JP2004051641A - ヘデラゲニン3−O−α−L−ラムノピラノシル(1→2)−[β−D−グルコピラノシル(1→4)]−α−L−アラビノピラノシド、及びそれを含有する白頭翁抽出物の固形腫瘍治療剤としての用途 - Google Patents
ヘデラゲニン3−O−α−L−ラムノピラノシル(1→2)−[β−D−グルコピラノシル(1→4)]−α−L−アラビノピラノシド、及びそれを含有する白頭翁抽出物の固形腫瘍治療剤としての用途 Download PDFInfo
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- JP2004051641A JP2004051641A JP2003277209A JP2003277209A JP2004051641A JP 2004051641 A JP2004051641 A JP 2004051641A JP 2003277209 A JP2003277209 A JP 2003277209A JP 2003277209 A JP2003277209 A JP 2003277209A JP 2004051641 A JP2004051641 A JP 2004051641A
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- Prior art keywords
- hederagenin
- glucopyranosyl
- arabinopyranoside
- fraction
- therapeutic agent
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Abstract
【解決手段】本発明は、ヘデラゲニン3−O−α−L−ラムノピラノシル(1→2)−[β−D−グルコピラノシル(1→4)]−α−L−アラビノピラノシド、又はこれを含有する白頭翁抽出物を含む固形腫瘍治療剤に関する。
【選択図】なし
Description
従って、本発明の目的は有効成分として、白頭翁から分離された抗腫瘍物質又はそれを含有する白頭翁分画を含む、固形腫瘍治療剤を提供することにある。
白頭翁粉末を50%エタノール水溶液で抽出し、減圧下で乾燥した。得られた乾燥物に5〜10倍量のアセトンを加えて振った後、混合物を3000rpmで遠心分離し、上澄液を除去して沈澱物を得た。この沈澱物に対して上記操作を2回繰り返した。最終的に得られた沈澱物は水によく溶解されるので、“分画WT”として標示した。この分画は、LLC細胞を移植したBDF1マウス及びNCI−H23を移植したヌードマウスに対して、比較的高い抗腫瘍活性を示した。
分画WTから一定量を採って、様々な濃度のメタノール水溶液の一定量に溶解させた後、同じ溶媒で安定化させたセファデックス LH20カラムに加えて分画を行った。この時、80%メタノール水溶液を使用したとき、分離効果が最も良く、分画WT 500mgを採った場合、カラムの充填サイズは60×4cmが好適であった。その結果、分画SPX1(試験管番号 26−66)、SPX2(試験管番号 66−91)、SPX3(試験管番号 91−111)及びSPX4(試験管番号 111−138)をそれぞれ得た。その中、SPX3は硫酸噴霧後、加熱した時、最初は赤色を示したが、時間の経過と共に青色を示し、主構成成分としてRf値が0.48〜0.50の化合物を含み、LLC細胞を移植したBDF1マウス及びNCI−H23を移植したヌードマウスに対して高い抗腫瘍性活性を有していることが判った。
抗腫瘍活性を示したSPX3分画から抗腫瘍物質を単離するために、HPLC処理を行って純粋な物質SB365を得た。SB365の構造を確認するために、リーベルマン・バーチャード(Lieberman-Burchard)反応、IR、1H−NMR、13C−NMR及びエタノール/硫酸加水分解を実施した結果、SB365は白頭翁で既に分離された、サポニン成分であるヘデラゲニン3−O−α−L−ラムノピラノシル(1→2)−[β−D−グルコピラノシル(1→4)]−α−L−アラビノピラノシドであることが明らかになった。
白頭翁粉末50gを50%エタノール水溶液500mLで3回抽出し、減圧下で乾燥して乾燥物22gを得た。この乾燥物にアセトン300mLを加えて振盪した後、3000rpmで遠心分離し、上澄液を除去して沈澱物を得た。この沈澱物に対してアセトン処理を2回繰返した後、アセトン層は捨て、不溶分を乾燥して乾燥物(WT分画)17.8gを得た。得られたWT分画に対してシリカゲルTLCを実施し(展開溶媒;ブタノール:酢酸:水=4:1:1、呈色反応;硫酸を噴霧した後、加熱する)、その結果を図1に示した。図1で、Rf値が0.48〜0.50の間にある青色スポットが後述する本発明の有効成分に該当する。WT分画は下記実験例1に示す通りに、LLC細胞を移植したBDF1マウスに対して比較的高い抗腫瘍活性(腫瘍成長抑制率(inhibition rate of tumor growth):57%)を示した。
分画WT560mgをメタノール:水=80:20を使用してセファデックス LH20カラム(200g,60×4cm)で、流出速度を1分当り1mL、分画量を1分当たり0.5mL/チューブにして分画を行った。これらの分画を順次シリカゲル薄層上にスポットした後、展開して分画を分けた(展開溶媒;ブタノール:酢酸:水=4:1:1、呈色反応;硫酸を噴霧した後、加熱する)。その結果を図2に示した。図2で、SPX1(139mg,24.8%)は試験管番号26〜66を集めたものであり、主なスポットは4個で、下部のスポットは硫酸に対して黄色反応を示した。SPX2(344mg,61.4%)は試験管番号66〜91を集めたものであり、2個の主たるスポットで構成される分画である。SPX3(61mg,10.9%)は試験管91〜111を集めたものであり、硫酸噴霧後、加熱した時、最初は赤色を示したが時間が経過と共に青色を示した。SPX3分画は、Rf値が0.48〜0.50の間にあるスポットを主物質とする分画である。SPX4(15.7mg,2.8%)は試験管111〜138を集めた分画であり、SPX3とSPX4は薄層上では1個のスポットを示す比較的純度が高い分画である。
SPX3分画から純粋物質を分離するために、下記のようにHPLCを行なった。
固定相としてはシリカゲル(RP−C18,250×10mm,Metachem社)を、移動相としてはメタノール:水=80:20を使用し、検出波長は210nm、流速は1mL/分であった。その結果を図3に示した。図3に示す通りに、SPX3は3個の主物質で構成されている。実際の分画量からすると、Rt8.5分、10.4分のピークは少量の物質を含有しており、Rt=23.3分のピークに該当する物質が主物質であった。したがって、後者が抗腫瘍活性を有している可能性が大きいと考えられた。このように活性成分である可能性が高く、硫酸に対して青色反応するRt23.3分の分画を採取し、SPX3 31mgからSB365 2.8mgを得た。採取したRt=23.3分の分画を乾燥した後、純度を確認するために同じ条件下で再びHPLCを行った。その結果を図4に示した。これによりSB365が純粋な物質であることが確認された。このようにして得たSB365を下記構造同定及び抗腫瘍実験に直接用いた。
上記で分離した物質SB365は、m.p.239〜241℃、[α]D=+23.6゜(c,0.2,MeOH)の白色無定形であり、リーベルマン・バーチャード反応(陽性)により配糖体として確認された。また、IR(cm−1)では3400(br,−OH),2940(br,C−H),1695(C=O),1455,1040(C−O)で観察され、1000−1100,3000−3400の範囲での吸収ピークを示すことから、配糖体である可能性が大きいと推測された。
この実験に使用したマウスの種はBDF1マウスで、雄性の体重18〜25gに属する健康なマウスであった。この動物を23〜24℃に温度調節された所で水と餌を制限無く供給し、飼料は抗生剤無添加マウス用を使用して飼育した。C57BL/6マウスの皮下に14日間培養されたLLC細胞を含有した組職を採取した後、組織1g当たり5mLの滅菌された冷生理食塩水を加えて細胞懸濁液を調製した。この細胞懸濁液 0.2mLをBDF1マウスの鼠径部に皮下移植した。
腫瘍体積(mm3)=長さ(mm)×幅2(mm2)/2
腫瘍成長抑制率(%)=(C−T)×100/C
(C;対照群の平均腫瘍体積、T;投薬群の平均腫瘍体積)
その結果を表2に示した。
実験動物としては、5週齢の体重16〜25g、米国Harlan社の雌性ヌードマウスを使用した。実験動物は1週間以上無菌動物室で適応させた後、実験に使用した。動物室の温度は22±2℃、湿度は55±5%、明暗は12時間周期で自動調節した。実験動物用の固体飼料は放射線滅菌製品であり、飲水は高圧蒸気滅菌器で滅菌した。飼料と飲水は自由に摂取させた。細胞株は米国国立腫瘍研究所(NCI)から供給を受け、韓国生命工学研究所で保存中のヒト腫瘍細胞株を使用した。
実験に使用した腫瘍細胞であるA549、SK−MEL−2及びMCF7は韓国生命工学研究所から分譲を受けて使用した。培養液は滅菌注射用蒸留水にL−グルタミンが含まれたRPMI 1640培地1パック、50℃水槽で30分間加熱して不活性化させた牛胎児血清(FBS)100mL、NaHCO3 2g、ペニシリン 10万ユニット、ストレプトマイシン 100mgを加えて溶解させた後、0.1N塩酸でpHを調節して全体を1Lとなるようにし、細菌濾過して製造し、4℃で保管しながら使用した。細胞は3日に一回ずつ増殖させて維持し、細胞を付着面から分離するためにリン酸緩衝食塩水(PBS)に0.5%トリプシンと2%EDTAを溶解した溶液を使用した。
実施例1で得たWT分画250mgを生理食塩水10mLに溶解させて注射用溶液を製造した。
実施例2で得たSPX3分画25mgをリンガー液10mLに溶解させた後、凍結乾燥して直時使用型の注射用乾燥粉末を製造した。この粉末は注射時、注射用蒸留水で再調剤して使用する。
実施例3で得たSB365 6.5mgをリンガー液10mLに溶解し、注射用溶液を製造した。
Claims (8)
- 有効成分として、ヘデラゲニン3−O−α−L−ラムノピラノシル(1→2)−[β−D−グルコピラノシル(1→4)]−α−L−アラビノピラノシドを含有する白頭翁(Pulsatillae radix)の抽出物を含む固形腫瘍治療剤。
- 白頭翁の抽出物が、白頭翁をエタノール水溶液で抽出した後、アセトンを加え、沈澱させて得た水溶性分画である請求項1に記載の治療剤。
- 白頭翁の抽出物を1日当り200〜300mg/kg体重の用量で投与する請求項2に記載の治療剤。
- 白頭翁の抽出物が、白頭翁をエタノール水溶液で抽出した後、アセトンを加え、沈澱させて水溶性分画を得て、これをセファデックス LH20カラムを通過させて得たRfが0.48〜0.50であり、硫酸噴霧後、加熱したとき、赤色を示した後、青色を示す分画である請求項1に記載の治療剤。
- 白頭翁の抽出物を1日当り20〜40mg/kg体重の用量で投与する請求項4に記載の治療剤。
- 有効成分として、ヘデラゲニン3−O−α−L−ラムノピラノシル(1→2)−[β−D−グルコピラノシル(1→4)]−α−L−アラビノピラノシドを含む固形腫瘍治療剤。
- ヘデラゲニン3−O−α−L−ラムノピラノシル(1→2)−[β−D−グルコピラノシル(1→4)]−α−L−アラビノピラノシドを1日当り3.5〜8.0mg/kg体重の用量で投与する請求項6に記載の治療剤。
- 生理食塩水、リンガー液及び栄養剤からなる群より選択される溶液に溶解させて投与する請求項1〜7の何れかに記載の治療剤。
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WO2000025802A1 (en) * | 1998-11-03 | 2000-05-11 | Kim Song Bae | Pharmaceutical composition having antitumor activity and process for the preparation thereof |
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KR940000234B1 (ko) * | 1989-09-04 | 1994-01-12 | 김송배 | 신규 항암작용을 가지는 약학적 제제 및 제조방법 |
US5098870A (en) * | 1990-07-12 | 1992-03-24 | Lanxide Technology Company, Lp | Process for preparing self-supporting bodies having controlled porosity and graded properties and products produced thereby |
US5595756A (en) * | 1993-12-22 | 1997-01-21 | Inex Pharmaceuticals Corporation | Liposomal compositions for enhanced retention of bioactive agents |
KR0128494B1 (ko) * | 1994-07-26 | 1998-04-04 | 최무섭 | 색전이 없는 생약 추출물-함유 줄무늬 치약 조성물 |
KR100205045B1 (ko) * | 1996-12-05 | 1999-06-15 | 김송배 | 신규한 트리테르펜 글리코사이드 화합물, 그의 제조방법 및 그를 함유하는 항암제 조성물 |
ATE340191T1 (de) * | 1997-07-02 | 2006-10-15 | Univ Washington | Methoden zur isolation von proteinaseinhibitor proteinen von kartoffeln knollen |
KR19990016761A (ko) * | 1997-08-19 | 1999-03-15 | 김송배 | 신규한 트리테르펜 글리코사이드 화합물, 그의 제조방법 및 그를 함유하는 항암제 조성물 |
KR100315200B1 (ko) | 1998-11-10 | 2002-03-21 | 김송배 | 데옥시포도필로톡신을유효성분으로함유하는고형암치료제조성물 |
KR100340941B1 (ko) * | 1999-05-14 | 2002-06-20 | 김일웅 | 항 종양 효과가 있는 화합물 및 그것을 함유하는 항종양제 |
US7371418B2 (en) * | 2001-07-06 | 2008-05-13 | Sheabar Fayad Z | Method for controlling the yield and purity of proteinase inhibitor II during extraction |
US6686456B2 (en) * | 2001-07-06 | 2004-02-03 | Kemin Foods, L.C. | Method for the elimination of Kunitz and Bowman-Birk trypsin inhibitors and carboxypeptidase inhibitor from potato proteins |
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Patent Citations (1)
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WO2000025802A1 (en) * | 1998-11-03 | 2000-05-11 | Kim Song Bae | Pharmaceutical composition having antitumor activity and process for the preparation thereof |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2008508263A (ja) * | 2004-07-30 | 2008-03-21 | キム、ソンベ | 白頭翁根の抗腫瘍効果を向上させる方法及びその方法により調合した組成物 |
JP2006169181A (ja) * | 2004-12-17 | 2006-06-29 | Taisho Pharmaceut Co Ltd | 脂肪吸収抑制剤 |
JP2012246311A (ja) * | 2012-09-05 | 2012-12-13 | Sk Chemicals Co Ltd | 脳機能改善効果を有するオキナグサ抽出物 |
Also Published As
Publication number | Publication date |
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AU2003208120B2 (en) | 2008-09-11 |
JP4642330B2 (ja) | 2011-03-02 |
US8075923B2 (en) | 2011-12-13 |
RU2003122817A (ru) | 2005-01-27 |
CA2435524A1 (en) | 2004-01-22 |
KR100568607B1 (ko) | 2006-04-07 |
US20050239718A1 (en) | 2005-10-27 |
CN1308000C (zh) | 2007-04-04 |
US20100152124A1 (en) | 2010-06-17 |
TW200410704A (en) | 2004-07-01 |
BR0302590A (pt) | 2004-08-24 |
CN1494910A (zh) | 2004-05-12 |
ES2292883T3 (es) | 2008-03-16 |
DK1388542T3 (da) | 2008-01-02 |
EP1388542A1 (en) | 2004-02-11 |
DE60316389D1 (de) | 2007-10-31 |
KR20040009172A (ko) | 2004-01-31 |
US7682638B2 (en) | 2010-03-23 |
MXPA03006473A (es) | 2004-02-04 |
ATE373670T1 (de) | 2007-10-15 |
AU2003208120A1 (en) | 2004-02-05 |
RU2325178C2 (ru) | 2008-05-27 |
DE60316389T2 (de) | 2008-06-26 |
US20040082528A1 (en) | 2004-04-29 |
EP1388542B1 (en) | 2007-09-19 |
CA2435524C (en) | 2009-11-03 |
TWI280881B (en) | 2007-05-11 |
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