JP2001288079A - Specific carcinostatic agent and composition obtained by formulating the same - Google Patents
Specific carcinostatic agent and composition obtained by formulating the sameInfo
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- JP2001288079A JP2001288079A JP2000136449A JP2000136449A JP2001288079A JP 2001288079 A JP2001288079 A JP 2001288079A JP 2000136449 A JP2000136449 A JP 2000136449A JP 2000136449 A JP2000136449 A JP 2000136449A JP 2001288079 A JP2001288079 A JP 2001288079A
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Abstract
Description
【０００１】[0001]
【発明の属する技術分野】本発明は、特定の共役不飽和
脂肪酸類を有効成分としてなる殺癌細胞剤及びこれを配
合してなる組成物に係るものである。より詳しくは、炭
素−炭素間二重結合（以下、単に二重結合という）を３
〜６個有する共役多価不飽和脂肪酸類であって、二重結
合の全部もしくは一部が共役関係にある前記共役多価不
飽和脂肪酸類を有効成分としてなる、ヒト由来の正常細
胞には悪影響を与えず癌細胞のみを効率的に死滅させ得
る特異的殺癌細胞剤、及び、これを配合してなる医薬用
組成物又は食用組成物に関するものである。TECHNICAL FIELD The present invention relates to a cancer killing agent comprising a specific conjugated unsaturated fatty acid as an active ingredient and a composition comprising the same. More specifically, the carbon-carbon double bond (hereinafter simply referred to as double bond) is 3
Conjugated polyunsaturated fatty acids having up to 6 conjugated polyunsaturated fatty acids having all or part of double bonds in a conjugated relationship as an active ingredient, which have an adverse effect on human-derived normal cells The present invention relates to a specific cancer killing cell agent capable of efficiently killing only cancer cells without giving the same, and a pharmaceutical or edible composition containing the same.
【０００２】[0002]
【従来の技術】近年、脂質の生理活性、薬理作用に関す
る研究が急速に進展し、とりわけ炭素数１８以上の不飽
和脂肪酸と各種疾病との関係が解明されつつある。ま
た、高齢化社会の本格的な到来を背景に、生活習慣や食
事パターンと疾病との関連性が注目され、各種疾病の治
療はもとより疾病予防の観点からも生活様式の見直しや
各種食材に含まれる成分の機能評価が行われている。2. Description of the Related Art In recent years, studies on the physiological activity and pharmacological action of lipids have been rapidly progressing, and in particular, the relationship between unsaturated fatty acids having 18 or more carbon atoms and various diseases has been elucidated. Also, with the full-scale arrival of an aging society, attention has been paid to the relationship between lifestyle and dietary patterns and diseases.Reviewing lifestyles and including them in various food ingredients from the viewpoint of treatment of various diseases as well as disease prevention. Functional evaluation of the components to be performed has been performed.
【０００３】前記不飽和脂肪酸のうち二重結合を３個以
上もつ多価不飽和脂肪酸としては、シソ、エゴマ、アマ
等の種子油を構成する脂肪酸であるα−リノレン酸（Ｃ
１８：３ ｎ−３系、以下α−ＬＮＡという。）、母乳
や月見草の油脂の構成脂肪酸であるγ−リノレン酸（Ｃ
１８：３ ｎ−６系、以下γ−ＬＮＡという。）、動物
臓器組織の油脂を構成するアラキドン酸（Ｃ２０：４
ｎ−６系、以下ＡＡという。）、カツオやマグロ等の魚
油や鶏卵黄油の構成脂肪酸であるエイコサペンタエン酸
（Ｃ２０：５ ｎ−３系、以下ＥＰＡという。）、ドコ
サヘキサエン酸（Ｃ２２：６ ｎ−３系、以下ＤＨＡと
いう。）等が知られている。これらは主に食品原材料に
含れる脂質の構成成分であるが、微細藻類や微生物の組
織中にも油分の構成脂肪酸として存在する。Among the unsaturated fatty acids, polyunsaturated fatty acids having three or more double bonds include α-linolenic acid (C) which is a fatty acid constituting seed oils such as perilla, perilla and flax.
18: 3 n-3 system, hereinafter referred to as α-LNA. ), Γ-linolenic acid (C) which is a fatty acid constituting fatty acids of breast milk and evening primrose
18: 3 n-6 system, hereinafter referred to as γ-LNA. ), Arachidonic acid (C20: 4) constituting oils and fats of animal organ tissues
n-6 system, hereinafter referred to as AA. ), Eicosapentaenoic acid (C20: 5 n-3 type, hereinafter referred to as EPA) and docosahexaenoic acid (C22: 6 n-3 type, hereinafter referred to as DHA), which are constituent fatty acids of fish oil such as skipjack and tuna, and egg yolk oil. Etc. are known. These are mainly components of lipids contained in food raw materials, but are also present as constituent fatty acids of oil components in microalgae and microbial tissues.
【０００４】また、これら多価不飽和脂肪酸の生理機能
として、α−ＬＮＡの記憶学習能の向上作用（特開平１
−１５３６２９号公報）、抗アレルギー作用、血清脂質
改善作用等、ＡＡの血小板凝集作用等、ＥＰＡのコレス
テロール低減効果、血小板粘着能の低下や赤血球変形能
の増加（田村 泰ら、「食の科学」、第１６１巻、第３
３−３９頁、１９９１年）等、ＤＨＡの血中脂質低下
（今泉勝巳、「臨床栄養」、第８３巻、第４号、第４４
０頁、１９９３年等）、血小板凝集能抑制（氷川祐三
ら、「血液と脈管」、第１５巻、第２号、第１３８−１
４１頁、１９８４年）、記憶・学習能の改善（Ａ．ｈｕ
ｃａｓ ｅｔ ａｌ．，Ｔｈｅ Ｌａｎｃｅｔ，３３
９，２６１，１９９２など）、抗痴呆（Ｍ．Ｓｏｄｅｒ
ｂｅｒｇ ｅｔａｌ．，Ｌｉｐｉｄｓ，２６（６），４
２１，１９９１）、抗腫瘍（成沢富雄ら、「医学のあゆ
み」、第１４５巻、第９１１頁、１９８８年）、抗アレ
ルギー（Ｍ．Ｓｈｉｋａｎｏ ｅｔ ａｌ．，Ｊ．Ｉｍ
ｍｕｎｏｌｏｇｙ，１５０，３５２５，１９９３）等の
作用が見出され、治療薬や食品への利用をはじめ様々な
用途への応用が提案されている。Further, as a physiological function of these polyunsaturated fatty acids, an action of improving the memory and learning ability of α-LNA (Japanese Patent Laid-Open No.
No. 153629), antiallergic action, serum lipid improving action, etc., AA platelet aggregation action, cholesterol lowering effect of EPA, decrease in platelet adhesion and increase in erythrocyte deformability (Yasu Tamura et al., “Food Science” , Volume 161 and 3
3-39, 1991), etc., blood lipid lowering of DHA (Katsumi Imaizumi, "Clinical Nutrition", Vol. 83, No. 4, 44).
0, 1993, etc.), suppression of platelet aggregation (Yuzo Hikawa et al., "Blood and Vessel", Vol. 15, No. 2, 138-1
41, 1984), improvement of memory and learning ability (A. hu)
cas et al. , The Lancet, 33
9 , 261, 1992), anti-dementia (M. Soder)
berg et al. , Lipids, 26 (6), 4
21, 1991), antitumor (Tomio Narisawa et al., "Ayumi of Medicine", Vol. 145, pp. 911, 1988), antiallergic (M. Shikano et al., J. Im.
Munology, 150 , 3525, 1993), and applications to various uses, including use in therapeutic drugs and foods, have been proposed.
【０００５】ところで、多価不飽和脂肪酸の一種として
共役多価不飽和脂肪酸がある。一般に、共役不飽和脂肪
酸はそれに対応する非共役不飽和脂肪酸に比べて化学的
反応性に富み、酸化されやすく、即乾性の被膜を形成す
るため、この特性を利用したものにキリ油あるいはキリ
油分解脂肪酸であるエレオステアリン酸（シス−９，ト
ランス−１１，トランス−１３−オクタデカトリエン
酸）の塗料、ペンキ分野への応用が従来から行われてき
た。また、バターやチーズ等の乳製品や牛肉にはリノー
ル酸の共役異性体である共役リノール酸（シス−９，ト
ランス−１１−オクタデカジエン酸を主体とする二重結
合の位置異性体および幾何異性体の混合物）が微量では
あるが存在することが知られており、最近ではリノール
酸を共役化処理した共役リノール酸が食品素材として上
市され、体脂肪の低減作用（Ｌｉｐｉｄｓ，３１，８５
３（１９９７））、血中コレステロール低減作用、抗腫
瘍活性（Ｍ．Ａ．Ｂｅｌｕｒｙ，Ｎｕｔｒ．Ｒｅｓ．，
５３，８３（１９９５））等の生理機能も見出されてい
る。[0005] Incidentally, there is a conjugated polyunsaturated fatty acid as a kind of polyunsaturated fatty acid. Generally, conjugated unsaturated fatty acids are more chemically reactive than the corresponding non-conjugated unsaturated fatty acids, are easily oxidized, and form a quick-drying film. The application of eleostearic acid (cis-9, trans-11, trans-13-octadecatrienoic acid), which is a decomposed fatty acid, to coatings and paints has been conventionally performed. In addition, dairy products such as butter and cheese, and beef are conjugated linoleic acids, which are conjugated isomers of linoleic acid (positional isomers of double bonds mainly composed of cis-9, trans-11-octadecadienoic acid and geometrical isomers). It is known that linoleic acid (a mixture of isomers) is present, albeit in a trace amount. Recently, conjugated linoleic acid obtained by conjugating linoleic acid has been marketed as a food material, and a body fat reducing action (Lipids, 31 , 85)
3 (1997)), blood cholesterol lowering effect, antitumor activity (MA Belury, Nutr. Res.,
53, 83 (1995)).
【０００６】[0006]
【発明が解決しようとする課題】前述のように、脂質を
構成する多価不飽和脂肪酸の生理作用を解明し、これを
各種疾病の、治療や予防に応用する試みが行われている
が、共役不飽和脂肪酸の生理機能に関する研究はごく最
近になって詳細に検討されはじめた段階であり、とりわ
け二重結合を３個以上有する共役多価不飽和脂肪酸類に
ついての知見はほとんど見あたらない。かかる現状に鑑
み、本発明では、前記共役多価不飽和脂肪酸類の生理機
能とりわけ癌細胞及び正常細胞に対する影響を解明し、
癌細胞に対して特異的かつ効果的に増殖抑制作用ないし
は殺細胞作用を有し、ひいては癌疾患の予防あるいは治
療に応用し得る素材、及びこれを配合してなる医薬用組
成物あるいは食用組成物を提供することを解決すべき課
題とした。As described above, attempts have been made to elucidate the physiological actions of polyunsaturated fatty acids constituting lipids and apply them to the treatment and prevention of various diseases. Research on the physiological function of conjugated unsaturated fatty acids has only recently begun to be studied in detail, and little is known about conjugated polyunsaturated fatty acids having three or more double bonds. In view of this situation, the present invention elucidated the physiological functions of the conjugated polyunsaturated fatty acids, particularly the effects on cancer cells and normal cells,
A material that has a specific and effective growth-inhibiting or cell-killing effect on cancer cells and can be applied to the prevention or treatment of cancer diseases, and a pharmaceutical or edible composition containing the same. The task to be solved was to be solved.
【０００７】[0007]
【課題を解決するための手段】本発明者らは、前記課題
を解決するために、種々の形態の共役多価不飽和脂肪酸
類について鋭意検討した結果、二重結合を３〜６個有す
る共役多価不飽和脂肪酸類が顕著な殺癌細胞効果を奏
し、かつ正常細胞に対しては悪影響を及ぼさないことを
見出し、本発明を完成するに至った。以下において、共
役多価不飽和脂肪酸類とは、共役多価不飽和脂肪酸の単
一物もしくは混合組成物や共役多価不飽和脂肪酸を構成
脂肪酸とする各種誘導体を包含する意味で用いる。Means for Solving the Problems In order to solve the above-mentioned problems, the present inventors have conducted intensive studies on various forms of conjugated polyunsaturated fatty acids, and as a result, have found that conjugates having 3 to 6 double bonds are available. The present inventors have found that polyunsaturated fatty acids have a remarkable cancer-killing cell effect and do not adversely affect normal cells, thereby completing the present invention. In the following, conjugated polyunsaturated fatty acids are used to mean a single or mixed composition of conjugated polyunsaturated fatty acids and various derivatives having conjugated polyunsaturated fatty acids as constituent fatty acids.
【０００８】すなわち、本発明において解決すべき課題
である特異的殺癌細胞剤は、二重結合を３〜６個有する
共役多価不飽和脂肪酸類を有効成分としてなる殺癌細胞
剤によって達成される。ここで、共役多価不飽和脂肪酸
類の構成脂肪酸は共役トリエン脂肪酸に富むものである
ことがより好ましく、さらには、α−ＬＮＡ、ＥＰＡ、
ドコサペンタエン酸（Ｃ２２：５ ｎ−３系、以下ＤＰ
Ａという）及びＤＨＡからなる群から選ばれる１種又は
２種以上の非共役多価不飽和脂肪酸を共役化処理して得
られるものが望ましい。また、共役多価不飽和脂肪酸類
のより望ましい態様は、二重結合を３〜６個有する共役
多価不飽和脂肪酸を構成脂肪酸とするカルボン酸、エス
テル及び塩からなる群から選択される１種又は２種以上
のものである。ここで、エステルとしては低級１価アル
コールのエステルであることが望ましく、さらにはアシ
ルグリセリド及び／又はグリセロリン脂質であることが
望ましい。[0008] That is, the specific cancer killer which is a problem to be solved in the present invention is achieved by a cancer killer comprising a conjugated polyunsaturated fatty acid having 3 to 6 double bonds as an active ingredient. You. Here, the constituent fatty acids of the conjugated polyunsaturated fatty acids are more preferably rich in conjugated triene fatty acids, and furthermore, α-LNA, EPA,
Docosapentaenoic acid (C22: 5 n-3 type, hereinafter DP
A) and one obtained by conjugating one or more non-conjugated polyunsaturated fatty acids selected from the group consisting of DHA. Further, a more preferable embodiment of the conjugated polyunsaturated fatty acid is one selected from the group consisting of carboxylic acids, esters and salts having a conjugated polyunsaturated fatty acid having 3 to 6 double bonds as a constituent fatty acid. Or two or more types. Here, the ester is preferably an ester of a lower monohydric alcohol, and more preferably an acyl glyceride and / or a glycerophospholipid.
【０００９】なお、本発明において用いる前記共役多価
不飽和脂肪酸類は、これに対応する非共役多価不飽和脂
肪酸類を共役化処理して調製することができるが、該共
役化処理は二重結合を３〜６個有する非共役多価不飽和
脂肪酸類１重量部に対して１０〜３０重量％のアルカリ
金属水酸化物を含むジオール溶液５０〜１００重量部を
加え、１７０〜１９０℃にて５〜３０分間、共役化反応
させることを特徴とする共役トリエン脂肪酸に富む共役
多価不飽和脂肪酸類の製造方法によるものであることが
望ましい。なお、本発明の特異的殺癌細胞剤が対象とす
る癌細胞は、ヒト由来のものであって、大腸癌細胞、肝
臓癌細胞、肺癌細胞、乳癌細胞又は胃癌細胞であるこ
と、また、正常細胞はヒト由来の肺線維芽細胞、皮膚線
維芽細胞又は胚線維芽細胞であることがより好ましい。[0009] The conjugated polyunsaturated fatty acids used in the present invention can be prepared by conjugating the corresponding non-conjugated polyunsaturated fatty acids. 50 to 100 parts by weight of a diol solution containing 10 to 30% by weight of an alkali metal hydroxide is added to 1 part by weight of a non-conjugated polyunsaturated fatty acid having 3 to 6 heavy bonds, and the mixture is heated to 170 to 190 ° C. It is preferable to use a method for producing conjugated polyunsaturated fatty acids rich in conjugated triene fatty acids, characterized in that the conjugate reaction is carried out for 5 to 30 minutes. The cancer cells targeted by the specific cancer killing cell agent of the present invention are human-derived, and are colon cancer cells, liver cancer cells, lung cancer cells, breast cancer cells or gastric cancer cells, and More preferably, the cells are human-derived lung fibroblasts, skin fibroblasts or embryonic fibroblasts.
【００１０】また、本発明の医薬用組成物及び食用組成
物は、前記特異的殺癌細胞剤を配合した組成物となすこ
とによって達成される。[0010] The pharmaceutical composition and the edible composition of the present invention can be attained by forming a composition containing the specific cancer killing agent.
【００１１】[0011]
【発明の実施の形態】本発明の特異的殺癌細胞剤及びこ
れを配合してなる医薬用組成物又は食用組成物について
以下にさらに詳述する。本発明によれば、まず、二重結
合を３〜６個有する共役多価不飽和脂肪酸類を有効成分
としてなる特異的殺癌細胞剤が提供される。本発明でい
う共役多価不飽和脂肪酸類における共役多価不飽和脂肪
酸とは、該脂肪酸１分子中に二重結合を３〜６個有する
多価不飽和脂肪酸であって、二重結合の一部又は全部が
共役の位置関係にある異性体を包含する。また、個々の
二重結合の幾何異性体はシス型又はトランス型のいずれ
であってもよい。BEST MODE FOR CARRYING OUT THE INVENTION The specific cancer killing cell agent of the present invention and a pharmaceutical or edible composition containing the same will be described in more detail below. According to the present invention, first, there is provided a specific cancer killing cell agent comprising a conjugated polyunsaturated fatty acid having 3 to 6 double bonds as an active ingredient. The conjugated polyunsaturated fatty acid in the conjugated polyunsaturated fatty acids referred to in the present invention is a polyunsaturated fatty acid having 3 to 6 double bonds in one molecule of the fatty acid, and one of the double bonds. Part or all includes isomers having a conjugated positional relationship. The geometric isomer of each double bond may be either cis or trans.
【００１２】本発明の共役多価不飽和脂肪酸類の構成脂
肪酸は共役ジエン脂肪酸（以下、共役ジエン体というこ
とがある。）、共役トリエン脂肪酸（以下、共役トリエ
ン体ということがある。）、共役テトラエン脂肪酸（以
下、共役テトラエン体ということがある。）、共役ペン
タエン脂肪酸（以下、共役ペンタエン体ということがあ
る。）及び共役ヘキサエン脂肪酸（以下、共役ヘキサエ
ン体ということがある。）にタイプ分けできる。共役ジ
エン脂肪酸の例としてシス−９，トランス−１１，シス
−１５−オクタデカトリエン酸、シス−５，トランス−
７，シス−１１，シス−１４−エイコサテトラエン酸、
シス−５，トランス−７，シス−１１，シス−１４，シ
ス−１７−エイコサペンタエン酸、シス−４，トランス
−６，シス−１０，シス−１３，シス−１６，シス−１
９−ドコサヘキサエン酸等をあげることができる。ま
た、共役トリエン脂肪酸としてシス−９，トランス−１
１，トランス−１３−オクタデカトリエン酸（エレオス
テアリン酸）、シス−６，トランス−８，トランス−１
０−オクタデカトリエン酸、シス−８，トランス−１
０，シス−１２−エイコサトリエン酸、シス−５，トラ
ンス−７，トランス−９，シス−１４，シス−１７−エ
イコサペンタエン酸、シス−４，シス−６，トランス−
８，シス−１３，シス−１６，シス−１９−ドコサヘキ
サエン酸等を例示できる。共役テトラエン脂肪酸として
シス−９，トランス−１１，トランス−１３，トランス
−１５−オクタデカテトラエン酸（パリナリン酸）、シ
ス−５，トランス−７，シス−９，シス−１１−エイコ
サテトラエン酸、シス−５，トランス−７，トランス−
９，シス−１１，シス−１７−エイコサペンタエン酸、
シス−４，シス−６，トランス−８，トランス−１０，
シス−１６，シス−１９−ドコサヘキサエン酸等を例示
できる。同様に、シス−５，トランス−７，トランス−
９，トランス−１１，トランス−１３−エイコサペンタ
エン酸、シス−４，トランス−６，シス−８，トランス
−１０，トランス−１２，シス−１９−ドコサヘキサエ
ン酸等の共役テトラエン酸、シス−４，トランス−６，
トランス−８、トランス−１０，トランス−１２，トラ
ンス−１４−ドコサヘキサエン酸等の共役ヘキサエン酸
も本発明の共役多価不飽和脂肪酸類の範ちゅうに含める
ことができる。The constituent fatty acids of the conjugated polyunsaturated fatty acids of the present invention are conjugated diene fatty acids (hereinafter sometimes referred to as conjugated diene derivatives), conjugated triene fatty acids (hereinafter sometimes referred to as conjugated triene derivatives), and conjugated. It can be classified into tetraene fatty acids (hereinafter sometimes referred to as conjugated tetraenes), conjugated pentaene fatty acids (hereinafter sometimes referred to as conjugated pentaenes), and conjugated hexaene fatty acids (hereinafter sometimes referred to as conjugated hexaenes). . Examples of conjugated diene fatty acids include cis-9, trans-11, cis-15-octadecatrienoic acid, cis-5, trans-
7, cis-11, cis-14-eicosatetraenoic acid,
Cis-5, trans-7, cis-11, cis-14, cis-17-eicosapentaenoic acid, cis-4, trans-6, cis-10, cis-13, cis-16, cis-1
9-docosahexaenoic acid and the like. Further, cis-9, trans-1 is used as a conjugated triene fatty acid.
1, trans-13-octadecatrienoic acid (eleostearic acid), cis-6, trans-8, trans-1
0-octadecatrienoic acid, cis-8, trans-1
0, cis-12-eicosatrienoic acid, cis-5, trans-7, trans-9, cis-14, cis-17-eicosapentaenoic acid, cis-4, cis-6, trans-
8, cis-13, cis-16, cis-19-docosahexaenoic acid, and the like. As conjugated tetraene fatty acids, cis-9, trans-11, trans-13, trans-15-octadecatetraenoic acid (parinaric acid), cis-5, trans-7, cis-9, cis-11-eicosatetraene Acid, cis-5, trans-7, trans-
9, cis-11, cis-17-eicosapentaenoic acid,
Cis-4, cis-6, trans-8, trans-10,
Examples thereof include cis-16, cis-19-docosahexaenoic acid. Similarly, cis-5, trans-7, trans-
Conjugated tetraenoic acid such as 9, trans-11, trans-13-eicosapentaenoic acid, cis-4, trans-6, cis-8, trans-10, trans-12, cis-19-docosahexaenoic acid, cis-4, Trans-6
Conjugated hexaenoic acids such as trans-8, trans-10, trans-12, trans-14-docosahexaenoic acid can also be included in the category of the conjugated polyunsaturated fatty acids of the present invention.
【００１３】本発明に係る共役多価不飽和脂肪酸類は、
前記のように共役異性体の混合物であるが、二重結合の
数が３〜６個であることが重要である。二重結合数が２
個の共役リノール酸の場合は本発明の所望の効果である
殺癌細胞作用が小さく、一方、７個以上の共役多価不飽
和脂肪酸類はそのもの及びその原料の入手が困難であ
り、実用的ではない。また、前記の共役多価不飽和脂肪
酸類の構成脂肪酸は共役トリエン脂肪酸に富むものがよ
り好ましく、このような組成の共役多価不飽和脂肪酸類
においては所望の効果がより一層顕著に発現するように
なる。共役トリエン脂肪酸に富むものとは、共役多価不
飽和脂肪酸類を構成する脂肪酸の総重量に対して共役ト
リエン脂肪酸を少なくとも５％（重量基準。以下とくに
ことわらないかぎり同様。）以上含有し、より望ましく
は１０％以上含むものである。なお、かかる共役多価不
飽和脂肪酸類はこれを構成する共役多価不飽和脂肪酸の
炭素数の多少にかかわらず、また二重結合の位置異性体
や幾何異性体の種類は任意の割合の組成であるものでも
さしつかえない。The conjugated polyunsaturated fatty acids according to the present invention include:
It is a mixture of conjugated isomers as described above, but it is important that the number of double bonds is 3 to 6. 2 double bonds
In the case of a single conjugated linoleic acid, the desired effect of the present invention, that is, the carcide-killing effect is small, while the conjugated polyunsaturated fatty acids of 7 or more are difficult to obtain themselves and the raw materials thereof, and is not. Further, the constituent fatty acids of the conjugated polyunsaturated fatty acids are more preferably rich in conjugated triene fatty acids, and in the conjugated polyunsaturated fatty acids having such a composition, the desired effect is more remarkably exhibited. become. The term "rich in conjugated triene fatty acids" means that the conjugated triene fatty acids contain at least 5% (by weight, unless otherwise specified) of the total weight of the fatty acids constituting the conjugated polyunsaturated fatty acids, and More preferably, the content is 10% or more. Such conjugated polyunsaturated fatty acids may have any composition regardless of the number of carbon atoms in the conjugated polyunsaturated fatty acids constituting the conjugated polyunsaturated fatty acids. Can be anything.
【００１４】本発明においては、共役多価不飽和脂肪酸
類の態様として、二重結合を３〜６個有する共役多価不
飽和脂肪酸の単一物もしくは混合物を構成脂肪酸とする
カルボン酸、エステル及び塩からなる群から選択される
１種又は２種以上のものを採用することができる。ここ
に、塩としてはカリウム、ナトリウム、カルシウム、マ
グネシウム等のアルカリ金属塩又はアルカリ土類金属塩
がよい。エステルは任意のものでよいが、メタノール、
エタノール、ｎ−プロパノール、イソプロパノール、ｎ
−ブタノール、イソブタノール等の炭素数が１〜５程度
のもののエステルが望ましく、さらに、モノグリセリ
ド、ジグリセリド、トリグリセリド等のアシルグリセリ
ド、モノアシル型あるいはジアシル型のホスファチジル
コリン、ホスファチジルエタノールアミン、ホスファチ
ジルイノシトール、ホスファチジルセリン等のアシルグ
リセロリン脂質がより望ましい。かかるアシルグリセリ
ドとアシルグリセロリン脂質は単独で又は２種以上の混
合物として用いることができ、これらにさらに前記のカ
ルボン酸や塩や低級１価アルコールエステルを適宜併用
してもさしつかえない。In the present invention, as the conjugated polyunsaturated fatty acids, carboxylic acids, esters and conjugated polyunsaturated fatty acids having a single or mixture of conjugated polyunsaturated fatty acids having 3 to 6 double bonds are used as constituent fatty acids. One or more selected from the group consisting of salts can be employed. Here, the salt is preferably an alkali metal salt such as potassium, sodium, calcium, magnesium or the like or an alkaline earth metal salt. The ester may be any, but may be methanol,
Ethanol, n-propanol, isopropanol, n
Esters of about 1 to 5 carbon atoms such as butanol and isobutanol are desirable, and furthermore acylglycerides such as monoglyceride, diglyceride, triglyceride, monoacyl or diacyl phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine, etc. The acyl glycerophospholipid is more desirable. Such acyl glycerides and acyl glycerophospholipids can be used alone or as a mixture of two or more, and the above carboxylic acids, salts and lower monohydric alcohol esters may be used in combination as appropriate.
【００１５】本発明の共役多価不飽和脂肪酸類を得るに
はさまざまな方法を採用でき、例えば、非共役多価不飽
和脂肪酸類を原料としてこれを共役化処理する方法、動
植物、微生物、藻類等の組織あるいはそれらの産生物か
ら分離、精製処理して採取する方法等がある。Various methods can be used to obtain the conjugated polyunsaturated fatty acids of the present invention, for example, a method of conjugating non-conjugated polyunsaturated fatty acids as a raw material, animals, plants, microorganisms and algae. Etc., or a method of separating and purifying from the tissues or their products and collecting them.
【００１６】前者の方法では、二重結合を３〜６個有す
る非共役多価不飽和脂肪酸類、より好ましくは生理機能
の点から望ましいｎ−３系脂肪酸であるα−ＬＮＡ、Ｅ
ＰＡ、ＤＰＡ及びＤＨＡからなる群から選ばれる１種又
は２種以上もしくはこれらを構成脂肪酸とする前述のエ
ステルや塩を原料とし、あるいはｎ−６系脂肪酸である
γ−ＬＮＡ、ジホモ−γ−リノレン酸（Ｃ２０：３）及
びＡＡ等からなる群から選択される単独又は混合脂肪酸
もしくはそれらのエステルや塩を原料とし、あるいは前
記ｎ−３系脂肪酸およびｎ−６系脂肪酸の混合物もしく
はこれらを構成脂肪酸とするエステルや塩を原料とす
る。In the former method, non-conjugated polyunsaturated fatty acids having 3 to 6 double bonds, more preferably α-LNA, E-3, which are n-3 fatty acids which are desirable from the viewpoint of physiological function,
One or more selected from the group consisting of PA, DPA and DHA or the above-mentioned esters or salts containing these as constituent fatty acids, or γ-LNA or dihomo-γ-linolenic n-6 fatty acids A single or mixed fatty acid selected from the group consisting of acid (C20: 3) and AA, or an ester or salt thereof, or a mixture of the above n-3 fatty acid and n-6 fatty acid or a constituent fatty acid Ester or salt as a raw material.
【００１７】ついで、これを水酸化カリウム、水酸化ナ
トリウム等のアルカリ金属水酸化物、ヨウ素、ヨウ化カ
リウム、二酸化硫黄やチオール類等の硫黄化合物等を触
媒とし、又は無触媒下で紫外線を照射しながら、窒素ガ
ス等の不活性ガス雰囲気中で、１５０〜２５０℃にて５
分〜１時間、共役化反応を行わしめ、必要に応じて触媒
除去等の精製処理を施して目的とする共役多価不飽和脂
肪酸類を製造することができる。Then, this is treated with an alkali metal hydroxide such as potassium hydroxide or sodium hydroxide, iodine, potassium iodide, a sulfur compound such as sulfur dioxide or thiols as a catalyst, or irradiated with ultraviolet rays in the absence of a catalyst. In an inert gas atmosphere such as nitrogen gas at 150 to 250 ° C.
The conjugation reaction is carried out for 1 minute to 1 hour, and if necessary, purification treatment such as removal of a catalyst is performed to produce the desired conjugated polyunsaturated fatty acid.
【００１８】なお、共役化処理にあたっては、前記原料
１重量部に対して、１０〜３０重量％、より好ましくは
１５〜２５重量％のアルカリ金属水酸化物（前記同様）
を含むジオール、より好ましくは水溶性のエチレングリ
コール、プロピレングリコール等の溶液５０〜１００重
量部を加え、１７０〜１９０℃にて５〜３０分間、より
好ましくは５〜１５分間、前記同様の不活性ガス雰囲気
中で共役化反応を行わせることによって、特異的な殺癌
細胞活性の高い共役トリエン脂肪酸に富む共役多価不飽
和脂肪酸類を製造することが可能となる。In the conjugation treatment, 10 to 30% by weight, more preferably 15 to 25% by weight of alkali metal hydroxide (same as above) is added to 1 part by weight of the raw material.
Diol, more preferably 50 to 100 parts by weight of a solution of a water-soluble ethylene glycol, propylene glycol or the like, and the mixture is inert at 170 to 190 ° C. for 5 to 30 minutes, more preferably 5 to 15 minutes. By performing the conjugation reaction in a gas atmosphere, it becomes possible to produce conjugated polyunsaturated fatty acids rich in conjugated triene fatty acids having a high specific carcinogenic cell activity.
【００１９】後者の方法では、動植物、微生物、藻類等
の組織を原料とし、これから共役多価不飽和脂肪酸を構
成脂肪酸とする油脂、例えばキリ油、サクランボやホウ
センカの種子油を常法により搾油し、これをそのまま又
は適宜にエステル交換、水素添加、ケン化分解、精製等
の各処理を施すことによって目的とする共役多価不飽和
脂肪酸類を採取することができる。なお、キリ油の構成
脂肪酸はエレオステアリン酸であり、サクランボやホウ
センカの種子油からパリナリン酸が得られる。これらの
共役多価不飽和脂肪酸類は単独で又は混合して本発明の
特異的殺癌細胞剤の有効成分として使用することが可能
である。In the latter method, tissues such as animals and plants, microorganisms and algae are used as raw materials, and oils and fats containing conjugated polyunsaturated fatty acids as constituent fatty acids, for example, krill oil, cherry or balsam seed oil are squeezed by a conventional method. The desired conjugated polyunsaturated fatty acids can be collected by subjecting them to various treatments such as transesterification, hydrogenation, saponification decomposition, and purification as they are or as appropriate. The constituent fatty acid of tung oil is eleostearic acid, and parinaric acid can be obtained from cherry or balsam seed oil. These conjugated polyunsaturated fatty acids can be used alone or in combination as an active ingredient of the specific cancer killing cell agent of the present invention.
【００２０】本発明の特異的殺癌細胞剤は前述の共役多
価不飽和脂肪酸類そのものを単一成分として又は適宜に
組み合わせて混合成分として用いることによって調製す
ることができる。また、該共役多価不飽和脂肪酸類を有
効成分として、これに他の成分、すなわち食品及び／又
は医薬品を製造する場合にはこれに許容され、かつ本発
明の所望の効果の発現を阻害しない公知の添加物、安定
化剤、賦活剤等を適宜に併用して本発明の特異的殺癌細
胞剤を調製することも可能である。この併用成分あるい
は原材料の例としてアミノ酸、ペプチド、蛋白質、各種
糖質、澱粉およびこの分解物、油脂、アスコルビン酸、
ビタミンＥ、トコフェロール、フィトステロール、ミネ
ラル、カテキン等のポリフェノール類等およびこれらの
誘導体をあげることができるが、本発明はこれらに限定
されるものではない。本発明の特異的殺癌細胞剤に含ま
れる前記有効成分の量は、殺癌細胞剤の形態、使用目
的、用途、操作および作業性等の条件により一律に規定
しがたいが、概ね２０重量％以上、より好ましくは３０
重量％以上である。２０重量％未満では後述する用途組
成物を調製する際に多量の殺癌細胞剤を配合せざるを得
ない等の使用上の利便性を欠くことがある。The specific cancer killing cell agent of the present invention can be prepared by using the above-mentioned conjugated polyunsaturated fatty acids themselves as a single component or by appropriately combining them as a mixed component. In addition, the conjugated polyunsaturated fatty acid is used as an active ingredient, and other ingredients, that is, when producing a food and / or a pharmaceutical, are acceptable and do not inhibit the expression of the desired effect of the present invention. It is also possible to prepare the specific cancer killing cell agent of the present invention by appropriately combining known additives, stabilizers, activators and the like. Examples of the concomitant components or raw materials include amino acids, peptides, proteins, various sugars, starches and their decomposed products, fats and oils, ascorbic acid,
Examples thereof include polyphenols such as vitamin E, tocopherol, phytosterol, mineral, and catechin, and derivatives thereof, but the present invention is not limited thereto. The amount of the active ingredient contained in the specific cancer cell-killing agent of the present invention cannot be uniformly defined depending on the form, purpose of use, use, operation and workability of the cancer cell-killing agent. % Or more, more preferably 30%
% By weight or more. If the amount is less than 20% by weight, convenience in use may be lacking such that a large amount of a cancer killing cell must be added when preparing a use composition described later.
【００２１】なお、本発明の特異的殺癌細胞剤の形態
は、本発明に係る共役多価不飽和脂肪酸類のみを用いる
ときは通常油状の液体であるが、前記併用物質を用いる
ときはその物性に適応させてさまざまな形態を採用でき
る。すなわち、併用物質がアスコルビン酸パルミテー
ト、フィトステロール、ビタミンＥ等のように油溶性の
場合は、本発明に係る共役多価不飽和脂肪酸類と混合し
て均一状態となし、また、アスコルビン酸、アミノ酸、
ミネラル、蛋白質等のように水溶性ないしは水分散性の
場合は、例えばその乾燥粉末を本発明に係る共役多価不
飽和脂肪酸類と混練して分散状態にするか、水及び適宜
に界面活性剤を共存させて乳化状態となすこともでき
る。The form of the specific cancer killing cell agent of the present invention is usually an oily liquid when using only the conjugated polyunsaturated fatty acids according to the present invention, but when using the above-mentioned concomitant substance, Various forms can be adopted according to physical properties. That is, when the concomitant substance is oil-soluble such as ascorbic acid palmitate, phytosterol, vitamin E, etc., it is mixed with the conjugated polyunsaturated fatty acids according to the present invention to make a uniform state, and ascorbic acid, amino acid,
In the case of water-soluble or water-dispersible substances such as minerals and proteins, for example, the dry powder is kneaded with the conjugated polyunsaturated fatty acids according to the present invention to form a dispersed state, or water and a surfactant are appropriately used. Can be coexisted to form an emulsified state.
【００２２】本発明の特異的殺癌細胞剤は、ヒト組織由
来の癌細胞とりわけ大腸癌細胞、肝臓癌細胞、肺癌細
胞、乳癌細胞又は胃癌細胞に対して顕著な死滅化効果を
発揮する。この効果は二重結合を２個有する場合の共役
ジエン脂肪酸のみから構成される共役リノール酸及びそ
の誘導体に比べて著しく大きいものである。The specific cancer killing cell agent of the present invention exerts a remarkable killing effect on cancer cells derived from human tissues, especially on colon cancer cells, liver cancer cells, lung cancer cells, breast cancer cells or gastric cancer cells. This effect is remarkably greater than that of a conjugated linoleic acid composed of only a conjugated diene fatty acid having two double bonds and a derivative thereof.
【００２３】本発明の特異的殺癌細胞剤は、ヒト組織由
来の正常細胞とりわけ肺線維芽細胞、皮膚線維芽細胞、
胚線維芽細胞に対しては該細胞の本来の機能の発現を阻
害したり死滅させたりする作用は認められず、正常細胞
に悪影響を及ぼさない。The specific cancer killing cell agent of the present invention comprises normal cells derived from human tissues, especially lung fibroblasts, skin fibroblasts,
The effect of inhibiting the expression of the original function of the cell or killing it is not observed for embryonic fibroblasts, and does not adversely affect normal cells.
【００２４】本発明では、前述のように、特定の共役多
価不飽和脂肪酸類を有効成分としてなる特異的殺癌細胞
剤が提供されるが、さらにこれを配合してなる組成物も
提供される。この組成物の態様としては医薬用組成物お
よび食用組成物が好適である。In the present invention, as described above, a specific cancer killing cell agent comprising a specific conjugated polyunsaturated fatty acid as an active ingredient is provided, and a composition further comprising the same is also provided. You. As an embodiment of this composition, a pharmaceutical composition and an edible composition are suitable.
【００２５】本発明の医薬用組成物は、前記の特異的殺
癌細胞剤すなわち二重結合を３〜６個有する共役多価不
飽和脂肪酸類を有効成分とし、これに本発明の趣旨に反
しない公知の賦型剤や添加剤を必要に応じて加え、常法
により加工して錠剤、カプセル剤、顆粒剤、散剤、注射
剤等の製剤となしたものである。経口摂取、経管投与ま
たは注射投与して、癌疾患の予防あるいは治療のために
適用する。前記製剤中に配合する本発明の特異的殺癌細
胞剤は、適宜に溶剤分別や吸着剤処理等の分画精製処理
を施して共役トリエン脂肪酸の含有量をできるだけ高め
たものを用いるのが望ましい。その配合量は製剤の種
類、形態や用法、用量等により一律に規定し難いが、概
ね０．０１〜５０重量％である。経口摂取する場合の摂
取量はとくに限定されないが、有効成分である前記共役
多価不飽和脂肪酸として、成人（体重５０ｋｇ）１日あ
たり０．０１〜１０ｇ、より好ましくは０．１〜５ｇで
ある。この範囲を外れて少ないと本発明の所望の効果を
奏することが難しくなり、逆に多すぎてもさらに顕著な
効果は認められない。The pharmaceutical composition of the present invention comprises, as an active ingredient, the above-mentioned specific cancer killing cell agent, that is, a conjugated polyunsaturated fatty acid having 3 to 6 double bonds, which is contrary to the spirit of the present invention. Known excipients and additives are added as necessary, and processed in a conventional manner to give tablets, capsules, granules, powders, injections and other preparations. Oral ingestion, tube administration or injection administration is applied for the prevention or treatment of cancer diseases. It is desirable that the specific cancer killing cell agent of the present invention to be incorporated into the above-mentioned preparation is appropriately subjected to fractionation purification treatment such as solvent fractionation or adsorbent treatment to increase the content of conjugated triene fatty acid as much as possible. . It is difficult to uniformly define the compounding amount depending on the type, form, usage, dosage, etc. of the preparation, but it is generally 0.01 to 50% by weight. The oral intake is not particularly limited, but the conjugated polyunsaturated fatty acid as an active ingredient is 0.01 to 10 g, more preferably 0.1 to 5 g per day for an adult (body weight 50 kg) per day. . If the amount is out of this range, it is difficult to achieve the desired effects of the present invention. Conversely, if the amount is too large, no more remarkable effects are observed.
【００２６】本発明の他の組成物の好適な態様は食用組
成物である。すなわち、前述のようにして得られる二重
結合を３〜６個有する共役多価不飽和脂肪酸類を有効成
分として含む特異的殺癌細胞剤は、これをそのまま液
状、ゲル状あるいは固形状の食品、例えばジュース、清
涼飲料、茶、スープ、ドレッシング、ゼリー、ヨーグル
ト、プリン、ふりかけ、育児用粉乳、ケーキミックス、
粉末状または液状の乳製品、パン、クッキー等に添加し
たり、必要に応じてデキストリン、乳糖、澱粉等の賦型
剤や香料、色素等とともにペレット、錠剤、顆粒等に加
工したり、またゼラチン等で被覆してカプセルに成形加
工して健康食品や栄養補助食品等として利用できる。こ
れらの食品類あるいは食用組成物における本発明の殺癌
細胞剤の配合量は、当該食品や組成物の種類や状態等に
より一律に規定しがたいが、約０．０１〜５０重量％、
より好ましくは０．１〜３０重量％である。配合量が
０．０１重量％未満では経口摂取による所望の効果が小
さく、５０重量％を超えると食品の種類によっては風味
を損なったり当該食品を調製できなくなる場合がある。
なお、本発明の特異的殺癌細胞剤は、これをそのまま食
用に供してもさしつかえない。A preferred embodiment of another composition of the present invention is an edible composition. That is, the specific cancer killing cell agent containing a conjugated polyunsaturated fatty acid having 3 to 6 double bonds as an active ingredient, which is obtained as described above, is a liquid, gel or solid food as it is. , E.g. juice, soft drink, tea, soup, dressing, jelly, yogurt, pudding, sprinkle, powdered milk for childcare, cake mix,
Add to powdered or liquid dairy products, bread, cookies, etc., or process as needed into pellets, tablets, granules, etc. with excipients such as dextrin, lactose, starch, etc. It can be used as a health food or dietary supplement, etc. The amount of the cancer-killing cell agent of the present invention in these foods or edible compositions cannot be uniformly defined depending on the type and condition of the food or composition, but is preferably about 0.01 to 50% by weight.
More preferably, it is 0.1 to 30% by weight. If the amount is less than 0.01% by weight, the desired effect by oral ingestion is small, and if it exceeds 50% by weight, depending on the type of food, the flavor may be impaired or the food may not be prepared.
It should be noted that the specific cancer killing cell agent of the present invention may be used for food as it is.
【００２７】[0027]
【実施例】実施例１ 反応容器に精製亜麻仁油（粗シグマ社製試薬。ＧＬＣに
よる脂肪酸組成分析によれば、α−ＬＮＡ：６７％）１
ｇ、２１重量％水酸化カリウムを含むエチレングリコー
ル溶液１００ｍｌを加え、容器内空気を窒素ガスで置換
した後、密閉して１８０℃で１０分間共役化反応を行わ
せた。ついで、該反応物をエタノールで繰返し洗浄し
て、共役α−ＬＮＡを構成脂肪酸とするトリグリセリド
（試料１）を調製した。共役多価不飽和脂肪酸の含量
は、分光光度計（島津製作所（株）製、ＶＵＶ２４００
ＰＣ）を用いて２２０〜３６０ｎｍの吸収スペクトルを
測定し、ＡＯＡＣ Ｏｆｆｉｃｉａｌ Ｍｅｔｈｏｄｓ
ｏｆ Ａｎａｌｙｓｉｓ（１９９０年、９５７．１
３）に記載の方法に準じて求めた（以下、とくにことわ
らないかぎり同様）。試料１に含まれる共役多価不飽和
脂肪酸の共役ジエン体は１９．５％であり、共役トリエ
ン体は６３．０％であった。試料１をそのまま本発明の
特異的殺癌細胞剤とした。Example 1 Purified linseed oil (reagent manufactured by Crude Sigma Co., Ltd .; according to fatty acid composition analysis by GLC, α-LNA: 67%) was placed in a reaction vessel.
g, 100 ml of an ethylene glycol solution containing 21% by weight of potassium hydroxide was added, the air in the container was replaced with nitrogen gas, and the container was closed and a conjugate reaction was performed at 180 ° C. for 10 minutes. Next, the reaction product was repeatedly washed with ethanol to prepare a triglyceride having conjugated α-LNA as a constituent fatty acid (sample 1). The content of the conjugated polyunsaturated fatty acid was measured by a spectrophotometer (VUV2400, manufactured by Shimadzu Corporation).
PC) was used to measure the absorption spectrum at 220 to 360 nm, and the AOAC Official Methods
of Analysis (1990, 957.1)
It was determined according to the method described in 3) (hereinafter the same unless otherwise specified). The conjugated diene form of the conjugated polyunsaturated fatty acid contained in Sample 1 was 19.5%, and the conjugated triene form was 63.0%. Sample 1 was used as it was as the specific cancer killing cell agent of the present invention.
【００２８】実施例２ 実施例１の方法で別に調製した試料１の１ｇを常法によ
り塩酸加水分解反応を行わしめ精製処理し、共役α−Ｌ
ＮＡを含む混合脂肪酸（試料２）を調製した。共役ジエ
ン体：１８．０％、共役トリエン体：６２．０％であっ
た。試料２を本発明の特異的殺癌細胞剤とした。Example 2 1 g of Sample 1 separately prepared in the same manner as in Example 1 was subjected to a hydrochloric acid hydrolysis reaction in a conventional manner, purified, and treated with conjugated α-L.
A mixed fatty acid containing NA (sample 2) was prepared. The conjugated diene derivative was 18.0%, and the conjugated triene derivative was 62.0%. Sample 2 was used as the specific cancer killing cell agent of the present invention.
【００２９】実施例３ 反応容器に魚油由来のＥＰＡ（備前化成（株）製、ＧＣ
Ｌ純度：９８％）１ｇ、１５重量％水酸化ナトリウムを
含むプロピレングリコール溶液１００ｍｌを加え、実施
例１と同様にして１７０℃で２０分間共役化反応を行わ
せ、精製して共役ＥＰＡ（試料３）を調製した。これに
含まれる共役多価不飽和脂肪酸の共役ジエン体：５８．
０％、共役トリエン体：２３．７％、共役テトラエン
体：１５．０％、共役ペンタエン体：２．５％であっ
た。試料３を本発明の特異的殺癌細胞剤とした。Example 3 A fish oil-derived EPA (manufactured by Bizen Kasei Co., Ltd., GC
L purity: 98%), 100 ml of a propylene glycol solution containing 15% by weight of sodium hydroxide was added thereto, and a conjugation reaction was carried out at 170 ° C. for 20 minutes in the same manner as in Example 1; ) Was prepared. Conjugated diene body of conjugated polyunsaturated fatty acid contained therein: 58.
0%, conjugated triene: 23.7%, conjugated tetraene: 15.0%, and conjugated pentaene: 2.5%. Sample 3 was used as the specific cancer killing cell agent of the present invention.
【００３０】実施例４ 反応容器に魚油由来のＤＨＡ（備前化成（株）製、ＧＬ
Ｃ純度：９９％）１ｇ、２５重量％水酸化カリウムを含
むエチレングリコール溶液１００ｍｌを加え、実施例１
と同様にして１８０℃で１５分間共役化反応を行わせ、
精製して共役ＤＨＡ（試料４）を調製した。これに含ま
れる共役多価不飽和脂肪酸の共役ジエン体：５４．８
％、共役トリエン体：２２．０％、共役テトラエン体：
１４．７％、共役ペンタエン体：５．２％であった。試
料４を本発明の特異的殺癌細胞剤とした。Example 4 DHA derived from fish oil (GL, manufactured by Bizen Chemical Co., Ltd., GL
C purity: 99%) Example 1 was added by adding 1 g of an ethylene glycol solution containing 25% by weight of potassium hydroxide.
The conjugation reaction is performed at 180 ° C. for 15 minutes in the same manner as described above.
Purification was performed to prepare a conjugated DHA (Sample 4). Conjugated polyene unsaturated fatty acid conjugated diene compound contained therein: 54.8
%, Conjugated triene: 22.0%, conjugated tetraene:
14.7%, conjugated pentaene derivative: 5.2%. Sample 4 was used as the specific cancer killing cell agent of the present invention.
【００３１】実施例５ 実施例３および４の方法で別にそれぞれ調製した試料３
および試料４の各１ｇ混合物を冷却器つきエステル化用
フラスコに入れ、硫酸−エタノール溶液を６０ｍｌ加え
て１時間沸騰させ、室温まで冷却した。その後、水１０
０ｍｌおよび石油エーテル５０ｍｌを用いて抽出し、該
抽出液を水洗し、洗浄水がメチルオレンジ指示薬で酸性
を示さなくなるまで水洗を繰返した。石油エーテル溶液
を無水硫酸ナトリウムで脱水後、減圧下に脱溶剤処理し
て共役ＥＰＡおよび共役ＤＨＡを構成脂肪酸とするエチ
ルエステル（試料５）を調製した。これに含まれる共役
多価不飽和脂肪酸の共役ジエン体：５６．０％、共役ト
リエン体：１５．０％、共役テトラエン体：１８．０
％、共役ペンタエン体：３．５％であった。試料５を本
発明の特異的殺癌細胞剤とした。Example 5 Sample 3 separately prepared by the methods of Examples 3 and 4
Then, 1 g of each mixture of Sample 4 was placed in an esterification flask equipped with a condenser, 60 ml of sulfuric acid-ethanol solution was added, the mixture was boiled for 1 hour, and cooled to room temperature. Then water 10
Extraction was carried out using 0 ml and 50 ml of petroleum ether, and the extract was washed with water, and was repeatedly washed with water until the washing water was no longer acidic with a methyl orange indicator. After dehydrating the petroleum ether solution with anhydrous sodium sulfate, the solvent was removed under reduced pressure to prepare an ethyl ester having conjugated EPA and conjugated DHA as constituent fatty acids (Sample 5). Conjugated polyunsaturated fatty acid conjugated diene compound contained therein: 56.0%, conjugated triene compound: 15.0%, conjugated tetraene compound: 18.0%
%, Conjugated pentaene compound: 3.5%. Sample 5 was used as the specific cancer killing cell agent of the present invention.
【００３２】実施例６ 実施例３および４の方法でそれぞれ別に調製した試料３
および試料４の各１ｇ混合物を冷却器つきケン化用フラ
スコに入れ、１モル／リットル水酸化カリウム−エタノ
ール溶液を５０ｍｌ加えて１時間加熱還流させ室温まで
冷却した。その後、水５０ｍｌおよび石油エーテル１０
０ｍｌを用いて抽出、精製処理して共役ＥＰＡおよび共
役ＤＨＡを構成脂肪酸とするカリウム塩を調製した。こ
れに含まれる共役多価不飽和脂肪酸の共役ジエン体：５
９．５％、共役トリエン体：２０．７％、共役テトラエ
ン体：１２．０％、共役ペンタエン体：１．５％であっ
た。Example 6 Sample 3 prepared separately by the methods of Examples 3 and 4
Then, 1 g of each mixture of Sample 4 was placed in a saponification flask equipped with a condenser, 50 ml of a 1 mol / l potassium hydroxide-ethanol solution was added, and the mixture was heated under reflux for 1 hour and cooled to room temperature. Then, 50 ml of water and 10 parts of petroleum ether
Extraction and purification were carried out using 0 ml to prepare a potassium salt having conjugated EPA and conjugated DHA as constituent fatty acids. Conjugated polyunsaturated fatty acid conjugated diene compound contained therein: 5
9.5%, conjugated triene: 20.7%, conjugated tetraene: 12.0%, conjugated pentaene: 1.5%.
【００３３】実施例７ 脂肪酸組成がＥＰＡ：２７．５重量％およびＤＨＡ：１
８．３重量％を含む精製分別魚油１０ｇと、１５重量％
水酸化カリウム含有エチレングリコール溶液４００ｍｌ
とを用い、実施例１に記載の方法に準じて１８０℃で２
５分間共役化反応を行わせ、精製して共役ＥＰＡおよび
共役ＤＨＡを構成脂肪酸とするトリグリセリド（試料
７）を調製した。これに含まれる共役多価不飽和脂肪酸
の共役ジエン体：４７．０％、共役トリエン体：３３．
０％、共役テトラエン体：１０．５％、共役ペンタエン
酸：３．５％であった。試料７にビタミンＥ及びデキス
トリンを混合して本発明の特異的殺癌細胞剤とした。Example 7 The fatty acid composition was 27.5% by weight of EPA and 1 of DHA.
10 g of refined fractionated fish oil containing 8.3% by weight and 15% by weight
400 ml of ethylene glycol solution containing potassium hydroxide
At 180 ° C. and 2 according to the method described in Example 1.
A conjugation reaction was performed for 5 minutes, followed by purification to prepare a triglyceride containing conjugated EPA and conjugated DHA as constituent fatty acids (sample 7). Conjugated polyunsaturated fatty acids contained therein: conjugated diene: 47.0%, conjugated triene: 33.
0%, conjugated tetraene derivative: 10.5%, conjugated pentaenoic acid: 3.5%. Sample 7 was mixed with vitamin E and dextrin to obtain a specific cancer killing cell agent of the present invention.
【００３４】比較例１ 反応容器にリノール酸（米国シグマ社製試薬、ＧＬＣ純
度：９９％）１ｇ、６重量％水酸化カリウムを含むエチ
レングリコール溶液１００ｍｌを加え、実施例１と同様
にして１８０℃で２５分間共役化反応を行わせ、精製し
て共役リノール酸を調製した。このものは共役ジエン
体：９０．６％であった。ついで、この共役リノール酸
を実施例５に記載の方法に準じてエステル化処理し、精
製処理して共役リノール酸を構成脂肪酸とするエチルエ
ステル（比較試料１）を調製した。Comparative Example 1 A reaction vessel was charged with 1 g of linoleic acid (a reagent manufactured by Sigma, USA, GLC purity: 99%) and 100 ml of an ethylene glycol solution containing 6% by weight of potassium hydroxide. For 25 minutes, and purified to prepare conjugated linoleic acid. This was a conjugated diene compound: 90.6%. Next, this conjugated linoleic acid was subjected to an esterification treatment according to the method described in Example 5 and purified to prepare an ethyl ester having conjugated linoleic acid as a constituent fatty acid (Comparative Sample 1).
【００３５】試験例１ 前述の各種共役多価不飽和脂肪酸類の殺癌細胞作用を以
下に述べる方法で評価した。すなわち、東北大学加齢医
学研究所付属癌細胞保存施設より分譲され、入手したヒ
ト由来の５種類の癌細胞である大腸癌細胞（細胞番号
（以下同様）：ＴＫＧ０３７９、以下ＤＬＤ−１とい
う。）、肝臓癌細胞（ＴＫＧ０２０５、以下ＨｅｐＧ２
という。）、肺癌細胞（ＴＫＧ０１８４、以下Ａ５４９
という。）、乳癌細胞（ＴＫＧ０４７９、以下ＭＣＦ７
という。）及び胃癌細胞（ＴＫＧ０２２８、以下ＭＫＮ
−７という。）を用い、各細胞を９６穴マイクロプレー
トに播種し、８０％コンフレント（細胞充満度）に達し
た時点で、１５μＭの共役多価不飽和脂肪酸類を含む
０．５％牛血清アルブミンを加え、５％二酸化炭素雰囲
気下３７℃で２４時間インキュベートした後に生細胞数
をＭＴＴ（３−（４，５−ジメチルアゾール−２−イ
ル）−２，５−ジフェニル−２Ｈ−テトラゾリウムブロ
マイド）法で調べた。なお、ＭＴＴ法は生細胞内酵素活
性を指標としているためほとんどの細胞に適用でき、こ
の結果も比較的安定しているので殺細胞作用の評価法と
して採用した。この結果を表１に示す。また、非共役Ｅ
ＰＡおよび非共役ＤＨＡを構成脂肪酸とする魚油（比較
試料２）について同様に試験した結果を併記した。Test Example 1 The cancer killing action of the various conjugated polyunsaturated fatty acids described above was evaluated by the method described below. That is, colorectal cancer cells (cell numbers (the same applies hereinafter): TKG0379, hereinafter referred to as DLD-1), which are five kinds of cancer cells derived from humans, which were obtained from the cancer cell preservation facility attached to the Tohoku University Institute for Aging and Medicine. , Liver cancer cells (TKG0205, hereinafter HepG2
That. ), Lung cancer cells (TKG0184, hereinafter A549)
That. ), Breast cancer cells (TKG0479, hereinafter MCF7)
That. ) And gastric cancer cells (TKG0228, hereinafter MKN)
It is called -7. ), Seed each cell in a 96-well microplate, and when it reaches 80% confluence (cell fullness), add 0.5% bovine serum albumin containing 15 μM conjugated polyunsaturated fatty acids, After incubation at 37 ° C. for 24 hours in a 5% carbon dioxide atmosphere, the number of viable cells was determined by the MTT (3- (4,5-dimethylazol-2-yl) -2,5-diphenyl-2H-tetrazolium bromide) method. . Since the MTT method uses the enzyme activity in living cells as an index, it can be applied to almost all cells. Since the result is relatively stable, it was adopted as a method for evaluating cell killing action. Table 1 shows the results. Also, the non-conjugated E
The results of similar tests for fish oil containing PA and non-conjugated DHA as constituent fatty acids (Comparative Sample 2) are also shown.
【００３６】[0036]
【表１】 [Table 1]
【００３７】表１において、数値は試験試料を添加しな
いときのＭＴＴ活性（細胞生存率、％）を１００とし、
試験試料の添加濃度（１５μＭ）における相対値を平均
値±標準偏差（ｎ＝６）で示す（以下同様）。各試験試
料の数値は比較試料１および２の場合の値と比較して有
意差があった（Ｐ＜０．０５）。このデータから、本発
明に係る共役多価不飽和脂肪酸類は、魚油に比べて、大
腸癌細胞に対して殺細胞効果が認められた。また、肝臓
癌細胞、肺癌細胞及び胃癌細胞に対しても同様の殺細胞
効果が認められた。In Table 1, MTT activity (cell viability,%) when no test sample was added was 100,
The relative value of the test sample at the added concentration (15 μM) is shown as an average value ± standard deviation (n = 6) (the same applies hereinafter). The value of each test sample was significantly different from that of Comparative Samples 1 and 2 (P <0.05). From this data, it was confirmed that the conjugated polyunsaturated fatty acids according to the present invention had a cell killing effect on colon cancer cells as compared with fish oil. Similar cell killing effects were also observed on liver cancer cells, lung cancer cells and gastric cancer cells.
【００３８】試験例２ 前述の各種共役多価不飽和脂肪酸類の正常細胞に対する
影響を試験例１に記載の方法と同様にして評価した。ヒ
ト由来の正常細胞は、ヒューマンサイエンス研究資源バ
ンク（大阪）から入手した肺線維芽細胞（以下ＭＲＣ−
５という）、皮膚線維芽細胞（以下ＴＩＧ−１０３とい
う）、胚線維芽細胞（以下ＫＭＳ−６という）を用い
た。この結果を共役リノール酸エチルエステルおよび魚
油（未変性）についての結果とともに表２に示す。同表
中の数値、記号の意味は表１と同じである。これらのデ
ータから、ｎ−３系脂肪酸の一種であるα−ＬＮＡ、Ｅ
ＰＡ、ＤＨＡ等の共役多価不飽和脂肪酸類はヒト正常細
胞の生育（***、増殖等）に対してほとんど影響を及ぼ
さず、とりわけ共役トリエン体を多く含むものでは当該
作用が強いことが明らかになった。Test Example 2 The effect of the various conjugated polyunsaturated fatty acids on normal cells was evaluated in the same manner as in Test Example 1. Normal human-derived cells are lung fibroblasts (hereinafter referred to as MRC-human) obtained from Human Science Research Resource Bank (Osaka).
5), skin fibroblasts (hereinafter referred to as TIG-103), and embryonic fibroblasts (hereinafter referred to as KMS-6). The results are shown in Table 2 together with the results for conjugated linoleic acid ethyl ester and fish oil (unmodified). The meanings of the numerical values and symbols in the table are the same as in Table 1. From these data, α-LNA, a kind of n-3 fatty acid, E
Conjugated polyunsaturated fatty acids such as PA and DHA hardly affect the growth (division, proliferation, etc.) of normal human cells, and it is clear that the effect is particularly strong in those containing a large amount of conjugated trienes. became.
【００３９】[0039]
【表２】 [Table 2]
【００４０】実施例８ 試料４又は試料７の共役多価不飽和脂肪酸類２５０ｍ
ｇ、精製大豆油３０ｍｇ、ミツロウ１０ｍｇ及びビタミ
ンＥ１０ｍｇを窒素ガス雰囲気下で約４０℃に加温し、
十分に混合して均質な液状物とした。これをカプセル充
填機に供給して１粒内容量が３００ｍｇのゼラチン被覆
カプセル製剤を試作した。これらの製剤は医薬用組成物
又は食用組成物として利用できるものである。Example 8 250 m of conjugated polyunsaturated fatty acids of sample 4 or sample 7
g, refined soybean oil 30 mg, beeswax 10 mg and vitamin E 10 mg were heated to about 40 ° C. under a nitrogen gas atmosphere,
The mixture was thoroughly mixed to obtain a homogeneous liquid. This was supplied to a capsule filling machine to prepare a gelatin-coated capsule preparation having a content per grain of 300 mg. These preparations can be used as a pharmaceutical composition or an edible composition.
【００４１】実施例９ 市販の牛乳１リットルに対して試料７の共役多価不飽和
脂肪酸類５ｇ及びビタミンＥ０．２ｇを添加し、十分に
混合して均等な飲料物を試作した。このものは通常の牛
乳と比較して風味、色あい、食感等の食品適性に遜色な
く、癌予防用あるいは当該疾患用の食品として好適に利
用され得るものである。Example 9 To 1 liter of commercially available milk, 5 g of the conjugated polyunsaturated fatty acids of Sample 7 and 0.2 g of vitamin E were added and mixed well to produce an even beverage. This product is not inferior to food suitability such as flavor, color and texture as compared with ordinary milk, and can be suitably used as a food for preventing cancer or as a disease.
【００４２】[0042]
【発明の効果】本発明によれば、二重結合を３〜６個有
する共役多価不飽和脂肪酸類を有効成分としてなる特異
的殺癌細胞剤が提供される。この殺癌細胞剤はヒト由来
の大腸癌、肝臓癌、肺癌、乳癌あるいは胃癌等の癌細胞
を死滅させる効果を奏し、かつ正常細胞の生育には悪影
響を与えない。かかる効果は共役多価不飽和脂肪酸類を
構成する脂肪酸が共役トリエン脂肪酸を多量に含む場合
により一層顕著なものとなる。ちなみに、二重結合を２
個しかもたない共役リノール酸等の共役ジエン脂肪酸で
は前記殺癌細胞作用が認められない。また、本発明によ
れば、α−リノレン酸、エイコサペンタエン酸、ドコサ
ヘキサエン酸等のｎ−３系非共役多価不飽和脂肪酸を構
成脂肪酸とするものを原料として、これを共役トリエン
脂肪酸に富む共役多価不飽和脂肪酸類に効率的に共役異
性化できる共役化方法が提供される。さらに、本発明に
よれば、前記特異的殺癌細胞剤を配合してなる医薬用組
成物又は食用組成物が提供される。該組成物は癌疾患の
予防あるいは治療用途に利用され得るものである。According to the present invention, there is provided a specific cancer killing cell agent comprising a conjugated polyunsaturated fatty acid having 3 to 6 double bonds as an active ingredient. This cancer killing cell agent has an effect of killing cancer cells such as human colon cancer, liver cancer, lung cancer, breast cancer and gastric cancer, and does not adversely affect the growth of normal cells. Such an effect becomes more remarkable when the fatty acids constituting the conjugated polyunsaturated fatty acids contain a large amount of conjugated triene fatty acids. By the way, double bond
Conjugated diene fatty acids, such as conjugated linoleic acid, which do not have any of these, do not show the above-mentioned carcinocidal cell action. Further, according to the present invention, a conjugated material rich in conjugated triene fatty acids is used as a raw material, which uses an n-3 non-conjugated polyunsaturated fatty acid such as α-linolenic acid, eicosapentaenoic acid, docosahexaenoic acid or the like as a constituent fatty acid. A conjugation method capable of efficiently conjugate isomerizing polyunsaturated fatty acids is provided. Further, according to the present invention, there is provided a pharmaceutical composition or an edible composition comprising the specific cancer killing cell agent. The composition can be used for preventing or treating cancer diseases.
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.7 識別記号 ＦＩ テーマコート゛(参考） Ｃ１１Ｃ 3/00 Ｃ１１Ｃ 3/00 3/14 3/14 (72)発明者 羽田 尚彦 岡山県赤磐郡熊山町徳富363番地 備前化 成株式会社内 (72)発明者 井上 良計 岡山県赤磐郡熊山町徳富363番地 備前化 成株式会社内 Ｆターム(参考） 4B018 MD11 MD12 MD13 MD15 MD17 ME08 MF01 MF10 4C086 AA01 AA02 DA41 MA01 MA04 NA14 ZB26 4C206 AA01 AA02 DA05 DB07 DB09 DB43 DB44 MA01 MA04 NA14 ZB26 4H059 BA26 BA30 BA33 BA34 BA83 BB05 BB06 CA46 EA21 ──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. 7 Identification symbol FI Theme coat ゛ (Reference) C11C 3/00 C11C 3/00 3/14 3/14 (72) Inventor Naohiko Haneda Kumayama-cho, Akaiwa-gun, Okayama Prefecture 363 Tokutomi Bizen Kasei Co., Ltd. (72) Inventor Ryokei Inoue 363 Tokutomi Kumayama-cho, Akaiwa-gun, Okayama Prefecture Bizen Kasei Co., Ltd.F-term (reference) MA01 MA04 NA14 ZB26 4C206 AA01 AA02 DA05 DB07 DB09 DB43 DB44 MA01 MA04 NA14 ZB26 4H059 BA26 BA30 BA33 BA34 BA83 BB05 BB06 CA46 EA21
Claims (11)
役多価不飽和脂肪酸類を有効成分としてなる、正常細胞
に悪影響を及ぼさない特異的殺癌細胞剤。1. A specific cancer killing cell which does not adversely affect normal cells, comprising a conjugated polyunsaturated fatty acid having 3 to 6 carbon-carbon double bonds as an active ingredient.
役トリエン脂肪酸に富むものである請求項１に記載の特
異的殺癌細胞剤。2. The specific cancer killing cell according to claim 1, wherein the constituent fatty acids of the conjugated polyunsaturated fatty acids are rich in conjugated triene fatty acids.
−リノレン酸、エイコサペンタエン酸、ドコサペンタエ
ン酸及びドコサヘキサエン酸からなる群から選ばれる１
種又は２種以上の非共役多価不飽和脂肪酸を共役化処理
して得られるものである請求項１又は２に記載の特異的
殺癌細胞剤。3. The constituent fatty acid of the conjugated polyunsaturated fatty acid is α
1 selected from the group consisting of linolenic acid, eicosapentaenoic acid, docosapentaenoic acid and docosahexaenoic acid
The specific cancer killing cell agent according to claim 1 or 2, which is obtained by conjugate treatment of one or more non-conjugated polyunsaturated fatty acids.
〜６個有する非共役多価不飽和脂肪酸類１重量部に対し
て１０〜３０重量％アルカリ金属水酸化物を含むジオー
ル溶液５０〜１００重量部を加え、１７０〜１９０℃に
て５〜３０分間、共役化反応させることを特徴とする共
役トリエン脂肪酸に富む共役多価不飽和脂肪酸類の製造
方法によるものである請求項３に記載の特異的殺癌細胞
剤。4. The method according to claim 1, wherein the conjugation treatment includes the step of forming a carbon-carbon double bond into three.
50 to 100 parts by weight of a diol solution containing 10 to 30% by weight of an alkali metal hydroxide is added to 1 part by weight of the non-conjugated polyunsaturated fatty acids having up to 6 parts, and the mixture is added at 170 to 190C for 5 to 30 minutes. The specific cancer killing cell agent according to claim 3, which is obtained by a method for producing conjugated polyunsaturated fatty acids rich in conjugated triene fatty acids, which is characterized by performing a conjugate reaction.
レオステアリン酸及び／又はパリナリン酸である請求項
１又は２に記載の特異的殺癌細胞剤。5. The specific cancer killing cell agent according to claim 1, wherein the constituent fatty acids of the conjugated polyunsaturated fatty acids are eleostearic acid and / or parinaric acid.
炭素間二重結合を３〜６個有する共役多価不飽和脂肪酸
を構成脂肪酸とするカルボン酸、エステル及び塩からな
る群から選択される１種又は２種以上のものである請求
項１、２、３又は５に記載の特異的殺癌細胞剤。6. An embodiment of the conjugated polyunsaturated fatty acid is carbon-
The conjugated polyunsaturated fatty acid having 3 to 6 carbon-carbon double bonds is one or more selected from the group consisting of carboxylic acids, esters and salts having a constituent fatty acid. 6. The specific cancer killing cell agent according to 3 or 5.
である請求項６に記載の特異的殺癌細胞剤。7. The specific cancer killing cell according to claim 6, wherein the ester is an ester of a lower monohydric alcohol.
シルグリセロリン脂質である請求項６に記載の特異的殺
癌細胞剤。8. The specific cancer killing cell according to claim 6, wherein the ester is an acyl glyceride and / or an acyl glycerophospholipid.
胞、肺癌細胞、乳癌細胞又は胃癌細胞である請求項１〜
８のいずれか１項に記載の特異的殺癌細胞剤。9. The cancer cell according to claim 1, wherein the cancer cell is human colon cancer cell, liver cancer cell, lung cancer cell, breast cancer cell or gastric cancer cell.
9. The specific cancer killing cell agent according to any one of 8.
膚線維芽細胞又は胚線維芽細胞である請求項１〜８のい
ずれか１項に記載の特異的殺癌細胞剤。10. The specific cancer killing cell agent according to any one of claims 1 to 8, wherein the normal cells are human-derived lung fibroblasts, skin fibroblasts or embryonic fibroblasts.
特異的殺癌細胞剤を配合してなる医薬用組成物又は食用
組成物。11. A pharmaceutical or edible composition comprising the specific cancer killing cell agent according to any one of claims 1 to 10.
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| JP2000136449A JP4594489B2 (en) | 2000-03-31 | 2000-03-31 | Specific cancer killing agent and composition comprising the same |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005005367A1 (en) * | 2003-07-09 | 2005-01-20 | Inoue, Yoshikazu | Chemically synthesized and highly unsaturated fatty acid of conjugated type |
| JP2005264077A (en) * | 2004-03-19 | 2005-09-29 | Nisshin Oillio Group Ltd | Conjugated trienoic acid-containing fat-and-oil composition and manufacturing method therefor |
| US8612759B2 (en) | 2006-08-29 | 2013-12-17 | Brother Kogyo Kabushiki Kaisha | Communication system for communicating data utilizing challenge data |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2000355538A (en) * | 1999-04-15 | 2000-12-26 | Kanegafuchi Chem Ind Co Ltd | Receptor agonist responsive to peroxisome activator |
-
2000
- 2000-03-31 JP JP2000136449A patent/JP4594489B2/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2000355538A (en) * | 1999-04-15 | 2000-12-26 | Kanegafuchi Chem Ind Co Ltd | Receptor agonist responsive to peroxisome activator |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005005367A1 (en) * | 2003-07-09 | 2005-01-20 | Inoue, Yoshikazu | Chemically synthesized and highly unsaturated fatty acid of conjugated type |
| JP2005264077A (en) * | 2004-03-19 | 2005-09-29 | Nisshin Oillio Group Ltd | Conjugated trienoic acid-containing fat-and-oil composition and manufacturing method therefor |
| US8612759B2 (en) | 2006-08-29 | 2013-12-17 | Brother Kogyo Kabushiki Kaisha | Communication system for communicating data utilizing challenge data |
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| Publication number | Publication date |
|---|---|
| JP4594489B2 (en) | 2010-12-08 |
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