JPH03133926A - Metastasis inhibitor - Google Patents
Metastasis inhibitorInfo
- Publication number
- JPH03133926A JPH03133926A JP27343089A JP27343089A JPH03133926A JP H03133926 A JPH03133926 A JP H03133926A JP 27343089 A JP27343089 A JP 27343089A JP 27343089 A JP27343089 A JP 27343089A JP H03133926 A JPH03133926 A JP H03133926A
- Authority
- JP
- Japan
- Prior art keywords
- glucaro
- lactone
- dilactone
- cancer
- metastasis
- 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.)
- Pending
Links
- 239000002257 antimetastatic agent Substances 0.000 title claims description 7
- XECPAIJNBXCOBO-MMPJQOAZSA-N D-glucaro-1,4-lactone Chemical compound OC(=O)[C@@H](O)[C@H]1OC(=O)[C@H](O)[C@H]1O XECPAIJNBXCOBO-MMPJQOAZSA-N 0.000 claims abstract description 11
- 238000001727 in vivo Methods 0.000 claims abstract description 6
- DSLZVSRJTYRBFB-LLEIAEIESA-N D-glucaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O DSLZVSRJTYRBFB-LLEIAEIESA-N 0.000 claims abstract description 4
- XECPAIJNBXCOBO-HTVIOJJOSA-N (2s)-2-[(2s,3r,4s)-3,4-dihydroxy-5-oxooxolan-2-yl]-2-hydroxyacetic acid Chemical compound OC(=O)[C@@H](O)[C@H]1OC(=O)[C@@H](O)[C@H]1O XECPAIJNBXCOBO-HTVIOJJOSA-N 0.000 claims abstract description 3
- 206010028980 Neoplasm Diseases 0.000 claims description 23
- 201000011510 cancer Diseases 0.000 claims description 22
- 206010027476 Metastases Diseases 0.000 abstract description 11
- 230000009401 metastasis Effects 0.000 abstract description 11
- 230000001394 metastastic effect Effects 0.000 abstract description 9
- 206010061289 metastatic neoplasm Diseases 0.000 abstract description 9
- 150000001875 compounds Chemical class 0.000 abstract description 8
- 230000000694 effects Effects 0.000 abstract description 6
- 230000002401 inhibitory effect Effects 0.000 abstract description 4
- 239000004480 active ingredient Substances 0.000 abstract description 3
- 238000001959 radiotherapy Methods 0.000 abstract description 3
- 238000002560 therapeutic procedure Methods 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 239000003112 inhibitor Substances 0.000 abstract 3
- 239000003795 chemical substances by application Substances 0.000 abstract 1
- 230000002708 enhancing effect Effects 0.000 abstract 1
- 231100001083 no cytotoxicity Toxicity 0.000 abstract 1
- -1 D-glucaro-1,4-lactone (D-glucaro-1,4-lactone) Chemical compound 0.000 description 11
- 239000003814 drug Substances 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 150000003839 salts Chemical class 0.000 description 5
- 210000004072 lung Anatomy 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 102000004142 Trypsin Human genes 0.000 description 2
- 108090000631 Trypsin Proteins 0.000 description 2
- 239000003708 ampul Substances 0.000 description 2
- 230000002001 anti-metastasis Effects 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- 239000003855 balanced salt solution Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 201000001441 melanoma Diseases 0.000 description 2
- 239000012457 nonaqueous media Substances 0.000 description 2
- 229920001592 potato starch Polymers 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000003760 tallow Substances 0.000 description 2
- 238000011282 treatment Methods 0.000 description 2
- 239000012588 trypsin Substances 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- 244000215068 Acacia senegal Species 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 241000581650 Ivesia Species 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 229940009456 adriamycin Drugs 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 230000022534 cell killing Effects 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- UDGSVBYJWHOHNN-UHFFFAOYSA-N n',n'-diethylethane-1,2-diamine Chemical compound CCN(CC)CCN UDGSVBYJWHOHNN-UHFFFAOYSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 125000005633 phthalidyl group Chemical group 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 230000000384 rearing effect Effects 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Furan Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明は、癌細胞の転移巣形成を顕著に阻害するＤ−グ
ルカ０−１．４−ラクトン（Ｄ −ｇｌｕｃａｒｏ −
１、４−１ａｃｔｏｎｅ）＋ Ｄ−グルカロ−３，６−
ラクトン（Ｄ−ｇｌｕｃａｒｏ −Ｌ ６−１ａｃｔｏ
ｎｅ）及びＤ−グルカリ、り酸（Ｄ −ｇｌｕｃａｒｉ
ｃ ａｃｉｄ）及び生体内でこれらを生成するＤ−グル
カロ−１，４，３，６−ジラクトン（Ｄ−ｇｌｕｃａｒ
ｏ −１，４，３，６−ｄｉｌａｃｔｏｎｅ）及びその
２．５−ジアシル体である２、５−ジアシル−Ｄ−グル
カロ−１、４，３，６−ジラクトン（２，５−ｄｉａｃ
ｙｌ −Ｄ −ｇｌｕｃａｒ。Detailed Description of the Invention [Field of Industrial Application] The present invention provides D-glucaro-1,4-lactone (D-glucaro-1,4-lactone), which significantly inhibits the formation of metastatic foci of cancer cells.
1,4-1actone)+D-glucaro-3,6-
Lactone (D-glucaro-L 6-1acto
ne) and D-glucari, phosphoric acid (D-glucari
c acid) and D-glucaro-1,4,3,6-dilactone (D-glucar), which is produced in vivo.
-1,4,3,6-dilactone) and its 2,5-diacyl form, 2,5-diacyl-D-glucaro-1,4,3,6-dilactone (2,5-diac
yl-D-glucar.
Ｌ ４＋ Ｌ ６ ｄ＋ １ａｃｔｏｎｅ）を含有す
る癌（癌細胞）転移抑制剤に関するものである。The present invention relates to a cancer (cancer cell) metastasis inhibitor containing L 4+ L 6 d+ 1actone).
従来の制癌剤は、悪性細胞を、物質の有する殺細胞性或
いは人の免疫系を介して死滅させる薬剤が主体である。Conventional anticancer drugs are mainly drugs that kill malignant cells through the cell-killing properties of substances or via the human immune system.
これらの薬剤は癌の治療に対して未だ充分なものとは言
えない。また、固型底に関しては外科手術による治療や
放射線療法が行われ、原発癌の除去という点では成功率
も大幅に向上している。しかし、これらの処置を施した
癌患者の予後を左右する最も大きな要因が癌の転移であ
る。These drugs are still not sufficient for the treatment of cancer. In addition, surgical treatment and radiation therapy are used to treat solid soles, and the success rate in terms of removing the primary cancer has greatly improved. However, the most important factor influencing the prognosis of cancer patients treated with these treatments is cancer metastasis.
従ってこれら現行の種々の療法の有効性は癌細胞の転移
を抑制することで、更に高められる事が期待されている
が、抗転移を作用の主体とする物質は少なく、臨床で用
いられているものは少なく、又効果も不充分である。Therefore, it is expected that the effectiveness of these current various therapies will be further enhanced by suppressing the metastasis of cancer cells, but there are few substances whose main action is anti-metastasis, and they are not used clinically. There are only a few, and the effects are insufficient.
本発明者らは先に７ジリマインン及びその誘導体が癌細
胞の転移を顕著に抑制することを見出し、これを有効成
分とする癌細胞転移抑制剤を、特願昭６３−３１０９５
号、同６３−９３６７３号、同６３−９７４５４号、同
６３−１０４８５０号、同６：（−１４７８１５号及び
同８３−１４７８１６号として出願した。The present inventors have previously discovered that 7-jirimaine and its derivatives significantly suppress metastasis of cancer cells, and have proposed a cancer cell metastasis inhibitor containing this as an active ingredient in Japanese Patent Application No. 63-31095.
No. 63-93673, No. 63-97454, No. 63-104850, No. 6:(-147815 and No. 83-147816).
本発明は更に別の系統の化合物の癌細胞転移抑制物質並
びにこれを含有する癌細胞転移抑制剤を提供することを
目的とするものである。Another object of the present invention is to provide another type of compound that suppresses cancer cell metastasis and a cancer cell metastasis inhibitor containing the same.
本発明はＤ−グルカロ−１，４−ラクトン（式１）、Ｄ
−グルカロ−３，６−ラクトン（式２）及びＤ−グルカ
リック酸（式３）及び生体内でこれらを生成するＤ−グ
ルカロ−１，４，３，６−ジラクトン（式４）及びその
２，５−ジアシル体である２、５−ジアシル−Ｄ−グル
カロ−１，４，３，６−ジラクトン（一般式５）を含有
する癌細胞転移抑制剤である。なお、本発明には式１〜
５で示した構造式で表わされる化合物以外にその互変異
性体も含まれる。また、これらの化合物の薬理上許容さ
れる塩類、エステル類も本発明に含まれる。The present invention provides D-glucaro-1,4-lactone (formula 1), D-glucaro-1,4-lactone (formula 1),
- Glucaro-3,6-lactone (Formula 2) and D-glucaric acid (Formula 3), and D-glucaro-1,4,3,6-dilactone (Formula 4) that produces these in vivo, and its 2, This is a cancer cell metastasis inhibitor containing 2,5-diacyl-D-glucaro-1,4,3,6-dilactone (general formula 5), which is a 5-diacyl compound. Note that the present invention includes formulas 1 to
In addition to the compound represented by the structural formula 5, tautomers thereof are also included. The present invention also includes pharmacologically acceptable salts and esters of these compounds.
このような塩類の例としてはアンモニウム塩、ナトリウ
ム、カリウム等のアルカリ金属塩、マグネシウム、カル
シウム等のアルカリ土類金属塩、トリエチルアミン、ト
リエタノールアミン、ジエチルアミノエチルアミン等の
有機塩基との塩、ピペリジン、ピペラジン、モルホリン
のようなヘテロ環アミンとの塩乃至はりジン等のアミノ
酸との塩などがあげられる。また、このようなエステル
の例としてはアセトキシメチル基、１〜アセトキシエチ
ル基、ピバロイルオキシメチル基、１−（エトキシカル
ボニルオキシ）エチル基、フタリジル基、（５−メチル
−２−オキソ−１，３−ジオキソレン−４−イル）メチ
ル基などの生体内で加水分解されるエステル基があげら
れる。Examples of such salts include ammonium salts, alkali metal salts such as sodium and potassium, alkaline earth metal salts such as magnesium and calcium, salts with organic bases such as triethylamine, triethanolamine and diethylaminoethylamine, piperidine and piperazine. , salts with heterocyclic amines such as morpholine, and salts with amino acids such as rigine. Examples of such esters include acetoxymethyl group, 1-acetoxyethyl group, pivaloyloxymethyl group, 1-(ethoxycarbonyloxy)ethyl group, phthalidyl group, (5-methyl-2-oxo-1 , 3-dioxolen-4-yl) methyl group, which are hydrolyzed in vivo.
なお、Ｄ−グルカロ−１，４−ラクトン及び２，５−ジ
アセチル−Ｄ−グルカロ−１，４，３，６−ジラクトン
は膀胱癌発癌抑制作用を示すことが知られている（Ｅ、
Ｂｏｙｌａｎｄ、 ｅｔ、 ａｌ、著 １ｎｖｅｓｔ
ｉｇａｔｉｖｅ Ｉｌｒｏｌｏｇｙ２、４３９〜４４５
．１９６５年；伊藤信行等著 癌の臨床１６、 ９９５
〜１００１．１９７０年）。しかしながら本発明に示し
たような癌転移抑制作用そのものについては知られてい
ない。癌転移の実験評価系は、その後Ｆｉｄｌｅｒ（Ｍ
ｅｔｈｏｄ ｉｎ Ｃａｎｃｅｒ Ｒｅ５ｅａｒｃｈ、
１５．３９９〜４３９．１９７８年）、キジマースダ
等（Ｃａｎｃｅｒ Ｒｅ５ｅａｒｃｈ、 ４６．８５８
〜８６２． １９８６年）によって構築され、今回初め
て本発明者らにより、これらの系を用いて癌転移抑制作
用が明らかにされた。In addition, D-glucaro-1,4-lactone and 2,5-diacetyl-D-glucaro-1,4,3,6-dilactone are known to exhibit bladder cancer carcinogenesis inhibitory effects (E,
Boyland, et al, 1nvest
Igative Irology 2, 439-445
．． 1965; Nobuyuki Ito et al. Cancer Clinic 16, 995
~1001.1970). However, the cancer metastasis suppressing effect itself as shown in the present invention is not known. The experimental evaluation system for cancer metastasis was subsequently developed by Fiddler (M
method in Cancer Research,
15.399-439.1978), Kijimasuda et al. (Cancer Research, 46.858
~862. (1986), and the present inventors have now revealed for the first time the cancer metastasis suppressive effect using these systems.
本発明の癌細胞転移抑制剤は経口、非経口製剤として臨
床的に静脈、動脈、皮膚、皮下、皮肉、直腸及び筋肉内
を経由、又は経口にて投与される。The cancer cell metastasis inhibitor of the present invention is clinically administered as an oral or parenteral preparation via the vein, artery, skin, subcutaneous route, dermatology, rectum, intramuscular route, or orally.
また肺癌に直接投与することにより、より強い効果が期
待できる。投与量は投与形態、剤型或いは患者の年令、
体重、病態により異なるか、概ね１日１００〜３０００
ｍｇを１回又は数回投与する。Moreover, stronger effects can be expected by direct administration to lung cancer. The dosage depends on the dosage form, dosage form, or age of the patient.
It varies depending on body weight and medical condition, but approximately 100 to 3000 per day
mg in one or several doses.
非経口製剤としては無菌の水性又は非水性溶液剤、或い
は乳濁剤があげられる。非水性の溶液剤又は乳濁剤の基
剤としてはプロピレングリコール、ポリエチレングリコ
ール、グリセリン、オリーフ浦、とうもろこし油、オレ
イン酸エチル等があげられる。また、経口製剤としては
カプセル剤、錠剤、顆粒剤、細粒剤、散剤等があげられ
る。これらの製剤には、賦形剤として澱粉、乳糖、マン
ニット、エチルセルロース、ナトリウムカルボキシメチ
ルセルロース等が配合され、滑沢剤としてステアリン酸
マグネシウム又はステアリン酸カルシウムを添加する。Parenteral preparations include sterile aqueous or non-aqueous solutions and emulsions. Examples of the base for non-aqueous solutions or emulsions include propylene glycol, polyethylene glycol, glycerin, olive oil, corn oil, and ethyl oleate. Oral preparations include capsules, tablets, granules, fine granules, powders, and the like. These preparations contain starch, lactose, mannitol, ethyl cellulose, sodium carboxymethyl cellulose, etc. as excipients, and magnesium stearate or calcium stearate is added as a lubricant.
結合剤としてはゼラチン、アラビアゴム、セルロースエ
ステル、ポリビニルピロリドン等が用いられる。As the binder, gelatin, gum arabic, cellulose ester, polyvinylpyrrolidone, etc. are used.
なお、本発明の有効成分であるＤ−グルカロ１．４−ラ
クトンのマウスでの急性毒性（ＬＤｓｏ値）は、腹腔内
投与で１ ｇ／ｋｇ以上であった。The acute toxicity (LDso value) of D-glucaro-1,4-lactone, which is the active ingredient of the present invention, in mice was 1 g/kg or more when administered intraperitoneally.
次に本発明の製剤例並びに効果について説明する。 Next, formulation examples and effects of the present invention will be explained.
実施例Ｉ
Ｄ−グルカロ−１，４，３，６−ジラクトン ６０ｍｇ
乳 糖
１３０ｍｇジャガイモデンプン ７
０ｍｇポリビニルピロリドン １０ｍ
ｇステアリン酸マグネシウム ２．５ｍｇＤ
−グルカロ−１，４，３，８−ジラクトン、乳糖及びジ
ャガイモデンプンを混合し、これにポリビニルピロリド
ンの２０％エタノール溶液を加え均一に湿潤させ、１ｍ
ｍの網目の篩を通し、４５°Ｃにて乾燥させ、再度１ｍ
ｍの網目の篩を通した。こうして得た顆粒をステアリン
酸マグネシウムと混和し錠剤に成型した。Example I D-glucaro-1,4,3,6-dilactone 60 mg
lactose
130mg potato starch 7
0mg polyvinylpyrrolidone 10m
gMagnesium stearate 2.5mgD
-Glucaro-1,4,3,8-dilactone, lactose, and potato starch were mixed, and a 20% ethanol solution of polyvinylpyrrolidone was added to the mixture to evenly moisten the mixture.
Pass through a 1 m mesh sieve, dry at 45°C, and 1 m mesh again.
It was passed through a sieve with a mesh size of m. The granules thus obtained were mixed with magnesium stearate and formed into tablets.
実施例２
Ｄ−グルカロ−１，４−ラクトンを５０ｍｇ／ｍＱの濃
度になるように注射用蒸留水に溶解し、ｌアンフル当た
り５ｍ１２ずつを無菌的に分注し、アンプルを封入した
。Example 2 D-glucaro-1,4-lactone was dissolved in distilled water for injection to a concentration of 50 mg/mQ, and 5 ml per ampule was aseptically dispensed, and the ampules were sealed.
効果試験
試験法
マウスの腫瘍であるメラノーマＢｌａ株よりフイドラ−
（Ｆｉｄｌｅｒ）の方法（Ｍｅｔｈｏｄ ｉｎ Ｃａｎ
ｃｅｒ Ｒｅ５ｅａｒｃｈ、 １５．３９９〜４３９．
１９７８）を基にして８１６高転移株を選択し使用した
。Efficacy test test method From melanoma Bla strain, which is a mouse tumor,
(Fiddler) Method in Can
cer Research, 15.399-439.
816 highly metastatic strain was selected and used based on 1978).
転移抑制作用の評価はキジマースダ（Ｋｉｊｉｍａ３ｕ
ｄａ）らの方法（Ｃａｎｃｅｒ Ｒｅ５ｅａｒｃｈ、
４Ｌ８５ｇ〜８６２１９８６）を基にして行った。The metastasis inhibitory effect was evaluated using Kijimasuda (Kijima3u).
da) et al.'s method (Cancer Research,
4L85g~8621986).
先ずＢｌａ高転移株を牛胎児血清を加えたダルベコ培地
に植え、本発明による化合物を加え、２〜４日間５％Ｃ
Ｏ，の存在下３７°Ｃで培養し、増殖しｔ：細胞をトリ
プシンとＥＤＴＡ溶液で培養容器より剥がした。この細
胞を平衡塩類溶液で生細胞として１ｍ１２当り１ｘｌＯ
６細胞になるように懸濁した。First, a Bla highly metastatic strain was planted in Dulbecco's medium supplemented with fetal bovine serum, a compound according to the present invention was added, and the cells were incubated at 5% C for 2 to 4 days.
The cells were grown by culturing at 37°C in the presence of O, and then detached from the culture vessel using a trypsin and EDTA solution. The cells were treated as living cells in a balanced salt solution at 1xlO per 1 m2.
The cells were suspended to a total of 6 cells.
この懸濁液の０．１ｍｆｆをマウス尾静脈より移植し、
１４日間飼育した後、開胸して肺を摘出して肺表面及び
内部に形成された８１６高転移株の結節を計数し、薬剤
処理をしなかった対照と比較した。0.1 mff of this suspension was transplanted from the mouse tail vein.
After being reared for 14 days, the lungs were removed through thoracotomy, and the nodules of the 816 highly metastatic strain formed on and inside the lungs were counted and compared with a control that was not treated with the drug.
試験例Ｉ
Ｄ−グルカロ−１，４−ラクトンの細胞障害性８１６高
転移株をｌＯ％牛脂児血清を加えたダルベコ培地で５％
ＣＯ９の存在下３７°Ｃで培養した後、トリプシンとＥ
ＤＴＡ溶液で細胞を培養容器より剥がし、１ｍ１２当た
りＢｌ＆高転移株はｌＸｌ０’細胞になるように上記培
地に懸濁した。Test Example I D-glucaro-1,4-lactone cytotoxic 816 highly metastatic strain was grown at 5% in Dulbecco's medium supplemented with 10% tallow serum.
After incubation at 37°C in the presence of CO9, trypsin and E
The cells were detached from the culture vessel with a DTA solution, and suspended in the above medium so that the Bl&high metastasis strain became 1X10' cells per 1 ml.
マウスの腫瘍であるメラノーマＢｌＳ株よりフイドラ−
（Ｆｉｄｌｅｒ）の方法（Ｍｅｔｈｏｄ ｉｎ Ｃａｎ
ｃｅｒ Ｐｅ５ｅａｒｃｈ、 １５．３９９〜４３９．
１９７８）を基にしてＢｌＳ高転移株を選択し使用した
。Fiddler from the mouse tumor melanoma BIS strain.
(Fiddler) Method in Can
cer Pe5arch, 15.399-439.
1978), a BIS highly metastatic strain was selected and used.
転移抑制作用の評価はキジマースタ（Ｋｉｊｉｍａｓｕ
ｄａ）らの方法（Ｃａｎｃｅｒ Ｒｅ５ｅａｒｃｈ、
４６，８５８〜８６２゜１９８６）を基にして行った。The metastasis inhibitory effect was evaluated using Kijimasu
da) et al.'s method (Cancer Research,
46,858-862°1986).
この懸濁液の１５０μｅをＤ−グルカロ−１，４−ラク
トン或いはアドリアマイシン（対照）溶液５０μＱにそ
れぞれ加え混合した。これを３日間培養し、倒立顕微鏡
下で生死を判定し、細胞障害性を判定した。その結果は
表１の通りであった。150 .mu.e of this suspension was added to 50 .mu.Q of D-glucaro-1,4-lactone or adriamycin (control) solution and mixed. This was cultured for 3 days, and the viability was determined under an inverted microscope to determine cytotoxicity. The results were as shown in Table 1.
表 １ 表中 ＋は生育 −は死滅を示す。Table 1 In the table, + means growth - indicates death.
試験例２
Ｄ−グルカロ−１，４−ラクトンの抗転移作用Ｂ１６高
転移株をｌＯ％牛脂児血清を加えたダルベコ培地に植え
、Ｄ−グルカロ−１，４−ラクトンを１ｍ＋！当たり１
００μｇ加え、５％Ｃｏｔの存在下３７℃で３日間培養
した。試験例１と同様の方法で細胞を培養容器より剥が
し、１ｍｆｆ当たり生細胞がｌＸ１０６細胞になるよう
平衡塩類溶液に懸濁し、その０．１−をＢＤＦ 、マウ
ス（６週令、雄）の尾静脈に投与して移植した。■４日
間飼育観察後、開胸して肺を摘出し、肺表面及び内部に
形成されたＢｌＳ高転移株の結節を計数した。その結果
を表２に示した。Test Example 2 Anti-metastatic effect of D-glucaro-1,4-lactone B16 highly metastatic strain was planted in Dulbecco's medium supplemented with 10% tallow serum, and 1 m+ of D-glucaro-1,4-lactone was added. 1 hit
00 μg was added and cultured at 37° C. for 3 days in the presence of 5% Cot. Cells were detached from the culture vessel in the same manner as in Test Example 1, suspended in a balanced salt solution so that the number of viable cells was 1×106 cells per mff, and 0.1- of the cells were added to BDF and the tail of a mouse (6 weeks old, male). It was administered intravenously and transplanted. (2) After 4 days of rearing and observation, the lungs were removed through thoracotomy, and the nodules of the BIS highly metastatic strain formed on and inside the lungs were counted. The results are shown in Table 2.
表 ２
に少ない薬剤である。従って、既存の制癌剤と同時に投
与して、また、外科手術療法或いは放射線療法時に使用
することで制癌効果を著しく高め得ることができる極め
て有用な薬剤である。Table 2 shows the number of drugs. Therefore, it is an extremely useful drug that can significantly enhance the anticancer effect when administered simultaneously with existing anticancer drugs or when used during surgical therapy or radiotherapy.
Claims (1)
−３，６−ラクトン、Ｄ−グルカリック酸及び生体内で
これらを生成するＤ−グルカロ−１，４，３，６−ジラ
クトン及び２，５−ジアシル−Ｄ−グルカロ−１，４，
３，６−ジラクトンを含有する癌（癌細胞）転移抑制剤(1) D-glucaro-1,4-lactone, D-glucaro-3,6-lactone, D-glucaric acid, and D-glucaro-1,4,3,6-dilactone and 2 which produce these in vivo ,5-diacyl-D-glucaro-1,4,
Cancer (cancer cell) metastasis inhibitor containing 3,6-dilactone
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP27343089A JPH03133926A (en) | 1989-10-20 | 1989-10-20 | Metastasis inhibitor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP27343089A JPH03133926A (en) | 1989-10-20 | 1989-10-20 | Metastasis inhibitor |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH03133926A true JPH03133926A (en) | 1991-06-07 |
Family
ID=17527796
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP27343089A Pending JPH03133926A (en) | 1989-10-20 | 1989-10-20 | Metastasis inhibitor |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH03133926A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113181173A (en) * | 2021-03-30 | 2021-07-30 | 嘉兴学院 | Medicinal composition and application thereof in preparing products for preventing and/or treating liver cancer |
-
1989
- 1989-10-20 JP JP27343089A patent/JPH03133926A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113181173A (en) * | 2021-03-30 | 2021-07-30 | 嘉兴学院 | Medicinal composition and application thereof in preparing products for preventing and/or treating liver cancer |
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