって、毎日、タモキシフェンによる治療を受けている。したがって、長期的なタモキシフェン投与の作用を評価するために、マウスに1カ月間にわたって週5日間のタモキシフェン(2.5μg/マウス)投与を行った。図15および図16のA〜Cに示されるように、長期的なタモキシフェン処理は、亜急性処理と類似する作用、すなわち、子宮重量の増加(図15)、VEGFタンパク質レベルの上方調節(図16のA)およびPEDFタンパク質レベルの下方調節(図16のB)が誘導された。結果として、VEGF/PEDF比は有意に増大し、亜急性処理モデルと対応していた(図16のC)。
子宮重量およびVEGF発現に対する長期的タモキシフェン処理の破壊作用を克服する、外因性組換えPEDF(rPEDF)の作用について検討した。予備分析から、rPEDFによる処理は、タモキシフェンによる短期の開始期を経てから投与した方が、より効果的であることがわかった(データは示さず)。そこでタモキシフェン処理開始から8日目からrPEDFのマウスへの投与を開始した。図18に示されるように、子宮重量は、タモキシフェン+rPEDFで処理したマウスにおいて下方調節されたが、統計的に有意ではなかった(p=0.2)。子宮VEGFタンパク質の発現レベルは、タモキシフェンのみで処理したマウスと比較した場合、タモキシフェン+rPEDFで処理したマウスにおいて有意に低下し(図19のA〜B)、これは、1カ月の処理後も子宮に対してrPEDFの効果が持続していることを示唆している。
ホルモン受容体の発現レベルは、乳がんのためのタモキシフェン治療における重要なアスペクトである。ER中介性シグナル伝達経路には特に注目が集まっている。これは、タモキシフェンはエストロゲン受容体(ER)に結合してその活性を発揮することができるため、ER発現レベルの変化はタモキシフェンに対する組織の応答を変化させ得るためである。したがって、次のステップでは、ホルモン受容体であるERα受容体、ERβ受容体およびプロゲステロン受容体(PR)のレベルを、亜急性in vivoタモキシフェン処理モデルおよび長期的なin vivoタモキシフェン処理モデルにおいて決定した。図21のAに示されるように、亜急性タモキシフェン処理は、ERα mRNAレベルを上方調節したものの、ERβおよびPRに対して有意な作用を示さなかった。また図21のAから明らかなように、rPEDF投与により、ERα mRNAレベルの亜急性タモキシフェン誘導性低下を減弱させることができた。さらに、ERαのタンパク質レベルは、同様の傾向を示したが、統計的に有意ではなかった(図21のB、p=0.1)。
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Claims (50)
- 薬剤により誘導される性腺毒性の治療または防止を、それを必要とする対象において実施するための方法であって、前記対象に、治療有効量の色素上皮由来因子(PEDF)を投与することによって、前記対象において薬剤により誘導される性腺毒性を治療または防止することを含む、方法。
- 対象において薬剤により誘導される性腺毒性を治療または防止するための、色素上皮由来因子(PEDF)。
- 薬剤により誘導される性腺毒性の治療または防止を、それを必要とする対象において実施するための方法であって、
(a)前記対象における性腺機能を決定し、そして
(b)前記対象に、治療有効量の色素上皮由来因子(PEDF)を投与して、前記対象において薬剤により誘導される性腺毒性を治療または防止する
ことを含む、方法。 - 前記性腺毒性が、性腺機能低下症、精子形成の減少、排卵の減少、早発卵巣不全および不妊症からなる群より選択される、請求項1〜3のいずれか一項に記載の方法または使用。
- 前記性腺毒性が排卵の減少を含む、請求項1〜3のいずれか一項に記載の方法または使用。
- 前記薬剤が化学療法および放射線療法からなる群より選択される、請求項1〜5のいずれか一項に記載の方法または使用。
- 前記薬剤が酸化ストレスを誘導するものである、請求項1〜6のいずれか一項に記載の方法または使用。
- 前記対象が雄である、請求項1〜7のいずれか一項に記載の方法または使用。
- 前記雄が生殖年齢にある、請求項8に記載の方法または使用。
- 前記雄が精液採取を受けていない、請求項8または9に記載の方法または使用。
- 前記対象ががんと診断されている、請求項1〜3のいずれか一項に記載の方法または使用。
- 前記がんが、精巣がん、乳がん、卵巣がん、リンパ腫および白血病からなる群より選択されるものである、請求項11に記載の方法または使用。
- 前記化学療法のための治療剤が最大耐量(MTD)で投与される、請求項6に記載の方法または使用。
- 前記化学療法が、メクロレタミン、プロカルバジン、シクロホスファミド、イホスファミド、ブスルファン、メルファラン、クロラムブシル、クロルメチン、ドキソルビシン、シスプラチンおよびカルボプラチンからなる群より選択されるものである、請求項6に記載の方法または使用。
- 前記化学療法が、アルキル化剤、プロカルバジン、白金類似体およびアントラサイクリン系抗生物質からなる群より選択されるものである、請求項6に記載の方法または使用。
- 前記化学療法が、アントラサイクリン系抗生物質、アルキル化剤、白金配位錯体、エピポドフィロトキシンおよびカンプトテシンからなる群より選択されるものである、請求項6に記載の方法または使用。
- 前記化学療法がドキソルビシンである、請求項6に記載の方法または使用。
- 前記対象に対する前記薬剤の投与をさらに含む、請求項1〜17のいずれか一項に記載の方法または使用。
- 前記PEDFの投与を、前記薬剤の投与と同時に行う、請求項18に記載の方法または使用。
- 前記PEDFの投与を、前記薬剤の投与後に行う、請求項18に記載の方法または使用。
- がんの治療を必要とする対象においてがんを治療するための方法であって、前記対象に、治療有効量のタモキシフェンおよび治療有効量の色素上皮由来因子(PEDF)を投与して、前記がんを治療することを含む、方法。
- 対象におけるがんを治療するための、タモキシフェンおよび色素上皮由来因子(PEDF)。
- タモキシフェン誘導性子宮毒性の治療または防止を、それを必要とする対象において実施するための方法であって、前記対象に、治療有効量の色素上皮由来因子(PEDF)を投与することによって、前記対象においてタモキシフェン誘導性子宮毒性を治療または防止することを含む、方法。
- 対象においてタモキシフェン誘導性子宮毒性を治療または防止するための、色素上皮由来因子(PEDF)。
- タモキシフェンおよび色素上皮由来因子(PEDF)をそれぞれ個別に収容した容器を含む、がんの治療用に同定された製品。
- 活性成分となるタモキシフェンおよび色素上皮由来因子(PEDF)と、薬学的に許容される担体または希釈剤とを含む医薬組成物。
- 対象におけるタモキシフェン誘導性子宮毒性を診断するための方法であって、タモキシフェンによる治療後の対象の生物試料中のPEDFレベルを決定することを含み、前記レベルが所定閾値を下回ることをもって、前記対象におけるタモキシフェン誘導性子宮毒性の指標とする方法。
- 前記生物試料中のVEGFのレベルを決定することをさらに含み、前記レベルが所定閾値を上回ることをもって、前記対象におけるタモキシフェン誘導性子宮毒性の指標とする、請求項27に記載の方法。
- VEGFレベルとPEDFとの比が、前記生物試料に対する所定の閾値を上回ることをもって、前記対象におけるタモキシフェン誘導性子宮毒性の指標とする、請求項28に記載の方法。
- 前記対象が雌である、請求項1〜7、21および22のいずれか一項に記載の方法または使用。
- 前記対象が生殖年齢にある、請求項21〜24、27および30のいずれか一項に記載の方法または使用。
- 前記雌が卵母細胞の回収を受けていない、請求項30または31に記載の方法または使用。
- 前記対象が閉経前の期間にある、請求項21、23および27〜29のいずれか一項に記載の方法または請求項22もしくは24に記載の使用。
- 前記対象が閉経後の期間にある、請求項21、23および27〜29のいずれか一項に記載の方法または請求項22もしくは24に記載の使用。
- 前記対象ががんと診断されている、請求項23および27〜29のいずれか一項に記載の方法または請求項24に記載の使用。
- 前記がんが乳がんである、請求項21、22および35のいずれか一項に記載の方法または使用。
- 前記PEDFの投与を、前記タモキシフェンの投与と同時に行う、請求項21または22に記載の方法または使用。
- 前記PEDFの投与を、前記タモキシフェンの投与後に行う、請求項21または22に記載の方法または使用。
- 前記PEDFがPEDFペプチドである、請求項1〜38のいずれか一項に記載の方法、使用、製品または医薬組成物。
- 卵母細胞の品質を改善するための方法であって、卵母細胞を含む培養細胞中の前記卵母細胞を、有効量の色素上皮由来因子(PEDF)とex vivoで接触させることによって、ex vivoで卵母細胞の質を改善することを含む、方法。
- 卵母細胞と、外部添加された色素上皮由来因子(PEDF)とを含む培養細胞。
- PEDFを含む、IVFにおける使用のためのIVFグレードの培地。
- (i)IVFにおける使用のためのIVFグレードの培地;および
(ii)PEDF
を含むキット。 - 前記卵母細胞が、体外受精(IVF)用の条件下で維持されている、請求項40に記載の方法または請求項41に記載の培養細胞。
- 前記接触を、前記卵母細胞の受精の前に実施する、請求項40に記載の方法。
- 前記接触を、前記卵母細胞の受精後に実施する、請求項40に記載の方法。
- 前記接触を、前記卵母細胞の受精と同時に実施する、請求項40に記載の方法。
- 前記接触を、前記培養細胞中の酸化物質が所定の閾値を上回って蓄積した後に実施する、請求項40に記載の方法。
- 前記卵母細胞が、卵巣または卵巣断片中に含まれる、請求項40および45〜48のいずれか一項に記載の方法または請求項41もしくは44に記載の培養細胞。
- 前記IVFのための卵母細胞が、卵巣または卵巣断片中に含まれる、請求項42に記載の培地または請求項43に記載のキット。
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AU2003275259A1 (en) * | 2002-09-26 | 2004-04-19 | Northwestern University | Anti-angiogenic fragments of pigment epithelium-derived factor (pedf) |
CA2588093A1 (en) * | 2004-11-16 | 2006-05-26 | Rony Seger | Variants of pigment epithelium derived factor and uses thereof |
WO2011058557A1 (en) * | 2009-11-12 | 2011-05-19 | Ramot At Tel-Aviv University Ltd. | Compositions comprising pedf and uses of same in the treatment and prevention of ovary-related syndromes |
EP3125924B1 (en) | 2014-03-30 | 2021-06-16 | Ramot at Tel-Aviv University Ltd. | Using pigment epithelium derived factor (pedf) for the treatment and prevention of agent-induced gonadal or uterine toxicity |
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2015
- 2015-03-30 EP EP15774029.1A patent/EP3125924B1/en active Active
- 2015-03-30 JP JP2016559972A patent/JP6666260B2/ja not_active Expired - Fee Related
- 2015-03-30 WO PCT/IL2015/050340 patent/WO2015151091A1/en active Application Filing
- 2015-03-30 US US15/129,007 patent/US10130682B2/en active Active
Non-Patent Citations (3)
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C.KAMPFERA ET AL., LIFE SCIENCES, vol. 97, no. 2, JPN6018045596, 3 March 2014 (2014-03-03), pages 129 - 136 * |
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STEPHANIE MORGAN ET AL., PLOS ONE, vol. 8, no. 7, JPN6018045599, 29 July 2013 (2013-07-29), pages e70117 * |
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US20170202916A1 (en) | 2017-07-20 |
EP3125924B1 (en) | 2021-06-16 |
JP6666260B2 (ja) | 2020-03-13 |
WO2015151091A1 (en) | 2015-10-08 |
EP3125924A4 (en) | 2018-04-25 |
EP3125924A1 (en) | 2017-02-08 |
US10130682B2 (en) | 2018-11-20 |
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