JP5340393B2 - 腎細胞癌の治療のための3,3’,4,4’−テトラヒドロキシ−2,2’−ビピリジン−n,n’−ジオキシド - Google Patents
腎細胞癌の治療のための3,3’,4,4’−テトラヒドロキシ−2,2’−ビピリジン−n,n’−ジオキシド Download PDFInfo
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- JP5340393B2 JP5340393B2 JP2011529583A JP2011529583A JP5340393B2 JP 5340393 B2 JP5340393 B2 JP 5340393B2 JP 2011529583 A JP2011529583 A JP 2011529583A JP 2011529583 A JP2011529583 A JP 2011529583A JP 5340393 B2 JP5340393 B2 JP 5340393B2
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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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2121/00—Preparations for use in therapy
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Urology & Nephrology (AREA)
- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
原発腫瘍(T):
TX:原発腫瘍の評価が不可能
T0:原発腫瘍を認めない
T1:7cm以下の、腎臓に限局する腫瘍
T2:7cmを超える、腎臓に限局する腫瘍
T3:腫瘍の主静脈/副腎/腎周囲組織中への進展;ジェロタ筋膜を越えない
T3a:腫瘍の副腎/腎周囲の脂肪への浸潤
T3b:腫瘍の(1つ若しくは複数の)腎静脈又は横隔膜下の大静脈中への進展
T3c:腫瘍の横隔膜上の大静脈中への進展
T4:腫瘍のジェロタ筋膜を越えた浸潤
N−所属リンパ節
NX:所属リンパ節の評価が不可能
N0:所属リンパ節の転移なし
N1:1個の所属リンパ節における転移
N2:複数の所属リンパ節における転移
M−遠隔転移
MX:遠隔転移の評価が不可能
M0:遠隔転移なし
M1:遠隔転移
1)血管新生阻害薬。この戦略においては、腫瘍組織に供給するのに必要な血管の形成の阻害により腫瘍に栄養及び酸素が与えられない。これは、いくつかの方法において達成することができる:1a)VEGF、PDGF、及びPIGFなどの増殖因子に対する抗体で治療することによる、循環するこれらの増殖因子の阻害、1b)標的細胞上における血管増殖因子受容体の、該受容体に対する抗体での阻止、並びに1c)血管増殖因子のその受容体への結合による生理学的な血管新生効果の誘発ができないような方法における、受容体機能を妨害する小型分子での治療。
2)免疫調節性治療。この戦略は内因性の免疫系を刺激して、腫瘍細胞をよそ者として認識させ、それらに対して戦いを開始するよう試みるものである。腎臓癌に対する治療としての免疫の刺激は、主な2つの経路をとる:2a)インターロイキン2(IL−2)での治療、及び2b)インターフェロンα(IFNα)治療法。
A.極性の方法:乾燥したコルチナリウス属キノコ2gを粉末にし、次いで25℃で24時間、50%メタノールで抽出した。混合液を遠心分離し、上清を除去して最終体積5mlとした。冷メタノール5容積を繰返し添加した際、澄明な溶液が形成するまで形成した沈殿物を捨てた。溶媒を蒸発させ、残渣を水中に溶解し、無極性の物質を石油エーテルで抽出することによって除去した。極性の相をSephadexカラム上に充填し、50%エタノールで溶出した。得られた分画を薄層セルロース上、ブタノール:酢酸:水(3:1:1)で溶出してクロマトグラフィー分離した。オレラニンを、Rf0.68に蛍光帯として同定した。
オレラニンを、本質的に他者によって記載されている通り、市販の3-ヒドロキシピリジンから合成した(Tiecco M、Tingoli M、Testaferri L、Chianelli D及びWenkert E:「キノコ、コルティナリウス−オレラヌスFriesの致死毒素、オレラニンの全合成(Total synthesis of orellanine, the lethal toxin of Cortinarius orellanus Fries Mushroom.)」Tetrahedron、42巻、1475〜1485頁(1986年))。
背景及び方法
母腫瘍及び転移性の増殖両方を代表する、5種の異なるヒト腎細胞癌(SKRC−52、786−0、SKRC−17、SKRC−7、及びSKRC−21)から収集した細胞を、標準の条件下で培養した。約70%のコンフルエンスに達し急速に増殖しているとき、細胞を24時間、オレラニン(400μM)を含む培地に曝した。次いで、培地を定型的な完全培地に戻し、さらに6日間細胞を観察した。
細胞の記載のオレラニン処置の効果を図1に示す。図より、オレラニンは試験を行った細胞型すべてに高度に毒性であったことが明らかである。さらに、最初の曝露後、オレラニンを培地から除去することによって毒性は影響を受けなかった。これは、オレラニンが細胞中に蓄積し、細胞外オレラニンが存在しない場合でもそこに残存することを示唆している。図2は、24時間のオレラニン曝露前、及び1週間後の細胞の外観を示すものである。
背景及び方法
母腫瘍及び転移性の増殖両方を代表する、2種の異なるヒト腎細胞癌(SKRC−7、786−0)から収集した細胞を、標準の条件下で培養した。約70%のコンフルエンスに達し急速に増殖しているとき、細胞を24時間、様々な濃度のオレラニン(400μM)を含む培地に曝した。次いで、培地を定型的な完全培地に戻し、さらに6日間細胞を観察した。
図3に見られるように、曝露濃度と死滅する細胞の分画の間には明らかな相関が存在する。オレラニンの24時間、1回の曝露に対する投与量反応間隔は、約5μg/mlと200μg/lの間である。
背景及び方法
ヒト腎細胞癌786−0から収集した細胞を、標準の条件下で培養した。約70%のコンフルエンスに達し急速に増殖しているとき、細胞を24時間、低濃度のオレラニン(20μg/ml)を含む培地に曝した。次いで、培地をオレラニン20μg/mlを含む新しい培地に交換して24時間置く(中央の棒グラフ)か、又は定型的な完全培地に戻して48時間置き、その後さらに24時間、オレラニン20μg/mlの存在下においた(右端の棒グラフ)。
1回の曝露反応間隔の下限の投与量でも、オレラニンに繰返し曝露すると、腎臓癌細胞に対して明らかな毒性効果がさらにもたらされた。
背景及び方法
多数のヒト組織(尿細管上皮、腎組織からの有足細胞及びメサンギウム細胞、線維芽細胞、マクロファージ、大動脈内皮、毛細血管内皮細胞、並びに臍帯内皮、腸管上皮(十二指腸、空腸、回腸、及び結腸の)並びに軟骨細胞)に由来する細胞系及び一次細胞を、標準の条件下で培養した。約70%のコンフルエンスに達し安定に増殖しているとき、細胞を、投与量反応を達成するために選択された濃度のオレラニンを含む培地に24時間曝露した。次いで、培地を、定型的な完全培地に戻し、さらに6日間細胞を観察し、その後生存率を決定した。大体積のオレラニン溶液を添加したことによって培地の希釈が引き起こす、いかなる増殖を遅らせる効果を埋め合わせるために、細胞すべてに等体積のオレラニンバッファーを補った。
試験した細胞型はどれも、実現可能な最高濃度であった1000μg/mlまでの濃度の、例4によるオレラニンに曝露した場合、生存率に対していかなる効果も示さなかった。
背景及び方法
本質的に例3に記載した通りに培養した腎臓癌細胞を、24時間、オレラニンで処理した(培地100μg/ml)。この期間中、0、2、6、及び24時間の曝露後に細胞を収集した。A)キナーゼ阻害薬p21、B)リン酸化網膜芽細胞腫タンパク質(増殖刺激因子)、及びC)細胞が分裂している場合、細胞周期のM期に細胞を進行させるcdc2タンパク質、に対する抗体で、収集した材料に対してウエスタンブロットを行った。
オレラニン曝露の、p21、網膜芽細胞腫タンパク質、及びcdc2のタンパク質発現に対する効果を図5に示す。細胞周期阻害薬p21の細胞内レベルは増大し、6時間頃に最大となるが、細胞周期刺激性の網膜芽細胞腫タンパク質のリン酸化型は、24時間の計測で完全に欠如している。同様に、細胞に細胞分裂期に入らせるcdc2タンパク質は、24時間で劇的に下方制御される。これは、オレラニンが細胞周期に対して著明な阻害効果を有し、この効果は少なくとも2つの重要なチェックポイントで行われることを明らかに示している。
背景及び方法
腎臓癌細胞を培養し、例7によるオレラニンに曝露し、最高24時間の様々な時間で収集した。p38MAPK系、p53系、Fasリガンド、腫瘍壊死因子α(TNF)、及び切断型のカスパーゼ3が、細胞死をもたらすアポトーシス経路における主要な因子である。ウエスタンブロットを用いて、A)p38、B)切断型のカスパーゼ3、及びC)増殖性因子リン酸化ERK1/2の細胞内レベルを決定した。定量PCRを用いて、D)p53経路のアポトーシス効果を実質的にすべて媒介する、p53上方制御性アポトーシス調節因子(PUMA)、E)Fasリガンド、及びF)TNF、のmRNA発現を決定した。
結果を図6〜8に概略する。24時間の観察期間にわたってリン酸化型(活性化型)p38の安定した増大があり、細胞中のアポトーシスシグナル強度を増大した(図6)。(増殖刺激物質であるリン酸化型ERK1/2が同時に上方制御されるのは、細胞がオレラニンのアポトーシス性の影響よりも「さらに増殖」しようとするためと本発明者らは解釈する。)
背景及び方法
胸腺欠損T細胞欠損ラット(RNU、Charles River Laboratories,FRG)を、ヒト腎細胞癌のin vivo増殖に対する系として用いる。これらの動物ではT細胞ベースの免疫防御が非存在であることで、これらの動物は異種移植片に対して寛容になっている。動物施設に到着して1週間後、動物10匹に、B細胞媒介性の反応も抑制するために5Gyの線量のX線を照射する。
食塩水/オレラニンの第1の注射の2週間後、皮下群における対照動物の腫瘍のサイズは約2倍になっていたが、オレラニンを注射した動物の腫瘍は、注射時に記録したサイズの25%未満に収縮していた。この時点で、オレラニン5mg/kg体重の投与量をさらに、以前にオレラニンを投与した皮下群の動物3匹の腫瘍部位中に注射し、対照動物にはオレラニン10mg/kg体重を腫瘍部位中に投与する。さらに2週間後、オレラニンを2回注射した動物において腫瘍の徴候は明らかではなく、前者の対照動物における腫瘍サイズは75%以上低減している。
Gottingenミニブタ系統5頭、及び雑種のイヌ5頭(体重10〜15kg)を、小児及び幼児用に設計された機器を用いて透析用にセットアップする。動物にオレラニン10mg/kg体重の初回量を投与する。24時間後、動物を約3時間透析のセッションに曝す。透析後、動物にオレラニン5mg/kg体重を注射する。透析/再注射の手順を8週間、週3回(月曜日、水曜日、金曜日)繰り返す。週1回、動物の全身状態の評価を行う。実験の終わりに動物をすべて屠殺し、心臓、肺、腎臓、肝臓、脾臓、小腸、大腸、脳、筋肉、及び皮膚から組織病理学評価用検体を採取する。
腎臓癌に対する治療を必要とする一患者に、一連の10回の、オレラニンの静脈内注射を毎日投与する。患者の最初の全身腫瘍組織量は約2kgと決定される。この値に基づき、好適な1日投与量を280mg(4mg/kgで体重70kg)と決定する。オレラニン処置は、癌細胞を死滅させるとともに健常な腎上皮組織を必然的に破壊し、したがって患者は腎機能のない状態になるので、第1の注射の前に患者に血液透析又は腹膜透析を準備する。各注射の2時間後、血液透析を開始し、2時間維持する。少量のオレラニンを繰返し投与することを含むこの手順には、腫瘍組織におけるオレラニンの致死レベルへの徐々の増大をもたらす利点があり、腫瘍組織はこの物質を積極的に取り込むが、毒素の細胞外濃度は副作用を起こし得るレベル未満に保たれる。任意選択により、疾患が片側性である場合、罹患していない腎臓を外科的に切除し、処置の間保存し、処置終了後再埋め込みを試みてもよい。患者の進行を1カ月間モニターし、その後、腎臓癌の増殖を阻害するために適宜オレラニンのさらなる連続投与を行う。処置の間、患者における腫瘍組織塊は低減し、処置終了時、腎臓癌は完全に根絶され、腎明細胞癌に対するオレラニンの有効性が実証される。
Claims (13)
- 式I:
[式中、
R1、R2、R3、及び/又はR4は、水素、アミノ、メルカプト、カルボキシ、リン酸、ハロ、C1〜C6アルキル、C1〜C6アルケニル、C1〜C6アルキニル、C1〜C6アルカノール、C1〜C6アルケノール、C1〜C6アルコキシ、及びC1〜C6アルケノキシからなる群から選択され;
ここで、そのC1〜C6アルキル、C1〜C6アルケニル、C1〜C6アルキニル、C1〜C6アルカノール、C1〜C6アルケノール、C1〜C6アルコキシ、及びC1〜C6アルケノキシの各々が、アミノ、メルカプト、カルボキシ、リン酸、及びハロからなる群から選択される基でさらに置換されていてよい]
による化合物;または
等モル量の薬学的に許容されるその塩
を活性成分として含む、腎細胞癌の治療のための医薬組成物。 - R1、R2、R3、及びR4が水素である、請求項1に記載の医薬組成物。
- 前記化合物を1mg/kgから100mg/kgまでの単回投与量として投与する、請求項2に記載の医薬組成物。
- 前記化合物を2回以上の投与量において投与し、各投与量が1mg/kgと20mg/kgの間の化合物を含む、請求項1に記載の医薬組成物。
- 逐次投与量を2日から7日の間、離して投与する、請求項1に記載の医薬組成物。
- 前記化合物を毎日投与する、請求項1に記載の医薬組成物。
- 少なくとも1つの薬学的に許容される担体、及び50mgから3500mgの式I:
[式中、
R1、R2、R3、及び/又はR4は、水素、アミノ、メルカプト、カルボキシ、リン酸、ハロ、C1〜C6アルキル、C1〜C6アルケニル、C1〜C6アルキニル、C1〜C6アルカノール、C1〜C6アルケノール、C1〜C6アルコキシ、及びC1〜C6アルケノキシからなる群から選択され;
ここで、そのC1〜C6アルキル、C1〜C6アルケニル、C1〜C6アルキニル、C1〜C6アルカノール、C1〜C6アルケノール、C1〜C6アルコキシ、及びC1〜C6アルケノキシの各々が、アミノ、メルカプト、カルボキシ、リン酸、及びハロからなる群から選択される基でさらに置換されていてよい]
による化合物、又は等モル量の薬学的に許容されるその塩を含む、腎細胞癌の治療のための医薬組成物。 - R1、R2、R3、及びR4が水素である、請求項7に記載の医薬組成物。
- 化合物が薬学的に許容される塩である、請求項7又は8に記載の医薬組成物。
- 患者に静脈内投与、皮下投与、又は腹腔内投与するために組成物が調合される、請求項7から9までのいずれか一項に記載の医薬組成物。
- 少なくとも1つの薬学的に許容される担体、及び50mgから3500mgの式I:
[式中、
R1、R2、R3、及び/又はR4は、水素、アミノ、メルカプト、カルボキシ、リン酸、ハロ、C1〜C6アルキル、C1〜C6アルケニル、C1〜C6アルキニル、C1〜C6アルカノール、C1〜C6アルケノール、C1〜C6アルコキシ、及びC1〜C6アルケノキシからなる群から選択され;
ここで、そのC1〜C6アルキル、C1〜C6アルケニル、C1〜C6アルキニル、C1〜C6アルカノール、C1〜C6アルケノール、C1〜C6アルコキシ、及びC1〜C6アルケノキシの各々が、アミノ、メルカプト、カルボキシ、リン酸、及びハロからなる群から選択される基でさらに置換されていてよい]
による化合物、又は等モル量の薬学的に許容されるその塩を含む、
腎細胞癌に罹患しているか又は腎細胞癌に感受性である患者を治療するためのキット。 - 式Iによる化合物、又は薬学的に許容されるその塩が担体中に完全に、又は実質的に溶解するようなやり方で、投与に関連して、式Iによる化合物、又は薬学的に許容されるその塩、及び薬学的に許容される担体を併用する、請求項11に記載のキット。
- 患者に静脈内投与、皮下投与、又は腹腔内投与するために化合物が調合される、請求項11または12に記載のキット。
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PCT/EP2009/062976 WO2010040750A1 (en) | 2008-10-06 | 2009-10-06 | 3, 3', 4, 4' -tetrahydroxy-2, 2' -bipyridine-n, n' -dioxides for the treatment of renal cell carcinoma |
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