JP4892473B2 - モノアセチルジアシルグリセロール誘導体を有効成分として含有する免疫調節剤、抗癌剤及び健康食品 - Google Patents
モノアセチルジアシルグリセロール誘導体を有効成分として含有する免疫調節剤、抗癌剤及び健康食品 Download PDFInfo
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
ここで、R1/R2は、9−オクタデセノイル(オレオイル)/ヘキサデカノイル(パルミトイル)、ヘキサデカノイル(パルミトイル)/9−オクタデセノイル(オレオイル)、ヘキサデカノイル(パルミトイル)/9,12−オクタデカジエノイル(リノレオイル)、ヘキサデカノイル(パルミトイル)/9,12,15−オクタデカトリエノイル(リノレノイル)又はヘキサデカノイル(パルミトイル)/5,8,11,14−エイコサテトラエノイル(アラキドノイル)である。
また、本発明は、前記化学式1のモノアセチルジアシルグリセロール誘導体を有効成分として含有するAIDS治療剤、敗血症治療剤及び抗癌剤を提供する。また、本発明は、前記化学式1のモノアセチルジアシルグリセロール誘導体を有効成分として含有する免疫調節用又は抗癌用の健康食品を提供する。
SI=実験群のウェルから吸収された3H−チミジン(サンプルのCPM)/対照群のウェルから吸収された3H−チミジン(対照群のCPM)
(実施例1−2)モノアセチルジアシルグリセロール誘導体が単核球の増殖に及ぼす影響
エリスポット生物定量法(ESAT−6enzyme−linked immunospot assay)は、この定量法で使用されるエリスポットプレートの各ウェルの底面がサイトカイン特異的な抗体で予めコートされているため、メンブレンに結合したサイトカインを検出するのに非常に敏感な定量法である。従って、エリスポット定量法によりT細胞の活性を測定した。T細胞を24ウェル滅菌組織培養プレート(Nunc、Denmark)に各ウエル当たり2×106細胞を接種した後、化合物3の0.01、0.1、1μg/ml濃度、或いは、IL−2の20ng/ml濃度で処理した。7日目に細胞を回収して、1次抗体(マウスIL−2)でコートされたマルチテストプレート(Elispot system kit、AID、Straberg、Germany)に5×105細胞を接種した。上記プレートを24時間5%CO2培養器で培養した後、細胞によるサイトカインの分泌があった。これは、製造会社の指針に従って市販のIL−2エリスポットキットを用いるエリスポットにより決定される1次抗体によりキャップチャされた。各サンプルに対して2回実験した。エリスポット読取機(AID Elispot Reader System)を用いてエリスポットによりIL−2を産生する細胞の数を算出した。その結果、化合物3処理群は、対照群に比べて1.52倍増加したT−4活性と、1.46倍増加したT−8活性とを示した(図1)。
バイオ−プレックスは、1つのウェルで多量のサイトカインを一度に測定できる。よって、バイオ−プレックスキットは、T細胞の活性化の際、分泌されるTh1/Th2経路の8種のサイトカインを定量するのに用いられた。24−ウェル滅菌組織培養プレート(Nunc、Denmark)を抗CD3および抗CD28で処理した。プレートに2×106/mlのT細胞が接種された。T細胞を活性化するために、0.1、1μg/ml化合物3で処理した後、5日間培養した。5日目、各段階にある培養液を回収して遠心分離した。上清液を回収し、その内部に分泌されたサイトカインをバイオ−プレックスキットを用いて製造会社(Bio−rad)の指針に従って定量化した。その結果、化合物3で処理した群において、8種のサイトカイン(IL−2、IL−4、IL−5、IL−10、IL−12、INF−γ、GM−CSF、TNF−α)のうちの3種(IL−2、IL−4、IL−5)が分泌され、その量は化合物3を処理しない対照群に比べて多かった(図2)。
化合物3がAIDS患者の免疫細胞に及ぼす影響を確認するために、次のような実験を遂行した。まず、AIDS患者の末梢血液からヒストパク(Histopaque)1077によって単核球細胞を回収した。塩化アンモニウムを用いて赤血球 細胞を除去した後、ナイロンウールを通過させながら細胞残屑と凝集塊とを除去した。T細胞をマグネチックビーズ(抗ヒトCD3)(MACS bead、Miltenyi Biotec)を用いて精製した。T細胞懸濁液は、10%牛胎児血清(Fetal Bovine serum;以下、“FBS”と称する。)(Gibco、Grand Island、NY)が補充されたIMDM(Isocove's modified dulbecco's medium)(Gibco、Grand Island、NY)で懸濁された。96ウェルプレートで、0.01、0.1、1μg/ml濃度の化合物3または20ng/ml濃度のIL−2とで処理して、ウェル別に5×104生育可能な細胞を培養した。培養6日目に3H−チミジンを各細胞培養ウェル当たり1μCiで処理して24時間培養した。培養7日目に細胞を回収して3H−チミジンの取り込みを計算した。SI(刺激指数)は前述した式1により計算された。その結果、表3に示すように、AIDS患者の場合、T細胞の増殖アッセイで、化合物3処理群における全ての患者(4名中の4名)のチミジンの摂取によるT細胞刺激指数が、対照群に比べて1.5〜3.9倍増加したことが表された。化合物3による刺激の全般的な結果は、IL−2による刺激と比較可能である。
骨髄細胞は、Balb/c AnNマウスの大腿骨及び脛骨から公知の方法により回収した(Park,J.etal.(2003)J.Korean Med. Sci.,18:372−380)。細胞をRPMIで3回洗浄した後、単核球を回収した。これらの単核球細胞をRPMI及び10%FBS内で3時間組織培養フラスコに付着されるようにした。培養後、付着細胞(単核球細胞)を除去した後、マウスrGM−CSF(R&D systems, Minneapolis, MN, USA)20ng/ml、およびマウスIL−4(R&D systems)10ng/ml及びマウスTNF−α(R&D systems)2.5ng/mlが補充された、10%FBS追加のRPMI中、未付着細胞を1×105細胞/mlにて100mm織培養皿に配置した。培養皿は3日毎に交換した。マウスTNF−α(R&D systems)を6日目に添加した後、11日になるまで3日毎に添加した。成熟樹状突起細胞は接着分子研究のRT−PCR用として採取された。その結果、円形の顆粒細胞を3日間培養したとき、これらの細胞は細胞培養プレートのウェルの底面に付着して成長するクラスターを形成し、成熟樹状突起細胞は培養6日又は7日目に群を形成しながら成長した。培養9日目に樹状突起細胞が特異的に小さく長い突起(protrusion)を形成した(図3)。
トリパンブルー染色に対して陰性であり、サイズが大きい細胞を計数して、これらのそれぞれの形態を調べた。1×106細胞/mlの細胞を培養した後、洗浄し、1%パラホルムアルデヒド溶液で固定した。固定された細胞はFACScan(Beckton Dickinson、Mountain View、CA、U.S.A)を用いてフローサイトメトリー解析(Flow cytometric analysis)を行うことで、下記のマーカーに対する抗体によって表現型を決定した。ハムスターIgGに対する同型(isotype)対照群、ラットIgG2a、DCマーカー:DEC−205(NLDC−145)及びCD11C、共同−刺激/接着(Co−stimutatory/adhesion)分子:CD80(B7−1)及びCD86(B7−2)、マクロファージマーカー:CD14及びF4/80、顆粒球(Granulocyte)マーカー:Gr−1(Pharmingen、Hamburg、Germany)。その結果、共同−刺激特異的分子マーカーであるCD80及びCD86、樹状突起細胞特異的マーカーであるCD11C及びDEC−205の水準は高かったが、単核球特異的マーカーであるCD14及びF4/80と、顆粒球特異的マーカーであるGr−1との水準は低かった。このような結果は、本発明で分離された樹状突起細胞が、樹状突起細胞の正確な表現型と97%〜98%の純度とを持つことを意味する(図4)。
一般的に、細胞間の相互作用が、多様な造血細胞及び免疫細胞の刺激の過程に関与することが知られている。よって、本発明者らは、化合物3が言及された細胞の多様な接着分子に影響を及ぼすかを確認しようと努力した。特に、前述した実施例で培養した樹状突起細胞を化合物3で1μg/ml濃度で処理し、RT−PCRを遂行した。
6週齢の雌のシリアンゴールデンハムスター(Harlan、Indianapolis、India、USA)を特定病原菌不在飼育場で飼育した。無血清RPMI 1640培地100μlに懸濁されたKIBG−5細胞(Molcular therapy、Vol.3、No4、pp431−437)5×105を、大腿部血管に静脈注射(intravenously inject、I.V)した。また、無血清RPMI 1640培地100μlに懸濁されたKIGB−5の5×105細胞は、ハムスターの横腹に皮下注射(subcutaneously inject、S.C)された。KIBG−5注入されたハムスターは、下記の7つの群に分けた;
1)RPMI培地処理された対照群、
2)変形されないBMSC細胞(2.5×106)(Leukemia & Lymphoma,Vol.44,No11,pp1973−1978)で処理された実験群、
3)Ad/ΔE150MOI改変BMSC細胞処理された実験群(Leukemia & Lymphoma,Vol.44,No11,pp1973−1978)、
4)DC+腫瘍溶菌液(5×106)処理された実験群、
5)Ad/hIL−2 50 MOI改変BMSC細胞処理された実験群(Leukemia & Lymphoma,Vol.44,No11,pp1973−1978)、
6)Ad/hIL−2 50 MOI改変BMSC細胞処理された実験群+化合物3(25mg/kg/日)処理された実験群、及び
7)化合物3(25mg/kg/日)処理された実験群。
6週齢の雌C57BL/6マウス(韓国ソウルの牙山生命科学研究所で提供)を無菌飼育場で飼育した。無血清RPMI 1640培地100μlに懸濁されたB16F10細胞(2×104)を尻尾静脈に注射した。腫瘍細胞注入1週間前、下記の3群に処理された。
1)RPMI対照群
2)樹状突起細胞(DC)(5×105細胞/日)+腫瘍溶菌液処理群
3)化合物3(50mg/kg/日)処理群
合成した化合物3を、20g当り0.1ml容量で経口投与されるエタノール5%溶液に溶かした。対照群はエタノール5%溶液で処理された。SPF設備内で飼育されたICRマウスを検査動物として使用した。薬物投与1日前、その動物を捕獲した後、水や飼料は自由に摂取させた。体重25〜35gのICRマウス8〜10匹を一つの群とした。投与量を62.5mg/kg、125mg/kg、250mg/kg、500mg/kg、1g/kg、2g/kgに増加させながら、試験薬は1回経口投与された。生存数及び異常の有無を投与日から14日間肉眼で観察した。LD50はLichfield-Wilcoxon法に`より計算し(白須、泰彦、吐山、豊秋:新毒性試験法−方法及び評価−急性毒性試験、Realize Inc.、Tokyo、1988)、体重増加率は次の数式2によって算出した。
体重増加率(%)={14日目の体重−0日目の体重}÷{0日目の体重}×100
長時間の肝毒性検査は、化合物3の投与量を100mg/kg体重/日としてマウスに4週間経口投与して実施し、肝機能検査、血中脂質検査及びシトクロームC−450活性度検査が観察された。4週末に肝組織が観察された。どのような重大な副作用も観察されなかった。
CLPテストは、上記化合物3の敗血性ショックに対する予防及び治療効果を確認するために行われた。10匹の7〜10週齢の同種交配雄C3H/HeNマウス(体重20〜25g)を一つの群として形成した。これらのマウスに2週間50mg/kg/日の容量で処置し、1週間休みの形式で化合物3を経口投与した後、ケタミン(ketamine)80mg/kg及びロムパン(rompun)16mg/kgを使用してマウスを麻酔した。麻酔されたマウスにCLPモデルによる敗血性ショックを誘導させた。敗血性ショックを誘導していから1時間後、化合物3の50mg/kgで処理し、以後、24時間毎に同様な処理が3日間継続された。対照群にPBS+5%エタノール溶液が経口投与された。化合物3処理群及び対照群の時間経過に従う生存率を表6に示す。化合物3処理群は120時間経過後にも100%の生存率を見せた。
化合物3 30%
ビタミンC 4.5%
ビタミンD3 0.001%
硫酸マンガン 0.1%
ワックス(Wax) 10%
パーム油 25%
紅花油(Carthamus tinctorius) 30.399%
化合物3 31.25%
月見草オイル 59.75%
大豆油 6.7%
ビタミンE酢酸エステル(DL-α- 酢酸トコフェロール)2.1%
大豆レシチン 0.2%
化合物3 98.0%
ビタミンE酢酸エステル(DL-α- 酢酸トコフェロール)2.0%
化合物3 30%
ビタミンC 10%
ビタミンD3 0.001%
硫酸マンガン 0.1%
結晶セルロース 25.0%
乳糖 32.999%
ステアリン酸マグネシウム 2%
化合物3 2%
プロピレングリコール 35%
モノグリセリド 8%
エタノール 5%
水 50%
前述した組成及び含量に基づき、通常の方法を用いて注射用製剤を製造した。
前記実験例により化合物3が優れた免疫調節効果、抗敗血性ショック及び抗癌活性を持つことを確認した後、本発明者らは化合物3を有効成分として含有する健康食品を製造した。
蜂蜜 522mg
チオクト酸アミド 5mg
ニコチン酸アミド 10mg
塩酸リボフラビンナトリウム 3mg
塩酸ピリドキシン 2mg
イノシトール 30mg
オルト酸 50mg
化合物3 0.48〜1.28mg
水 200ml
前述した組成及び含量に基づき、通常の方法を用いて飲料を製造した。
ガムベース 20%
砂糖 76.36〜76.76%
化合物3 0.24〜0.64%
フルーツ香料 1%
水 2%
チューインガムは、前記組成及び含量に基づき、下記の通常の方法を用いて製造した。
砂糖 50〜60%
水飴 39.26〜49.66%
化合物3 0.24〜0.64%
オレンジ香料 0.1%
キャンディは、前記組成及び含量に基づき、下記の通常の方法を用いて製造した。
強力粉1級 88kg
薄力粉1級 76.4kg
精白糖 16.5kg
食塩 2.5kg
グルコース 2.7kg
パームショートニング 40.5kg
アンモ 5.3kg
重曹 0.6kg
重硫酸ナトリウム 0.55kg
コメ粉 5.0kg
ビタミンB1 0.003kg
ビタミンB2 0.003kg
ミルク香料 0.16kg
水 71.1kg
全脂粉乳 4kg
代用粉乳 1kg
第1リン酸カルシウム 0.1kg
散布塩 1kg
噴霧乳 25kg
化合物3 0.2〜0.5kg
ビスケットは、前記組成及び含量に基づき、下記の通常の方法を用いて製造した。
乳脂肪 10.0%
無脂乳固形分 10.8%
砂糖 12.0%
水飴 3.0%
乳化安定剤(スパン) 0.5%
香料(ストロベリ) 0.15%
水 63.31〜62.91%
化合物3 0.24〜0.64%
アイスクリームは、前記組成及び含量に基づき、下記の通常の方法を用いて製造した。
砂糖 34.36〜34.76%
ココアバター 34%
ココアマット 15%
ココアパウダー 15%
レシチン 0.5%
バニラ香料 0.5%
化合物3 0.24〜0.64%
チョコレートは、前記組成及び含量に基づき、下記の通常の方法を用いて製造した。
Claims (3)
- 下記化学式で表されるモノアセチルジアシルグリセロールを有効成分として含有する、敗血症治療薬:
- 経口用である、請求項1記載の敗血症治療薬。
- 1日経口投与量が、1日1回〜3回で、1回50mg/kgである、請求項2記載の敗血症治療薬。
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2004
- 2004-09-04 KR KR1020040070650A patent/KR20050118057A/ko active Search and Examination
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- 2005-04-22 US US11/587,377 patent/US7662853B2/en active Active
- 2005-04-22 JP JP2007509400A patent/JP4892473B2/ja active Active
- 2005-04-22 CN CN2005800129149A patent/CN1946392B/zh active Active
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JPH05194244A (ja) * | 1991-07-24 | 1993-08-03 | Efamol Ltd | 必須脂肪酸を含有する薬剤 |
JPH0827010A (ja) * | 1994-07-19 | 1996-01-30 | Nichinichi Seiyaku Kk | 制癌免疫療法剤 |
WO1999026640A1 (en) * | 1997-11-20 | 1999-06-03 | Bukwang Pharm. Ind. Co., Ltd. | Pharmaceutical composition containing extracts of cervus nippon antlers having growth-stimulating activities of hematopoietic stem cells and megakaryocytes |
Also Published As
Publication number | Publication date |
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US7662853B2 (en) | 2010-02-16 |
US20080200543A1 (en) | 2008-08-21 |
CN1946392A (zh) | 2007-04-11 |
KR20050118057A (ko) | 2005-12-15 |
RU2006141418A (ru) | 2008-05-27 |
US20100137435A1 (en) | 2010-06-03 |
CN1946392B (zh) | 2010-12-29 |
JP2007534681A (ja) | 2007-11-29 |
RU2341257C2 (ru) | 2008-12-20 |
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