JP4685447B2 - 肥満症、糖尿病、高脂血症、ガン及び炎症治療用過フッ素化脂肪酸 - Google Patents
肥満症、糖尿病、高脂血症、ガン及び炎症治療用過フッ素化脂肪酸 Download PDFInfo
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Description
ペルフルオロヘプタン酸、ペルフルオロヘキサン酸、ペルフルオロオクタン酸、ペルフルオロスベリン酸、ペルフルオロペンタン酸、ペルフルオロブタン酸、ペルフルオロプロパン酸、ペルフルオロヘプタン酸メチル、ペルフルオロヘキサン酸メチル、ペルフルオロオクタン酸メチル、ペルフルオロペンタン酸メチル、ペルフルオロブタン酸メチル、ペルフルオロプロピオン酸メチル、及び、ペルフルオロスベリン酸ジメチル。
AF306566ヒトフォスフォリパーゼA2 (分泌形);Valentin et al. (2000) Biochem. Biophys. Res. Commun. 279(1), 223-228.
NM021628ヒトリポゲナーゼALOXE3
XM005818ヒトリポキシゲナーゼALOXE5
XM008328ヒトリポケゲナーゼALOX12
NM001141ヒトリポケゲナーゼALOX15;Brash et al. (1997)PNAS 94(12), 6148-6152
NM005090およびNM003706ヒトフォスフォリパーゼA2(cPLA2-ガンマ)、Underwood et al. (1998) J. Biol. Chem. 273(34), 21926-21932およびPickard et al. (1999) J. Biol. Chem. 274(13), 8823-8831.
M68874ヒトフォスフォリパーゼA2(cPLA2)、Sharp et al. (1991) J. Biol. Chem. 266(23), 14850-14853.
下記を実現するために様々な実験を行った。すなわち、
1.糖尿病および肥満症の治療における、特定の過フッ化化合物の治療効能を確定すること、
2.培養腫瘍細胞における、特定の過フッ化化合物の潜在的抗ガン活性を確定すること、
3.特定の過フッ化化合物と、ペルオキシソーム増殖剤応答性受容体(peroxisome proliferators activated receptors)との相互作用を確定すること、である。
特定の過フッ化化合物の生物学的作用を、各種インビトロ(in vitro)およびインビボ(in vivo)実験を用いて評価した。試験した化合物は、塩(ペルフルオロオクタン酸アンモニウム)、8個の炭素原子を含む酸(ペルフルオロオクタン酸およびペルフルオロスベリン酸(ジカルボン酸))、7、5および3個の炭素原子から成る鎖長を持つ酸(それぞれ、ペルフルオロヘプタン酸、ペルフルオロペンタン酸およびペルフルオロプロピオン酸)、エステル(ペルフルオロオクタン酸メチル)およびアルカン(ペルフルオロオクタン)を含んでいた。ペルフルオロオクタン酸アンモニウムは3Mから入手した。その他の過フッ化化合物は全てSigmaから購入した。
2.1 成長抑制実験
過フッ化化合物の、腫瘍細胞成長抑制に及ぼす作用を、3種のヒト腫瘍細胞系統を用いてインビトロにて評価した。ガン細胞系統を、スルフォローダミンB(SRB)試験法(細胞タンパクを測定し、細胞数に直接関わる)にて試験した。この試験は、国立ガン研究所/国立保健研究所(NIC/NIH)によって抗ガン剤スクリーニングに利用されているものである。
HT-29細胞(ヒト大腸ガン由来)、MCF7細胞(ヒト乳ガン由来)およびPC3細胞(ヒト前立腺ガン由来)を採取し、5%FBS、2mMグルタミンおよび50μg/mlのゲンタマイシンを含むRPMI 1640培養液にて希釈した(それぞれ、ml当たり5x104個細胞、1x105個細胞、および、7.5x104個細胞)。ウェル当たり100μlの細胞懸濁液を、96ウェルプレートに加え、一晩放置して定着させた。試験化合物のDMSO溶液を、100μlの培養液に溶解して最終薬剤濃度が0, 0.3, 1, 3, 10, 30, 100, 300, 1000および3000μM(およびDMSOには0.25%)としたものに、細胞を暴露した(各薬剤濃度につきn=6)。48時間後、細胞を4oCで1-2時間10%三塩化酢酸(TCA)中にて固定し、水にて洗浄し、次に空気乾燥させた。1%酢酸に溶解させた100μl SRB溶液(0.4%)を各ウェルに加え、プレートを室温にて10分インキュベートした。未結合の染料を、1%酢酸で洗浄することによって除去した。プレートを空気乾燥し、結合染料を、10mMトリス塩基に溶解し、吸収を520nmにて読み取った。細胞成長の50%抑制(IC50)が達成された濃度を、Graphpad Prismソフトウェアにて計算し、表にまとめた。
いくつかの化合物は、IC50値が3000μMに近いか、または、それを越えていて、成長抑制にたいしてほとんど作用を持たないことが判明した。それは、エステル誘導体(MPOA)、ジカルボキシル形(PFSA)および、鎖長が5以下の酸(PFPenAおよびPFPA)であった。他の化合物(APFO、PFOAおよびPFHA)は全てそのIC50値が200-600μMの範囲の中に入っていた。
本実験は、化合物のアンモニウム塩および酸形が、類似の濃度範囲において、一連のヒト腫瘍の成長を抑制するのに効果的であることを示した。化合物内部の炭素原子数も細胞成長に作用を及ぼしていた。すなわち、炭素原子数5以下は、細胞タンパクレベルにたいしてほとんど何の結果ももたらさなかった。ジカルボン酸およびメチルエステルも、その化合物に暴露されたガン細胞系統にたいして無毒であった。
化合物とPPARイソフォームとの相互作用を調べるために、ヒトPPARガンマおよびデルタ、および、ラットアルファcDNAを含むトランス活性化試験(transactivation assays)、および、ヒトPPARガンマによるリガンド結合試験(ligand binding assays)を実行した。
COS-1細胞(アフリカミドリザル腎臓細胞)(10%加熱不活性化ウシ胎児血清、2mM L-グルタミン、ペニシリン(50IU/ml)、および、ストレプトマイシン(50μg/ml)を添加した、ダルベッコの修正イーグルス培養液(DMEM)にて培養したもの)を、ウェル当たり1.5x105個細胞の濃度で12ウェル組織培養皿にプレートし、37oCで一晩放置して定着させた。翌日、培養液を吸引除去し、細胞をPBS, pH7.4で洗浄し、100μlの一過性トランスフェクションカクテル(transient transfection cocktail)を各ウェルに加えた。このトランスフェクションカクテルは、PPARアルファ、デルタまたはガンマを担持するベクターDNA 25 ng、肝臓脂肪酸結合タンパクのPPAR反応要素およびホタルルシフェラーゼを含むプラスミドDNA 250 ng、および、トランスフクションの対照として、β-ガラクトシダーゼを含むベクター250 ngから構成された。陰性の対照として、細胞をリポーターベクターのみでトランスフェクト(transfect)させた。すなわち、細胞を、プラスミドDNAを全く含まないトランスフェクションカクテルに暴露させた。DNAを、50μg.mlのDEAE-デキストランを含むPBSに溶解した。細胞を37oCで30分インキュベートし、次に80μMクロロキンをを含む1 mlの培養液を加え、細胞を37oCでさらに2.5時間インキュベートした。培養液を吸引除去し、細胞を、培養液に溶解した10%DMSO 0.5 mlにて室温で2.5分ショックを与えた。細胞はPBSで洗浄し、次に、37oCで48時間成長培養液中にて回復させた。
PPARアルファは、ベヒクルのみに暴露させた細胞から得られた値と比較すると、APFOによって11.25倍も活性化された。PFO、PFHAおよびPFPenAは、PPARアルファを約5倍活性化した。MPOAおよびPFPAは、当該受容体を約2倍活性化した。PFSAによるPPARアルファの活性化は見られなかったが、この化合物は、PPARガンマについては実に約4倍も活性化した。PPARガンマ活性化は、〜2−6倍の範囲で起こっているが、APFOおよびPFPenAではその範囲の上限値が得られた。この過フッ化化合物では、いずれにおいてもPPARデルタの活性化は見られなかった。しかしながら、PPARデルタ活性化の抑制が見られ、PFOAでは(4倍)、PFHAおよびPFPenAでは(2.2倍)、それより程度は低いが、PFPAおよびPFSAでは(1.6倍)の抑制が見られた(表3)。
上記結果は、これらの化合物は、PPARアルファおよびPPARガンマ受容体の両方を活性化するが、あるもの(PFSA)は、この受容体の単一イソフォームと特異的な相互作用を持つようである。PPARデルタ活性化の抑制は、過フッ化化合物はPPAR拮抗剤の可能性があることを示唆する。このことは、ガン治療に関連して重要である(なぜならPPARデルタの発現レベルは、大腸直腸ガン細胞(He, TC, Vogelstein, B. and Kinzler, KW. Cell 99:335-345(1991))および動脈硬化症(なぜなら、PPARは、マクロファージにおける脂質蓄積を誘発するから(Vosper, H. et al. J. Biol. Chem. 276:44258-44265(2001))において増加することが示されているからである)。
GSTタグ付きヒトPPARアルファおよびガンマのリガンド結合ドメイン(ligand binding domains)を大腸菌に発現させた。簡単に言うと、PPARアルファのアミノ酸179-468、および、PPARガンマのアミノ酸174-478を含むリガンド結合ドメインをPCRにて(必要な制限酵素部位を含むオリゴヌクレオチドを用いて)生成し、ベクターpCR-Blunt11-TOPO(Invitrogen社、ペイスリー、英国)にクローンした。ドメインをNco/Xho 1を用いて切り出し、ベクターpGEX6PB(Amersharm Biosciences、バックス、英国)にクローンした。このベクターは細菌GSTタグを含み、標準法により大腸菌を形質変換した。確証クローンを、アンピシリン選択の下で37oCで一晩培養した。一晩培養体を用いて、1:100で新鮮培養液に接種し、細胞が中央対数期にある時点で、タンパク発現を、0.5 mM β-D-イソプロピルチオガラクトピラノシド(IPGT)30oC3時間にて誘発した。誘発培養体から得られた可溶性タンパクを採取し、グルタチオンアガロース(Sigma、プール、英国)にたいするアフィニティークロマトグラフィー(affinity chromatography)により精製し、50 mM トリス‐HCl, pH8.0/5 mMグルタチオン(還元形)を用いて溶出した。
アンモニウム塩(APFO)は、PPARアルファにたいして、PFOAと同様のアフィニティーで結合した。すなわち、見かけのKd値は、それぞれ、8μMと6μMであった。ジカルボン酸(PFSA)および5炭素化合物(PFPenA)も、それぞれ、44μMおよび62μMと近似の結合アフィニティー(binding affinity)を持っていた。これは、PFOAに比べて、イソフォームに対する結合アフィニティーにおいて7および10倍の低下に相当する。7炭素化合物は、PPARアルファにたいして215μmのKd(PFOAに比べてリガンド結合において30倍の低下)という最低の結合アフィニティーを示したが、一方、PFPA(炭素数3)は、2μMのKdという、PFOAに比べて増大したアフィニティーを示した(表4)。
これらの結果は、過フッ化化合物は、インビトロにおいて、ヒトPPARアルファおよびガンマリガンド結合性ドメインに結合することを示唆する。
3.1 雄CRスプレイグドーリー(CR SD)ラットにおける代謝パラメータに及ぼす過フッ化化合物の作用
これまでの実験で、APFOは、糖尿病および肥満症の健康および疾病両モデルにおいて抗糖尿病および抗肥満症効能を有することが示された。他の過フッ化化合物も同じ治療効能を有するかどうかを証明するために、選択された過フッ化化合物を、SDラットに7日間投与し、物理的および生化学的パラメータを監視した。
2群(n=5)のCR SDラット(約300 g)を、2用量レベルの過フッ化化合物(15および25 mg/kg/日 体重)で処置した。動物に、コーン油に溶解させた試験物質を、経口胃管により、毎日7日間に渡って投与した。1群の20匹のCR SDラットについてもベヒクル(vehicle)(コーン油)のみにて処置した。体重と食物消費を連日監視した。
APFO、MPOAおよびPFPAにて15および25mg/kg/日で処置したラットは、3日目以降体重を減少し、これは、投与期間の終了まで続いた(図1)。25 mg/kgのMPOAおよびPFOAを投与された動物は早期に実験停止したが、6日目以降、それぞれ、体重の8%および11.7%を失っていた。上記3種の化合物を15 mg/kgとして投与された動物における体重減少はそれほど著明ではなかった。すなわち、APFOでは1%(高用量では11%)、MPOAおよびPFOAでは、それぞれ、8.2%および9.4%であった。その他の化合物で処置された動物では体重減少は観察されず、動物は、試験期間中に体重の12-18%が増加した(図2)。
要約すると、過フッ化化合物投与に関連すると考えられる、重大な生理作用がいくつかあった。この実験の結果から、過フッ化化合物の構造を変化させるといくつかの有利な作用が得られることが示された。
本実験の目的は下記の通りである。すなわち、
%直鎖性の異なる過フッ化化合物の治療効能を確定すること、
薬剤前駆物質としての過フッ化エステルの適性を確定すること、である。
2通りのインビボ実験によって4種の過フッ化化合物を評価した。試験した化合物は、100%および75%直鎖形のアンモニウム塩、ペルフルオロオクタン酸アンモニウム、および、2種のエステル(ペルフルオロオクタン酸メチルおよびペルフルオロオクタン酸エチル)である。
PFOA(ペルフルオロオクタン酸)の血漿レベルを測定するための経口暴露実験−実験計画および方法
実験は、8匹の雄CDスプレイグドーリー・ラット(8-10週齢、Harlan英国から入手)から成る1対照群、および、4匹のラットを含む4試験群から成っていた。実験期間を通じて、動物は自由にRM1粉末食を摂取した。ラットには、25 mg/kgで、XEN1001(75%直鎖APFO)、XEN1002(100%直鎖APFO)、MPFOおよびEPFOを連日11日間経口投与した。薬品は全てマゾーラコーン油に溶解し(2.5 mg/mlで)、試験化合物は、10 ml/kg体重で投与した。対照動物はマゾーラコーン油のみを摂取した。動物は全て11日後に屠殺した。動物を、濃度上昇させたCO2に暴露して屠殺し、血液をリチウム/ヘパリン管に採取して血漿を得た。
遊離酸PFOAの循環濃度を、試験化合物の最終投与後24時間時点で測定した。MS分析から、ラット血漿は、アンモニウム塩(XEN1001またはXEN1002)、または、メチルエステル(MPOA)またはエチルエステル(EPOA)投与のラットにおいて、等モル濃度のPFOAを含んでいることが示された(図1)。このことは、メチルおよびエチルエステルは、SDラットに経口胃管投与した場合、完全に代謝されて遊離酸(活性化合物)となることを示唆した。
以前の7日間実験において、XEN1001を投与されたラットは、実験期間中連続的な体重減少を示した。本実験は、さらに長期の試験期間における、異なる%直鎖性を有する化合物の体重に及ぼす作用を調べた。
XEN1001またはXEN1002を投与されたラットは、実験期間を通じて着実に体重を増やした対照ラットと比べると、それぞれ、7日目および10日目まで体重を減少させた。この初期の減少後は、試験グループは、対照グループと平行して体重を増やしたが、対照グループの体重と等しくなることはなかった。食物中にXEN1002を混ぜて投与された動物における体重減少は、XEN1001に暴露された動物に見られる体重減少よりも著明であった。これは、化合物の100%直鎖形の方が、インビボでは活性が高いことを示す(図2)。
エステルの胃管投与後に見られるPFOAの血漿濃度は、アンモニウム塩投与ラットに見られるものとそっくり同じであった。これは、本化合物のメチルおよびエチルエステルは、薬剤前駆物質として利用可能であることを示唆する。
Claims (3)
- 抗腫瘍治療に用いられる薬剤であって、
ペルフルオロヘプタン酸の有効量を含む。 - 請求項1に記載された薬剤であって、
ヒトの罹患者に投与するために用いる、
薬剤。 - 請求項1または2に記載された化合物の使用方法であって、
抗腫瘍剤の必要がある罹患者の治療用薬剤を製造する、
使用方法。
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US20090163481A1 (en) * | 2007-12-13 | 2009-06-25 | Murphy Brian J | Ppar-delta ligands and methods of their use |
KR20120099360A (ko) * | 2009-06-09 | 2012-09-10 | 마르디 메디신즈 리미티드 | 할로겐화 지방족 카르복실산류, 이의 올리고머 및/또는 폴리머, 및 외부 및 내부 신생물을 무력화시키는 용도 |
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