JPH04295423A - Carcinostatic agent and carcinostaticity-reinforcing agent - Google Patents
Carcinostatic agent and carcinostaticity-reinforcing agentInfo
- Publication number
- JPH04295423A JPH04295423A JP3061884A JP6188491A JPH04295423A JP H04295423 A JPH04295423 A JP H04295423A JP 3061884 A JP3061884 A JP 3061884A JP 6188491 A JP6188491 A JP 6188491A JP H04295423 A JPH04295423 A JP H04295423A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- acid
- anticancer
- active ingredient
- carcinostatic
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
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- 230000003327 cancerostatic effect Effects 0.000 title abstract 6
- 239000012744 reinforcing agent Substances 0.000 title abstract 3
- 239000002253 acid Substances 0.000 claims abstract description 39
- 239000004480 active ingredient Substances 0.000 claims abstract description 17
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 5
- 230000001093 anti-cancer Effects 0.000 claims description 32
- 239000002246 antineoplastic agent Substances 0.000 claims description 27
- -1 14-methylpentadecyl Chemical group 0.000 claims description 18
- 239000003623 enhancer Substances 0.000 claims description 18
- 229940041181 antineoplastic drug Drugs 0.000 claims description 15
- 239000000126 substance Substances 0.000 claims description 9
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
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- 235000014113 dietary fatty acids Nutrition 0.000 abstract description 24
- 239000000194 fatty acid Substances 0.000 abstract description 24
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- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 abstract description 2
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- APKFDSVGJQXUKY-INPOYWNPSA-N amphotericin B Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-INPOYWNPSA-N 0.000 description 1
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Abstract
Description
【０００１】0001
【産業上の利用分野】本発明は新規な制がん剤および制
がん増強剤に関するものである。TECHNICAL FIELD The present invention relates to novel anticancer agents and anticancer enhancers.
【０００２】0002
【従来の技術】従来から制がん剤には、核酸や酵素など
重要な機能を有する生体高分子をアルキル化することに
より制がん性を発揮するアルキル化剤、核酸代謝を阻害
する代謝拮抗剤、細胞の核酸の生合成に関与する細胞分
裂毒であり、***増殖の盛んな細胞に対して殺細胞作用
を示す制がん抗生物質、さらには植物由来の制がん物質
やホルモン剤などがある。一方、がん細胞に吸収されに
くい薬物の吸収改善に効果を示し、制がん剤ブレオマイ
シン、アドリアマイシンなどの制がん効果を強くする制
がん増強剤としてはアンフォテリシンＢなどが研究され
ているが著効にはいたっていない。[Background Art] Conventionally, anticancer drugs include alkylating agents that exert anticancer properties by alkylating biopolymers with important functions such as nucleic acids and enzymes, and antimetabolites that inhibit nucleic acid metabolism. anticancer antibiotics, which are cell division toxins that are involved in the biosynthesis of nucleic acids in cells, and which have a cell-killing effect on actively dividing and proliferating cells, as well as plant-derived anticancer substances and hormones. There is. On the other hand, amphotericin B is being researched as an anticancer enhancer that is effective in improving the absorption of drugs that are difficult to absorb by cancer cells and strengthens the anticancer effects of anticancer drugs such as bleomycin and adriamycin. It has not become effective.
【０００３】0003
【発明が解決しようとする課題】従来の制がん剤は、い
ずれも副作用があり、有効性に満足できるものは少なく
、よりすぐれた制がん剤の開発が要望されている。また
、制がん剤の効果を充分に発揮させるためにすぐれた制
がん増強剤が必要である。[Problems to be Solved by the Invention] Conventional anticancer drugs all have side effects and few have satisfactory efficacy, and there is a demand for the development of better anticancer drugs. In addition, in order to fully exhibit the effects of anticancer drugs, excellent anticancer enhancers are required.
【０００４】0004
【課題を解決するための手段】本発明者らは、副作用が
ない制がん剤について鋭意研究の結果、一般式が、[Means for Solving the Problems] As a result of intensive research into anticancer drugs without side effects, the present inventors found that the general formula is
【０
００５】0
005]
【化１１】[Chemical formula 11]
【０００６】で示され、Ｒ が炭素数１〜５のアルキル
基、およびｎが４〜２２の整数である高級脂肪酸が顕著
な制がん作用を有することを見出したものである。すな
わち、本発明は一般式（Ｉ） ：It has been discovered that a higher fatty acid represented by the following formula, in which R is an alkyl group having 1 to 5 carbon atoms and n is an integer of 4 to 22, has a remarkable anticancer effect. That is, the present invention provides general formula (I):
【０００７】[0007]
【化１２】[Chemical formula 12]
【０００８】（式中、Ｒ は炭素数１〜５のアルキル基
、およびｎは４〜２２の整数を表わす）で示される高級
脂肪酸を有効成分とする制がん剤を提供するものである
。また、本発明は前記高級脂肪酸を有効成分とする制が
ん増強剤を提供するものである。The present invention provides an anticancer drug containing a higher fatty acid represented by the formula (wherein R represents an alkyl group having 1 to 5 carbon atoms and n represents an integer of 4 to 22) as an active ingredient. The present invention also provides an anticancer enhancer containing the above-described higher fatty acid as an active ingredient.
【０００９】[0009]
【実施例】本発明において、高級脂肪酸のアルキル鎖の
鎖長は一般式（Ｉ） におけるｎが４〜２２の整数であ
り、またＲ は炭素数１〜５のアルキル基であるもので
ある。ｎが４より小さいときおよび２２より大きいとき
制がん作用および制がん増強作用を発揮しない。またＲ
が炭素数６以上のアルキル基であるばあいも、制がん
作用および制がん増強作用を発揮しない。前記一般式（
Ｉ） 中、制がん作用および制がん増強作用がとくに強
いものは、ｎの値が９〜１４、Ｒ がメチル基あるいは
エチル基のばあいである。なかでも、式（ＩＩ）：EXAMPLES In the present invention, the chain length of the alkyl chain of the higher fatty acid is such that n in the general formula (I) is an integer of 4 to 22, and R is an alkyl group having 1 to 5 carbon atoms. When n is smaller than 4 or larger than 22, anticancer effect and anticancer enhancing effect are not exhibited. Also R
When is an alkyl group having 6 or more carbon atoms, it does not exhibit anticancer effect or anticancer enhancing effect. The general formula (
I) Among these, those with particularly strong anticancer action and anticancer enhancing action are those in which the value of n is 9 to 14 and R is a methyl group or an ethyl group. Among them, formula (II):
【００１０】0010
【化１３】[Chemical formula 13]
【００１１】で示される１２− メチルトリデシル酸、
式（ＩＩＩ） ：12-methyltridecylic acid represented by
Formula (III):
【００１２】0012
【化１４】[Chemical formula 14]
【００１３】で示される１２− メチルテトラデシル酸
、式（ＩＶ）：12-methyltetradecylic acid represented by formula (IV):
【００１４】[0014]
【化１５】[Chemical formula 15]
【００１５】で示される１４− メチルペンタデシル酸
、および式（Ｖ）：14-methylpentadecyl acid represented by the formula (V):
【００１６】[0016]
【化１６】[Chemical formula 16]
【００１７】で示される１４− メチルヘキサデシル酸
はとくに高い制がん作用および制がん増強作用を示し、
とくに好ましい。14-Methylhexadecyl acid represented by
Particularly preferred.
【００１８】本発明に用いる高級脂肪酸はワックスのよ
うな天然物を分解してえられる。用いる天然物としては
、羊毛ロウ、鯨ロウ、ミツロウ、虫白ロウ、カルナウバ
ロウなどのワックスがあげられる。The higher fatty acids used in the present invention can be obtained by decomposing natural products such as wax. The natural products used include waxes such as wool wax, spermaceti wax, beeswax, insect white wax, and carnauba wax.
【００１９】本発明に用いる高級脂肪酸は、たとえば以
下の方法によってうることができる。The higher fatty acids used in the present invention can be obtained, for example, by the following method.
【００２０】（鹸化反応）たとえば、ウールグリースの
ような天然物を１．１８倍モルのアルカリ（たとえばＮ
ａＯＨ）存在下水中で懸濁物とし、１３５ ±５℃で加
圧下で３時間撹拌しながら鹸化反応を行なう（オートク
レーブ使用）。(Saponification reaction) For example, a natural product such as wool grease is mixed with 1.18 times the mole of alkali (for example, N
The suspension was made into a suspension in water in the presence of (aOH), and the saponification reaction was carried out at 135 ± 5°C with stirring for 3 hours under pressure (using an autoclave).
【００２１】（脂肪酸とアルコールの分離）鹸化反応終
了物（高級脂肪酸のＮａ塩と高級アルコールの混合物）
に Ｈ２ Ｏ とＣＨ３ ＣＯＣ２ Ｈ５ （以下
、ＭＥＫ という）を加え、分液漏斗に移し、７０〜７
５℃に加熱してアルコールをＭＥＫ 中に抽出分離除去
する。水層の高級脂肪酸ナトリウム塩を塩酸で遊離の脂
肪酸とし、ＭＥＫ で抽出する。ウール脂肪酸のＭＥＫ
溶液を減圧下で溶媒を除去して固形物としてのウール
脂肪酸をうる。(Separation of fatty acid and alcohol) Saponification reaction completed product (mixture of higher fatty acid Na salt and higher alcohol)
Add H2O and CH3COC2H5 (hereinafter referred to as MEK), transfer to a separatory funnel, and add 70 to 7
The alcohol is extracted and separated off in MEK by heating to 5°C. The higher fatty acid sodium salt in the aqueous layer is converted into free fatty acids with hydrochloric acid and extracted with MEK. MEK of wool fatty acids
The solvent is removed from the solution under reduced pressure to obtain the wool fatty acid as a solid.
【００２２】（ウール脂肪酸の分子蒸留）固形ウール脂
肪酸を分子蒸留し低沸点留分（温度：＜８０℃、圧力：
１×１０−２Ｔｏｒｒ）をうる。この留分をＭＤ１−Ａ
ｃｉｄとする。(Molecular distillation of wool fatty acids) Solid wool fatty acids are subjected to molecular distillation to obtain a low boiling point fraction (temperature: <80°C, pressure:
1 x 10-2 Torr). This fraction was converted into MD1-A
Let it be cid.
【００２３】（ＭＤ１−Ａｃｉｄの逆相カラムクロマト
グラフィーによる分画）ＭＤ１−Ａｃｉｄの逆相カラム
クロマトグラフィー（オープンカラム）で５分画する。(Fractionation of MD1-Acid by reverse phase column chromatography) MD1-Acid is fractionated into 5 fractions by reverse phase column chromatography (open column).
【００２４】最初から３番目と４番目に溶出した画分を
それぞれＭＤ１−３−Ａｃｉｄ、ＭＤ１−４−Ａｃｉｄ
とする。The third and fourth eluted fractions from the beginning were treated as MD1-3-Acid and MD1-4-Acid, respectively.
shall be.
【００２５】これら２つの画分をそれぞれ高速液体クロ
マトグラフィー（ＨＰＬＣ）で分画し、ＭＤ１−３−Ａ
ｃｉｄより、たとえば１２− メチルトリデシル酸、１
２− メチルテトラデシル酸、ＭＤ１−４−Ａｃｉｄよ
り、たとえば１４− メチルペンタデシル酸、１４−
メチルヘキサデシル酸などの目的化合物を単離する。These two fractions were separated by high performance liquid chromatography (HPLC), and MD1-3-A
From cid, for example, 12-methyltridecylic acid, 1
From 2-methyltetradecylic acid, MD1-4-Acid, for example, 14-methylpentadecylic acid, 14-
The target compound, such as methylhexadecyl acid, is isolated.
【００２６】分画条件
充填剤：オクチル基修飾シリカゲル、破砕状、細孔径６
０オングストローム、粒径６０／２００ メッシュ（商
品名：ＹＭＣ ・ＧＥＬ 、山村化学研究所（株）製）
溶離液：ＣＨ３ ＯＨ／ Ｈ２ Ｏ ＝９２／８（容量
比）そのほか、このようにしてえられる高級脂肪酸とし
ては、たとえばＲ がメチル基であるとき、イソ−Ｃ１
０−ＣＯＯＨ （９−メチルデシル酸）、イソ−Ｃ１１
−ＣＯＯＨ （１０− メチルウンデシル酸）、イソ−
Ｃ１２−ＣＯＯＨ （１１− メチルドデシル酸）、イ
ソ−Ｃ１４−ＣＯＯＨ （１３− メチルテトラデシル
酸）、イソ−Ｃ１５−ＣＯＯＨ （１４− メチルペン
タデシル酸）などがあげられ、また、Ｒ がエチル基で
あるとき、イソ−Ｃ１２−ＣＯＯＨ （１０− メチル
ドデシル酸）、イソ−Ｃ１３−ＣＯＯＨ （１１− メ
チルトリデシル酸）、イソ−Ｃ１５−ＣＯＯＨ （１３
− メチルペンタデシル酸）、イソ−Ｃ１７−ＣＯＯＨ
（１５−メチルヘプタデシル酸）などがあげられる。Fractionation conditions Packing agent: Octyl group-modified silica gel, crushed form, pore size 6
0 angstrom, particle size 60/200 mesh (product name: YMC/GEL, manufactured by Yamamura Kagaku Kenkyusho Co., Ltd.)
Eluent: CH3 OH/H2 O = 92/8 (volume ratio) In addition, higher fatty acids obtained in this way include, for example, when R is a methyl group, iso-C1
0-COOH (9-methyldecylic acid), iso-C11
-COOH (10-methylundecylic acid), iso-
Examples include C12-COOH (11-methyldodecyl acid), iso-C14-COOH (13-methyltetradecyl acid), and iso-C15-COOH (14-methylpentadecyl acid), and when R is an ethyl group, Sometimes, iso-C12-COOH (10-methyldodecylate), iso-C13-COOH (11-methyltridecylate), iso-C15-COOH (13
- Methylpentadecyl acid), iso-C17-COOH
(15-methylheptadecyl acid) and the like.
【００２７】これらの高級脂肪酸は単独または２種以上
混合して使用してもよい。These higher fatty acids may be used alone or in combination of two or more.
【００２８】本発明の制がん剤および制がん増強剤を注
射、点滴用製剤とするにはプルロニックＦ−６８（商品
名、旭電化工業（株）製）、ＨＣＯ−６０（商品名、日
光ケミカルズ（株）製）などの界面活性剤を添加し、超
音波で分散させるか、リポソームまたは水中油乳液とし
、ｐ−ヒドロキシ安息香酸メチルなどの防腐剤、レシチ
ン、リノール酸などの安定剤、ココナツ油などの非水性
ビヒクル、グルコースなどの懸濁剤を含ませることがで
きる。[0028] To prepare the anticancer agent and anticancer enhancer of the present invention for injection or infusion, Pluronic F-68 (trade name, manufactured by Asahi Denka Kogyo Co., Ltd.), HCO-60 (trade name, By adding a surfactant such as Nikko Chemicals Co., Ltd., and dispersing it using ultrasound, or making it into a liposome or oil-in-water emulsion, preservatives such as methyl p-hydroxybenzoate, stabilizers such as lecithin and linoleic acid, A non-aqueous vehicle such as coconut oil, a suspending agent such as glucose may be included.
【００２９】また、経口用製剤とするには腸管吸収に適
したカプセルとして、ゼラチンのような結合剤、ステア
リン酸マグネシウムのような安定剤、乳糖のような賦形
剤、ポテトスターチのような崩壊剤を含ませ、酢酸フタ
ル酸セルロース、アクリル酸メチル／メタクリル酸共重
合体などで腸溶性皮膜を形成することができる。その他
、顆粒剤、徐放性埋没カプセル、坐剤、ネブライザー、
バッカル剤としても製剤化できる。[0029] In addition, in order to prepare an oral preparation, a capsule suitable for intestinal absorption may be added, including a binder such as gelatin, a stabilizer such as magnesium stearate, an excipient such as lactose, and a disintegrating agent such as potato starch. An enteric coating can be formed using cellulose acetate phthalate, methyl acrylate/methacrylic acid copolymer, or the like. Others include granules, sustained-release implantable capsules, suppositories, nebulizers,
It can also be formulated as a buccal agent.
【００３０】本発明の制がん剤は、静脈内、皮下注射、
点滴などの非経口投与剤では、有効成分の投与量（成人
の体重１ｋｇ、１日あたり）１０〜２０００ｍｇ、とく
に５０〜６００ｍｇ が好ましく、カプセルなどの経口
投与剤では、０．２ 〜７０ｇ 、とくに１〜１５ｇ
が好ましい。制がん増強剤として用いるばあいは、非経
口投与剤として１．００〜２００ｍｇ 、好ましくは３
〜５０ｍｇ、経口投与剤としては０．０５〜８０ｇ 、
好ましくは０．１ 〜３．０ｇである。[0030] The anticancer agent of the present invention can be administered intravenously, subcutaneously,
For parenterally administered drugs such as infusions, the dosage of the active ingredient (per kg of adult body weight, per day) is preferably 10 to 2000 mg, especially 50 to 600 mg, and for orally administered drugs such as capsules, it is preferably 0.2 to 70 g, especially 1-15g
is preferred. When used as an anticancer enhancer, the dose is 1.00 to 200 mg, preferably 3 mg as a parenteral drug.
~50mg, 0.05-80g for oral administration,
Preferably it is 0.1 to 3.0 g.
【００３１】本発明の制がん剤および制がん増強剤は、
腹水がんや、白血病だけでなく固形がんにも有効であり
、各組織の腺がん、扁平上皮がん、未分化がん、肉腫な
ど広範囲の適応症を有する。また、がん移植動物だけで
なく、ヒト、マウス、ラット、ハムスターなどの培養悪
性細胞に対しても有効なので、直接的がん細胞致死効果
を有し、種特異性もなく、医薬や家畜および動物のがん
化学療法剤として使用できる。[0031] The anticancer agent and anticancer enhancer of the present invention are:
It is effective not only for ascites cancer and leukemia, but also for solid tumors, and has a wide range of indications including adenocarcinoma, squamous cell carcinoma, undifferentiated carcinoma, and sarcoma of various tissues. In addition, it is effective not only against cancer-transplanted animals but also against cultured malignant cells of humans, mice, rats, hamsters, etc., so it has a direct cancer cell-killing effect and is not species-specific. It can be used as a cancer chemotherapeutic agent in animals.
【００３２】なお、制がん増強剤としては、たとえば、
ブレオマイシン、アドリアマイシン、ビンクリスチンな
どの制がん剤と併用して使用することができる。[0032] The anticancer enhancer includes, for example,
It can be used in combination with anticancer drugs such as bleomycin, adriamycin, and vincristine.
【００３３】さらに本発明の制がん剤および制がん増強
剤は、腫瘍移植部位への直接投与だけでなく、遠隔投与
でも治療効果が認められる。毒性ＬＤ５０はラット皮下
注射で８．０ 〜２５ ｇ／ｋｇであり、１〜２ｇ ／
ｋｇの１０日間連続投与でも副作用は認められない。Furthermore, the anticancer agent and anticancer enhancer of the present invention exhibit therapeutic effects not only when administered directly to the site of tumor implantation, but also when administered remotely. Toxicity LD50 is 8.0 to 25 g/kg by subcutaneous injection in rats, and 1 to 2 g/kg.
No side effects were observed even after continuous administration of 10 kg of the drug for 10 days.
【００３４】以下に製造例および試験例をあげて本発明
の制がん剤および制がん増強剤の有効成分である高級脂
肪酸の製造法および有効性を説明するが、本発明はかか
る実施例のみに限定されるものではない。[0034] The production method and effectiveness of higher fatty acids, which are the active ingredients of the anticancer agent and anticancer enhancer of the present invention, will be explained below with reference to production examples and test examples. It is not limited to only.
【００３５】製造実施例１
ウールグリースを鹸化反応することによってえたウール
脂肪酸２００ｇを分子蒸留し、低沸点留分ＭＤ１−Ａｃ
ｉｄ（温度：＜８０℃、圧力：１×１０−２Ｔｏｒｒ）
２６ｇ をえた。Production Example 1 200 g of wool fatty acid obtained by saponifying wool grease was subjected to molecular distillation to obtain a low boiling point fraction MD1-Ac.
id (temperature: <80°C, pressure: 1 x 10-2 Torr)
I got 26g.
【００３６】ＭＤ１−Ａｃｉｄを逆相カラムクロマトグ
ラフィー（オープンカラム）に付し、移動相ＣＨ３ Ｏ
Ｈ／ Ｈ２ Ｏ ：９２／８（容量比）で５分画した。MD1-Acid was subjected to reverse phase column chromatography (open column), and the mobile phase was CH3O.
It was fractionated into 5 fractions with H/H2O:92/8 (volume ratio).
【００３７】このうち、３番めと４番めに溶出した画分
をそれぞれＭＤ１−３−Ａｃｉｄ、ＭＤ１−４−Ａｃｉ
ｄとする。Among these, the third and fourth eluted fractions were respectively treated as MD1-3-Acid and MD1-4-Aci.
Let it be d.
【００３８】これらＭＤ１−３−Ａｃｉｄ、ＭＤ１−４
−Ａｃｉｄを高速液体クロマトグラフィー（ＨＰＬＣ）
で分画し、目的化合物を単離した。These MD1-3-Acid, MD1-4
-Acid by high performance liquid chromatography (HPLC)
The target compound was isolated.
【００３９】ＭＤ１−３−Ａｃｉｄより、たとえば１２
− メチルトリデシル酸、１２− メチルテトラデシル
酸、ＭＤ１−４−Ａｃｉｄより、たとえば１４− メチ
ルペンタデシル酸、１４− メチルヘキサデシル酸をえ
た。From MD1-3-Acid, for example 12
- From methyltridecylic acid, 12-methyltetradecylic acid, and MD1-4-Acid, for example, 14-methylpentadecylic acid and 14-methylhexadecylic acid were obtained.
【００４０】そして、キャピラリーガスクロマトグラフ
ィーで各々の高級脂肪酸が明らかに単離されていること
を確認した。It was confirmed by capillary gas chromatography that each higher fatty acid was clearly isolated.
【００４１】構造決定には、１３Ｃ−ＮＭＲ およびＧ
Ｃ−ＭＳ を使用し、単離物質が本発明の一般式で示さ
れる高級脂肪酸群であることを同定した。For structure determination, 13C-NMR and G
Using C-MS, the isolated substance was identified as a group of higher fatty acids represented by the general formula of the present invention.
【００４２】試験例１
５週令のｄｄＹ 系マウスの腹腔にエールリッヒ腹水が
ん細胞１０６個を接種し、２４時間後より０．２５％（
重量％、以下同様）プルロニックＦ６８ 生理食塩水溶
液に各試料を５０ｍｇ／ｍｌの濃度に懸濁した液を１群
１０匹、１０ｍｇ／ｋｇ／日で５日間腹腔内注射した。Test Example 1 106 Ehrlich ascites cancer cells were inoculated into the peritoneal cavity of a 5-week-old ddY mouse, and 24 hours later, 0.25% (
Pluronic F68 A suspension of each sample in physiological saline solution at a concentration of 50 mg/ml was intraperitoneally injected to 10 animals per group at a dose of 10 mg/kg/day for 5 days.
【００４３】試料を含まない同液を投与した対照群は接
種後平均生存日数１４．０日であるのに対して、１２−
メチルトリデシル酸の投与群は５０日以上、１４−
メチルペンタデシル酸は４３日であり、これらの等量混
合物は４５日以上であり、有意の延命効果が認められた
。[0043] The control group administered the same solution without the sample had an average survival period of 14.0 days after inoculation, whereas
The methyltridecylic acid administration group was administered for 50 days or more, 14-
Methylpentadecyl acid lasted for 43 days, and a mixture of these equivalents lasted for more than 45 days, indicating a significant survival effect.
【００４４】試験例２
Ｃ５７ＢＬ／６ とＤＢＡ／２ 系の一代雑種の６週令
マウスの背部皮下にアデノカルシノーマ７５５ 細胞１
０６ 個を移植し、２４時間後より０．２５％ＨＣＯ−
６０生理食塩水溶液に各試料を５０ｍｇ／ｍｌの濃度に
懸濁した液を１群８匹、１０ｍｇ／ｋｇ／日で５日間皮
下注射した。アデノカルシノーマ７５５ 細胞移植後１
０日に、マウスを屠殺し、腫瘍を切取した。Test Example 2 One adenocarcinoma 755 cell was placed subcutaneously on the back of a 6-week-old mouse of a first-generation hybrid between C57BL/6 and DBA/2.
06 cells were transplanted, and 24 hours later, 0.25% HCO-
A suspension of each sample in 60% physiological saline solution at a concentration of 50 mg/ml was subcutaneously injected to 8 animals per group at a dose of 10 mg/kg/day for 5 days. Adenocarcinoma 755 cell transplantation 1
On day 0, mice were sacrificed and tumors were excised.
【００４５】平均腫瘍重量（ｇ ）は、対照群の６．３
に対して１２− メチルテトラデシル酸および１４−
メチルヘキサデシル酸投与群はそれぞれ２．５ およ
び３．１ であり、有意の腫瘍抑制効果が認められた。The average tumor weight (g) was 6.3 in the control group.
12-methyltetradecylic acid and 14-
The methylhexadecyl acid administration group had 2.5 and 3.1, respectively, indicating a significant tumor suppressive effect.
【００４６】試験例３および４ならびに比較試験例１ブ
レオマイシンを単独で用いたばあいおよびブレオマイシ
ンと１２− メチルテトラデシル酸または１４− メチ
ルヘキサデシル酸を併用したばあいについて、マウス腹
水がんエールリッヒ細胞およびヒト肺がん種Ａ５４９細
胞を用いて殺細胞効果（ＩＣ９０）を調べた。その結果
を表１に示す。Test Examples 3 and 4 and Comparative Test Example 1 When bleomycin was used alone and when bleomycin was used in combination with 12-methyltetradecylic acid or 14-methylhexadecyl acid, Ehrlich cells with ascites cancer in mice were tested. And the cell killing effect (IC90) was investigated using human lung cancer type A549 cells. The results are shown in Table 1.
【００４７】[0047]
【表１】[Table 1]
【００４８】表１に示した結果から明らかなように、本
発明の高級脂肪酸を制がん剤と併用したばあいには、制
がん剤を単独使用したばあいと比して格段に殺細胞効果
が向上することがわかる。[0048] As is clear from the results shown in Table 1, when the higher fatty acids of the present invention are used in combination with an anticancer drug, the cancer killing is significantly greater than when the anticancer drug is used alone. It can be seen that the cell effect is improved.
【００４９】試験例５および比較試験例２ブレオマイシ
ン（６０μｇ ／ｍｌ）と１０− メチルウンデシル酸
（０．０５μＭ）を併用したばあいについて、ブレオマ
イシンがエールリッヒ細胞内に取り込まれる量を経時的
に調べた。その結果を表２に示す。Test Example 5 and Comparative Test Example 2 When bleomycin (60 μg/ml) and 10-methylundecylic acid (0.05 μM) were used together, the amount of bleomycin taken into Ehrlich cells was investigated over time. Ta. The results are shown in Table 2.
【００５０】[0050]
【表２】[Table 2]
【００５１】表２に示した結果から明らかなように、本
発明の高級脂肪酸を制がん剤と併用したばあいには、制
がん剤を単独使用したばあいと比して制がん剤のエール
リッヒ細胞内への取り込み量が短時間で増大することが
わかる。As is clear from the results shown in Table 2, when the higher fatty acids of the present invention are used in combination with an anticancer drug, the anticancer effect is greater than when the anticancer drug is used alone. It can be seen that the amount of drug taken into Ehrlich cells increases in a short period of time.
【００５２】製剤例（代表的な剤型における配合比）
制がん剤（ブレオマイシンなど） ０
．００５ 〜１００ ｍｇ／ｋｇ
（成人の体重１ｋｇ、１日当り） 制がん増強
剤（本発明の高級脂肪酸） １．００〜２００ｍ
ｇ ／ｋｇ
（成人の体重１
ｋｇ、１日当り） 賦形剤（乳糖、結晶セルロースな
ど） １０〜９９．８％（ｗ／ｗ ） 滑沢剤
（ステアリン酸マグネシウムなど） ０〜５０％（ｗ／
ｗ ）Formulation example (compounding ratio in typical dosage forms)
Anticancer drugs (bleomycin, etc.) 0
．． 005 ~100 mg/kg
(Adult weight 1 kg, per day) Anticancer enhancer (higher fatty acid of the present invention) 1.00-200 m
g/kg
(Adult weight 1
kg, per day) Excipients (lactose, crystalline cellulose, etc.) 10-99.8% (w/w) Lubricants (magnesium stearate, etc.) 0-50% (w/w)
w)
【００５３】[0053]
【発明の効果】本発明の制がん剤および制がん増強剤は
、すぐれた制がん効果および制がん増強効果を示し、し
かもその有効成分は生体（高等動物）由来であり、生体
に重篤な副作用を示さないものである。Effects of the Invention The anticancer agent and anticancer enhancer of the present invention exhibit excellent anticancer effects and anticancer enhancing effects, and their active ingredients are derived from living organisms (higher animals). The drug does not show any serious side effects.
Claims (12)
４〜２２の整数を表わす）で示される高級脂肪酸を有効
成分とする制がん剤。Claim 1: General formula (I): [Formula 1] (wherein, R represents an alkyl group having 1 to 5 carbon atoms, and n represents an integer of 4 to 22) as an active ingredient. An anticancer drug.
メチル基またはエチル基、およびｎが９〜１４の整数で
ある請求項１記載の制がん剤。2. The anticancer agent according to claim 1, wherein in the general formula (I), R is a methyl group or an ethyl group, and n is an integer of 9 to 14.
記載の制がん剤。[Claim 3] Claim 1, wherein the active ingredient is 12-methyltridecylic acid represented by formula (II): [Claim 2]
Anticancer drugs listed.
】 で示される１２− メチルテトラデシル酸である請求項
１記載の制がん剤。[Claim 4] The active ingredient has the formula (III):
The anticancer agent according to claim 1, which is 12-methyltetradecylic acid represented by the following formula.
１記載の制がん剤。5. The anticancer agent according to claim 1, wherein the active ingredient is 14-methylpentadecyl acid represented by formula (IV):
１記載の制がん剤。6. The anticancer agent according to claim 1, wherein the active ingredient is 14-methylhexadecyl acid represented by formula (V): [Claim 6]
４〜２２の整数を表わす）で示される高級脂肪酸を有効
成分とする制がん増強剤。7. General formula (I): [Chemical formula 6] (wherein, R represents an alkyl group having 1 to 5 carbon atoms, and n represents an integer of 4 to 22) as an active ingredient. An anticancer enhancer.
メチル基またはエチル基、およびｎが９〜１４の整数で
ある請求項７記載の制がん増強剤。8. The anticancer enhancer according to claim 7, wherein in the general formula (I), R is a methyl group or an ethyl group, and n is an integer of 9 to 14.
記載の制がん増強剤。[Claim 9] Claim 7 wherein the active ingredient is 12-methyltridecylic acid represented by formula (II): [Claim 7]
The anticancer enhancer mentioned above.
８】 で示される１２− メチルテトラデシル酸である請求項
７記載の制がん増強剤。10. The anticancer enhancer according to claim 7, wherein the active ingredient is 12-methyltetradecylic acid represented by formula (III): [Image Omitted]
７記載の制がん増強剤。11. The anticancer enhancer according to claim 7, wherein the active ingredient is 14-methylpentadecyl acid represented by formula (IV): [Image Omitted]
７記載の制がん増強剤。12. The anticancer enhancer according to claim 7, wherein the active ingredient is 14-methylhexadecyl acid represented by formula (V): [Claim 10]
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3061884A JPH0772134B2 (en) | 1991-03-26 | 1991-03-26 | Anti-cancer agent and anti-cancer enhancer |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3061884A JPH0772134B2 (en) | 1991-03-26 | 1991-03-26 | Anti-cancer agent and anti-cancer enhancer |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH04295423A true JPH04295423A (en) | 1992-10-20 |
| JPH0772134B2 JPH0772134B2 (en) | 1995-08-02 |
Family
ID=13184021
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP3061884A Expired - Fee Related JPH0772134B2 (en) | 1991-03-26 | 1991-03-26 | Anti-cancer agent and anti-cancer enhancer |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0772134B2 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998030532A1 (en) * | 1997-01-14 | 1998-07-16 | Croda International Plc | Woolgrease |
| US7976830B2 (en) | 2000-03-29 | 2011-07-12 | Croda, Inc. | Fatty quat based on ante-iso compounds |
Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS58213716A (en) * | 1982-06-05 | 1983-12-12 | Junichi Iwamura | Carcisnostatic agent |
| JPS6067425A (en) * | 1983-09-22 | 1985-04-17 | Nisshin Flour Milling Co Ltd | Carcinostatic agent |
| JPS6212716A (en) * | 1985-07-11 | 1987-01-21 | Nippon Oil & Fats Co Ltd | Carcinostatic agent |
| JPS62265222A (en) * | 1986-02-14 | 1987-11-18 | ナギ− アドリ− ハビブ | Cell membrane lipid structure and function modification and pharmaceutical composition therefor |
| JPS63154626A (en) * | 1986-12-17 | 1988-06-27 | Harumi Okuyama | Fat and oils composition for suppressing metastasis of tumor cell |
| JPS63258816A (en) * | 1987-04-16 | 1988-10-26 | Nippon Oil & Fats Co Ltd | Anticancer agent composition |
| JPS63303925A (en) * | 1987-06-05 | 1988-12-12 | Nippon Oil & Fats Co Ltd | Anticancer agent composition |
| JPH01153629A (en) * | 1987-12-11 | 1989-06-15 | Nippon Oil & Fats Co Ltd | Anticancer agent |
| JPH02300139A (en) * | 1989-03-01 | 1990-12-12 | Roberto L Ceriani | Method for enhancing cancer treatment by dosing unsaturated fatty acid |
-
1991
- 1991-03-26 JP JP3061884A patent/JPH0772134B2/en not_active Expired - Fee Related
Patent Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS58213716A (en) * | 1982-06-05 | 1983-12-12 | Junichi Iwamura | Carcisnostatic agent |
| JPS6067425A (en) * | 1983-09-22 | 1985-04-17 | Nisshin Flour Milling Co Ltd | Carcinostatic agent |
| JPS6212716A (en) * | 1985-07-11 | 1987-01-21 | Nippon Oil & Fats Co Ltd | Carcinostatic agent |
| JPS62265222A (en) * | 1986-02-14 | 1987-11-18 | ナギ− アドリ− ハビブ | Cell membrane lipid structure and function modification and pharmaceutical composition therefor |
| JPS63154626A (en) * | 1986-12-17 | 1988-06-27 | Harumi Okuyama | Fat and oils composition for suppressing metastasis of tumor cell |
| JPS63258816A (en) * | 1987-04-16 | 1988-10-26 | Nippon Oil & Fats Co Ltd | Anticancer agent composition |
| JPS63303925A (en) * | 1987-06-05 | 1988-12-12 | Nippon Oil & Fats Co Ltd | Anticancer agent composition |
| JPH01153629A (en) * | 1987-12-11 | 1989-06-15 | Nippon Oil & Fats Co Ltd | Anticancer agent |
| JPH02300139A (en) * | 1989-03-01 | 1990-12-12 | Roberto L Ceriani | Method for enhancing cancer treatment by dosing unsaturated fatty acid |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998030532A1 (en) * | 1997-01-14 | 1998-07-16 | Croda International Plc | Woolgrease |
| US7976830B2 (en) | 2000-03-29 | 2011-07-12 | Croda, Inc. | Fatty quat based on ante-iso compounds |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0772134B2 (en) | 1995-08-02 |
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