JP5564267B2 - 増殖性疾患の治療のための、p27の分解の阻害物質、特にアルギリン及びその誘導体の使用 - Google Patents
増殖性疾患の治療のための、p27の分解の阻害物質、特にアルギリン及びその誘導体の使用 Download PDFInfo
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- C07D519/04—Dimeric indole alkaloids, e.g. vincaleucoblastine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/50—Cyclic peptides containing at least one abnormal peptide link
- C07K7/54—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring
- C07K7/56—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring the cyclisation not occurring through 2,4-diamino-butanoic acid
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
- G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
- G01N33/5011—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing antineoplastic activity
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Biomedical Technology (AREA)
- Immunology (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Hematology (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Urology & Nephrology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Toxicology (AREA)
- General Physics & Mathematics (AREA)
- Microbiology (AREA)
- Biotechnology (AREA)
- Tropical Medicine & Parasitology (AREA)
- Food Science & Technology (AREA)
- Physics & Mathematics (AREA)
- Analytical Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Cell Biology (AREA)
- Pathology (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Description
R3は水素、非置換か若しくはOHで置換されたC1〜C8アルキル、又はORであり、ここで、Rは水素、C1〜C4アルキル、アリール、又はアセチルから選択され、
R4は水素、ハロゲン、非置換か若しくはOHで置換されたC1〜C4アルキル、又はC1〜C4アルコキシであり
R5は水素又はハロゲンであり、
R6は水素又はC1〜C4アルキルであり、
XはC=CH2又はCHR7であり、ここで、R7は非置換か若しくは−S−C1〜C4アルキルで置換されたC1〜C4アルキルである)の化合物、及びその薬学的に許容可能な塩を使用することによって、この目的は解決される。
R4が水素、ハロゲン、非置換か若しくはOHで置換されたC1〜C4アルキル、又はC1〜C4アルコキシであり、
R5が水素又はハロゲンであり、
R6が水素又はC1〜C4アルキルであり、且つ
XがC=CH2又はCHR7であり、ここで、R7は非置換か若しくは−S−C1〜C4アルキルで置換されたC1〜C4アルキルである、対象における癌の治療用の薬剤を製造するための本発明による化合物、及びその薬学的に許容可能な塩の使用が好ましい。
R2が水素、又はメチル等の非置換C1〜C4アルキルか、若しくはヒドロキシメチル等のOHで置換されたC1〜C4アルキルであり、
R3が水素、又はメトキシ等のC1〜C4アルコキシであり、
R4が水素、又はメチル等の非置換C1〜C4アルキルであり、
R5が水素又はブロモであり、
R6が水素又はメチルであり、且つ
XがC=CH2又はCHR7であり、ここで、R7は非置換か若しくは−S−エチルで置換されたメチルである、本発明による化合物、及びその薬学的に許容可能な塩の使用がさらに好ましい。
R2がメチル又はヒドロキシメチルであり、
R3が水素又はメトキシであり、
R4が水素又はメチルであり、
R5が水素であり、
R6がメチルであり、且つ
XがC=CH2である、本発明による化合物、及びその薬学的に許容可能な塩の使用がまたさらに好ましい。
p27安定化物質に関するハイスループットスクリーニング(HTS)
p27安定化化合物に関するハイスループット細胞スクリーニングは、HeLa細胞におけるp27kip1−GFP融合タンパク質の発現を可能にする、DNAプラスミド(EGFP−N1、Clontech)を安定に導入することにより確立した。p27−GFP発現細胞をネオマイシンを用いて選択し、幾つかの独立クローンを継代培養した。HeLa p27−GFP細胞を、384ウェルプレート(Corning)に播種し、一連の多様な天然産物(ヘルムホルツ感染研究センターの粘液細菌代謝産物コレクションの一部)と70nM濃度でインキュベートした。GFP発光を処理開始の3時間後、24時間後、48時間後、及び60時間後にVictor 1420マルチラベルカウンター(Perkin Elmer)を用いて蛍光分析測定により求めた。プロテアソーム阻害物質MG132を陽性対照として使用した。
初代ヒト線維芽細胞(HKI);HCT116(大腸癌)、MCF7(乳癌)、CaCo(大腸癌)、A549(肺癌)、HeLa(頸癌)、及び不死化MEFは、5%FCS及び2mg/mlのペニシリン/ストレプトマイシンを補充したDMEM中で培養した。SW480細胞(大腸癌)は、5%FCS及び2mg/mlのペニシリン/ストレプトマイシンを補充したマッコイ培地中で培養した。
マウス腫瘍組織の免疫組織化学的染色、ウエスタンブロット、及び免疫蛍光の実験は、以前に記載されているように(Timmerbeul, I. et al. Testing the importance of p27 degradation by the SCFskp2 pathway in murine models of lung and colon cancer. Proc Natl Acad Sci U S A 103, 14009-14 (2006). Kossatz, U. et al. C-terminal phosphorylation controls the stability and function of p27kipl. Embo J 25, 5159-70(2006).)行なった。以下の抗体を使用した:p27(カタログ番号K25020−150;Transduction Labs)、p21(N20;SantaCruz)、p53(FL−393;Santa Cruz)、NfκB(C−20;Santa Cruz)、Bax(P−19;Santa Cruz)、Alexa fluor 488(#A11001;Invitrogen)、20Sプロテアソームサブユニットβ2(Z)(PW9300;Biomol、ヒト細胞用)、20Sプロテアソームサブユニットβ2(Z)(PW8145;BIOTREND、マウス細胞用);20Sプロテアソームサブユニットβ1(Y)(PW8140;BIO TREND)、20Sプロテアソームサブユニットβ5(PW8895;BIO TREND);PECAM抗体クローンMEC 13.3(#550274;BD Pharmingen)。
MTTアッセイは、以前に記載されているように(Sasse, F. et al. Argyrins, immunosuppressive cyclic peptides from myxobacteria. I. Production, isolation, physico-chemical and biological properties. J Antibiot (Tokyo) 55, 543-51 (2002))行なった。組織切片のTUNEL染色は、脱パラフィンし(deparafinised)、製造業者により推奨されるように処理した(In Situ Cell Death Detection Kit、Fluorescein;ROCHE、カタログ番号11 684 795 910)10μmの切片上で実施した。培養細胞のフローサイトメトリー分析は、Becton Dickinsonの蛍光フローサイトメーターを用いて、以前に記載されているように(Malek, N.P. et al. A mouse knock-inmodel exposes sequential proteolytic pathways that regulate p27Kip1 in G1 and S phase. Nature 413,323-7 (2001))行なった。細胞周期における細胞の分布及びsub−G1画分の分析は、Cell Questソフトウェアを用いて行なった。ヒストン結合DNA断片ELISAを使用して、製造業者の指定に従って(Roche;#11 774425001)アポトーシスを起こした細胞の数を求めた。
siRNAノックダウンは、トランスフェクション試薬FuGene6(登録商標)、又はHiPerFectトランスフェクション試薬を用いて実施した。トランスフェクションは、siRNAをPsmb1、Psmb2、PSMB1、PSMB2、及びCDKN1Bについては0.2nMの濃度で、Psmb5及びPSMB5については0.4nMの濃度で用いて行なった。siRNAは全て、Ambionから購入した。
p27 フォワード:5’−CGUAAACAGCUCGAAUUAAtt−3’(配列番号1)
バックワード:5’−UUAAUUCGAGCUGUUUACGtt−3’(配列番号2)
Psmb1 フォワード:5’−GGAUUUUCAAUUCAUACCCtt−3’(配列番号3)
バックワード:5’−GGGUAUGAAUUGAAAAUCCtt−3’(配列番号4)
Psmb2 フォワード:5’−GGACGAUCAUGACAAGAUGtt−3’(配列番号5)
バックワード:5’−CAUCUUGUCAUGAUCGUCCtt−3’(配列番号6)
Psmb5 フォワード:5’−GGUGCUUAUAUUGCUUCCCtt−3’(配列番号7)
バックワード:5’−GGGAAGCAAUAUAAGCACCtg−3’(配列番号8)
PSMB1 フォワード:5’−GACUGUCUUACGCUGACAAtt−3’(配列番号9)
バックワード:5’−UUGUCAGCGUAAGACAGUCtc−3’(配列番号10)
PSMB2 フォワード:5’−GAUAUUACUCCUGUGUGUUtt−3’(配列番号11)
バックワード:5’−AACACACAGGAGUAAUAUCtt−3’(配列番号12)
PSMB5 フォワード:5’−GAAGAGCCAGGAAUCGAAAtt−3’(配列番号13)
バックワード:5’−UUUCGAUUCCUGGCCUUCtg−3’(配列番号14)
精製20Sプロテアソームによるプロテアソームアッセイは、以前に記載されているように(Lightcap, E. S. et al. Proteasome inhibition measurements: clinical application. Clin Chem 46, 673-83 (2000))、赤血球由来20Sプロテアソーム(Biomol International、#LP PW8720)及び蛍光基質Succ−LLVY−AMC、BZ−VGR−AMC、及びZ−Lle−AMC(Biomol International、LP PW9905)をプローブとして用いて、製造業者の指定に従って実施した。細胞及び腫瘍切片からのプロテアソーム抽出は、以前に記載されているように(Crawford,L.J. et al. Comparative selectivity and specificity of the proteasome inhibitors BzLLLCOCHO, PS-341, and MG-132. Cancer Res 66, 6379-86 (2006))行なった。簡潔に言うと、細胞(MEF又はMCF−7)又は組織試料ホモジネート(腫瘍切片)を、1mLのATP/DTT溶解緩衝液(10mmol/LのTris−HCl(pH7.8)、5mmol/LのATP、0.5mmol/LのDTT、5mmol/LのMgCl2)に再懸濁し、氷上で10分間インキュベートし、続いて15秒間超音波処理した。溶解物を400×g、4℃で10分間遠心分離し、得られたプロテアソームを含有する上清を、20%グリセロールを添加して−80℃で少なくとも1ヶ月間固定した(stable)。試料のタンパク質濃度を、クマシータンパク質アッセイ(Pierce、Rockford、IL)を用いて測定した。
初代微小血管内皮細胞(HMVEC)をヒト包皮から単離した。細胞を基礎培地(EBM−2)、FBS、ヒドロコルチゾン、hFGF−B、VEGF、R3−IGF、アスコルビン酸、hEGF、ゲンタマイシン、及びアムホテリシンを含むEGM−2 MV(Cambrex)において、37℃及び10%CO2で維持した。in vitro血管形成に対するアルギリンA又はボルテゾミブの影響を、マトリゲル毛細血管様管構造形成アッセイにより求めた。種々の化合物のin vitro血管形成への影響を調べるために、マトリゲル(BDBiosciences、#354248)でプレコートした96ウェル培養プレートにHMVECを播種し、アルギリンA又はボルテゾミブに曝露した。無作為に選択した3つの領域からの管構造の閉鎖ネットワークを、顕微鏡(Leica、Cambridge、United Kingdom)下でスコアリングした。Axio Vision 3.1 Zeissカメラを用いて写真を撮り、管長及び閉鎖血管様構造の形成を求めることによりスコアリングした。
1×107個のSW480細胞又はHCT116細胞(100μlのDMEM培地及び100μlのマトリゲル中)を、NMRI nu/nuマウスの脇腹に皮下注射した。腫瘍を適当なサイズ(200mm3)に達するまで、およそ18日間増殖させた。腫瘍のサイズをデジタルノギスで測定し、以下の式:(長さ×幅2)×π/6を用いて算出した。実験は全て検討後に、Lower Saxony、Germanyの動物権利保護機関に従って行なった。
腫瘍の小試験片を、0.1Mカコジル酸ナトリウム(pH7.3)中2.5%グルタルアルデヒド(Polysciences、Warrington、PA、USA)中で固定し、同じ緩衝液中2%四酸化オスミウム(Polysciences)で後固定した。段階的(graded)アルコール中で脱水した後、Epon(Serva、Heidelberg、Germany)に包埋した。酢酸ウラニル及びクエン酸鉛で染色した薄片を、Philips EM 301電子顕微鏡において観察した。電子顕微鏡写真を選択し、デジタル化し、Adobe Photoshop 6.0を用いて処理した。
単離した全RNAの品質及び完全性を、全試料をAgilent Technologies 2100 Bioanalyzer(Agilent Technologies;Waldbronn、Germany)にかけることにより調整した。3μgの全RNAから始めるビオチン標識標的合成に関しては、反応を製造業者(Affymetrix;SantaClara、CA)により提供された標準プロトコルを用いて行なった。いずれの場合にも、10μgの標識cRNAを、Affymetrix GeneChips HG−U133 2.0の同一ロットに45℃で16時間ハイブリダイズさせた。ハイブリダイゼーション後、GeneChipを洗浄し、SA−PEで染色し、Affymetrix GeneChip流体装置及びスキャナーを用いて読み取った。
マイクロアレイデータの分析は、Affymetrix GCOS 1.2ソフトウェアを用いて実施した。正規化のために、全アレイ実験を標的強度150に合わせるか(scaled)、そうでなければGCOS 1.2のデフォルト値を用いた。完全データセットは、MIAME対応フォーマットのGEO公開データベースサーバーに寄託されており、アクセッション番号GSE8565で入手可能である。アレイ一組の相関係数は:
統計分析は、Microsoft Excelソフトウェアを用いて実行した。特に指定のない限り、全てのデータは平均+/−SD(エラーバーは全ての図においてSDを表す)として表す。群間比較は両側スチューデントt検定により実施した。p<0.05の確率値は、統計的有意性を示すものと解釈した。
(プラスミドベクターCS2+の)ヒトp27cDNAをEcoR1及びBamH1で消化し、得られた断片をゲル精製後、同じ制限酵素で切断したベクターpEGFP−N1(Clontech)にライゲーションした。このようにして、pEGFPベクターに含有されるGFPとのリーディングフレームシフト融合を生成した。次に、プラスミドをHela細胞にトランスフェクトし、続いてカナマイシンで細胞選択し、プラスミドがその染色体に安定に組込まれた細胞性クローンを単離した。p27EGFPタンパク質の発現を、ウエスタンブロット並びにp27及びGFPの両方に対する免疫沈降を用いて確認した。
2つの癌細胞株、H15(頸癌)及びSW480(大腸癌)に対するアルギリン誘導体A〜Hの効果を、以下の表に要約する。有効性を試験するために、p27−GFPクローンを使用した。
Claims (14)
- p27の分解を抑制することによる作用機作を発揮する大腸癌の治療用の薬剤を製造するための、アルギリンA〜F及びH並びにその薬学的に許容可能な塩から選択される少なくとも1つの化合物の使用。
- p27の分解を抑制することによる作用機作を発揮する乳癌の治療用の薬剤を製造するための、アルギリンA及びその薬学的に許容可能な塩から選択される少なくとも1つの化合物の使用。
- 対象が哺乳類である、請求項1又は2に記載の使用。
- 薬剤が、薬学的に活性のある付加的な抗腫瘍成分をさらに含む、又は薬学的に活性のある付加的な抗腫瘍成分との併用である、請求項1〜3のいずれか一項に記載の使用。
- 化合物が、0.01mg/kg〜200mg/kgの用量で投与される、請求項1〜4のいずれか一項に記載の使用。
- 式1の化合物との対比において、p27の分解を抑制する能力について抗癌化合物をスクリーニングする方法であって、
p27の分解を抑制すると推測される化合物と細胞を接触させること、
該細胞の含有物を分析して、p27の量及び/又は生物活性、及び/又は細胞周期の状態を求める、分析すること、並びに
求めたp27の量及び/又は生物活性、又は細胞周期の状態を、該化合物なしで得られたp27の量及び/又は生物活性、又は細胞周期の状態と比較することを含み、
前記p27の量及び/又は生物活性、又は細胞周期の状態の変化が、p27の分解を抑制する化合物の指標となる、方法;
式1
(式中、R1及びR2は独立して、水素、非置換か若しくはOHで置換されたC1〜C4アルキル、又はC1〜C4アルコキシであり、
R3は水素、非置換か若しくはOHで置換されたC1〜C8アルキル、又はORであり、
ここで、Rは水素、C1〜C4アルキル、アリール、又はアセチルから選択され、
R4は水素、ハロゲン、非置換か若しくはOHで置換されたC1〜C4アルキル、又はC1〜C4アルコキシであり
R5は水素又はハロゲンであり、
R6は水素又はC1〜C4アルキルであり、
XはC=CH2又はCHR7であり、ここで、R7は非置換か若しくは−S−C1〜C4アルキルで置換されたC1〜C4アルキルである)の化合物、及びその薬学的に許容可能な塩。 - 細胞が、乳癌細胞株、肝細胞癌細胞株、頸癌細胞株、肺癌細胞株、及び/又は大腸癌細胞株から選ばれる腫瘍細胞又は細胞株である、請求項6に記載の方法。
- p27 mRNAの量、又はp27−GFPの融合タンパク質の量を求める、請求項6又は7に記載の方法。
- 化合物がp27のプロテアソーム分解に影響を与える、請求項6〜8のいずれか一項に記載の方法。
- アルギリンA〜F及びH並びにその薬学的に許容可能な塩から選択される少なくとも1つの化合物を含み、p27の分解を抑制することによる作用機作を発揮する大腸癌治療剤。
- アルギリンA及びその薬学的に許容可能な塩から選択される少なくとも1つの化合物を含み、p27の分解を抑制することによる作用機作を発揮する乳癌治療剤。
- 対象が哺乳類である、請求項10又は11に記載の癌治療剤。
- 癌治療剤が、薬学的に活性のある付加的な抗腫瘍成分との配合又は併用である、請求項10〜12のいずれか一項に記載の癌治療剤。
- 患者がヒトである、請求項10〜12のいずれか一項に記載の癌治療剤。
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EP2120929A1 (en) | 2009-11-25 |
BRPI0808035B8 (pt) | 2021-05-25 |
AU2008220967B2 (en) | 2013-03-21 |
ES2396115T3 (es) | 2013-02-19 |
BRPI0808035B1 (pt) | 2020-11-17 |
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