JPS6312445B2 - - Google Patents
Info
- Publication number
- JPS6312445B2 JPS6312445B2 JP56157925A JP15792581A JPS6312445B2 JP S6312445 B2 JPS6312445 B2 JP S6312445B2 JP 56157925 A JP56157925 A JP 56157925A JP 15792581 A JP15792581 A JP 15792581A JP S6312445 B2 JPS6312445 B2 JP S6312445B2
- Authority
- JP
- Japan
- Prior art keywords
- gypenosides
- gypenoside
- active
- glc
- cells
- 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.)
- Expired
Links
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- 239000002246 antineoplastic agent Substances 0.000 claims description 6
- 239000004480 active ingredient Substances 0.000 claims description 5
- 210000000988 bone and bone Anatomy 0.000 claims description 4
- OORMXZNMRWBSTK-UHFFFAOYSA-N dammaran Natural products C1CCC(C)(C)C2CCC3(C)C4(C)CCC(C(C)CCCC(C)C)C4CCC3C21C OORMXZNMRWBSTK-UHFFFAOYSA-N 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims 1
- 229930187479 gypenoside Natural products 0.000 description 46
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
- FBFMBWCLBGQEBU-RXMALORBSA-N (2s,3r,4s,5s,6r)-2-[(2r,3r,4s,5s,6r)-2-[[(3s,5r,6s,8r,9r,10r,12r,13r,14r,17s)-3,12-dihydroxy-4,4,8,10,14-pentamethyl-17-[(2s)-6-methyl-2-[(2s,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyhept-5-en-2-yl]-2,3,5,6,7,9,11,12,13,15,16,17-dodecah Chemical class O([C@@](C)(CCC=C(C)C)[C@@H]1[C@@H]2[C@@]([C@@]3(C[C@@H]([C@H]4C(C)(C)[C@@H](O)CC[C@]4(C)[C@H]3C[C@H]2O)O[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)C)(C)CC1)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O FBFMBWCLBGQEBU-RXMALORBSA-N 0.000 description 27
- 210000004027 cell Anatomy 0.000 description 26
- ZRBFCAALKKNCJG-UHFFFAOYSA-N gypenoside-XVII Natural products C1CC(C2(CCC3C(C)(C)C(OC4C(C(O)C(O)C(CO)O4)O)CCC3(C)C2CC2O)C)(C)C2C1C(C)(CCC=C(C)C)OC(C(C(O)C1O)O)OC1COC1OC(CO)C(O)C(O)C1O ZRBFCAALKKNCJG-UHFFFAOYSA-N 0.000 description 19
- 239000000203 mixture Substances 0.000 description 17
- 239000000284 extract Substances 0.000 description 16
- 230000000694 effects Effects 0.000 description 14
- 206010028980 Neoplasm Diseases 0.000 description 9
- 240000006509 Gynostemma pentaphyllum Species 0.000 description 8
- 150000001721 carbon Chemical group 0.000 description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- 201000011510 cancer Diseases 0.000 description 7
- 239000002775 capsule Substances 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 241000196324 Embryophyta Species 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 239000002504 physiological saline solution Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 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 5
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 5
- 208000002495 Uterine Neoplasms Diseases 0.000 description 5
- 239000008101 lactose Substances 0.000 description 5
- 201000007270 liver cancer Diseases 0.000 description 5
- 208000014018 liver neoplasm Diseases 0.000 description 5
- 201000005202 lung cancer Diseases 0.000 description 5
- 208000020816 lung neoplasm Diseases 0.000 description 5
- 206010046766 uterine cancer Diseases 0.000 description 5
- 206010003445 Ascites Diseases 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 4
- 230000001093 anti-cancer Effects 0.000 description 4
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 description 4
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- 229930182490 saponin Natural products 0.000 description 4
- 150000007949 saponins Chemical class 0.000 description 4
- 235000017709 saponins Nutrition 0.000 description 4
- 210000002966 serum Anatomy 0.000 description 4
- 230000004083 survival effect Effects 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- SRBFZHDQGSBBOR-IOVATXLUSA-N D-xylopyranose Chemical group O[C@@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-IOVATXLUSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- OORMXZNMRWBSTK-LGFJJATJSA-N dammarane Chemical group C1CCC(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@H]([C@H](C)CCCC(C)C)[C@H]4CC[C@@H]3[C@]21C OORMXZNMRWBSTK-LGFJJATJSA-N 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000001397 quillaja saponaria molina bark Substances 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- NHBKXEKEPDILRR-UHFFFAOYSA-N 2,3-bis(butanoylsulfanyl)propyl butanoate Chemical compound CCCC(=O)OCC(SC(=O)CCC)CSC(=O)CCC NHBKXEKEPDILRR-UHFFFAOYSA-N 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- YERVVNJJSVYXJR-UHFFFAOYSA-N Gypenoside XXII Natural products C1CC(C2(C)C(C3(CCC(C(C)(C)C3CC2)OC2C(C(O)C(O)C(CO)O2)OC2C(C(O)C(O)C(CO)O2)O)CO)CC2)(C)C2C1C(CCC=C(C)C)OC(C(C(O)C1O)O)OC1COC1OCC(O)C(O)C1O YERVVNJJSVYXJR-UHFFFAOYSA-N 0.000 description 2
- 241001316290 Gypsophila Species 0.000 description 2
- 239000012981 Hank's balanced salt solution Substances 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 208000000453 Skin Neoplasms Diseases 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 102000004142 Trypsin Human genes 0.000 description 2
- 108090000631 Trypsin Proteins 0.000 description 2
- YKTSYUJCYHOUJP-UHFFFAOYSA-N [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] Chemical compound [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] YKTSYUJCYHOUJP-UHFFFAOYSA-N 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 229940099112 cornstarch Drugs 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000012091 fetal bovine serum Substances 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 201000000849 skin cancer Diseases 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 239000012588 trypsin Substances 0.000 description 2
- RTBXOFMHEMBXKG-UHFFFAOYSA-N 2-methyl-1,2-dihydrobenzo[j]aceanthrylene Chemical compound C1=CC2=CC=CC=C2C2=C1C(CC(C1=CC=C3)C)=C1C3=C2 RTBXOFMHEMBXKG-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 229920001817 Agar Polymers 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
- 241000219104 Cucurbitaceae Species 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 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
- 108010010803 Gelatin Proteins 0.000 description 1
- 206010060891 General symptom Diseases 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- KHPWSKNLAFECBO-NSMVKXLTSA-N Gypenoside XXV Chemical compound C([C@](O)(CCC=C(C)C)[C@@H]1[C@@H]2[C@@]([C@@]3(C)[C@@H]([C@]4(CC[C@@H](C(C)(C)[C@@H]4CC3)O[C@H]3[C@@H]([C@@H](O)[C@@H](O)CO3)O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O3)O)C=O)CC2)(C)CC1)O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O KHPWSKNLAFECBO-NSMVKXLTSA-N 0.000 description 1
- IROUVKVGJYDVOC-UHFFFAOYSA-N Gypenoside XXVI Natural products C1CC(C2(C)C(C3(CCC(C(C)(C)C3CC2)OC2C(C(O)C(O)CO2)OC2C(C(O)C(O)C(CO)O2)O)C=O)CC2)(C)C2C1C(CCC=C(C)C)OC1OC(CO)C(O)C(O)C1O IROUVKVGJYDVOC-UHFFFAOYSA-N 0.000 description 1
- 239000004166 Lanolin Substances 0.000 description 1
- 206010061523 Lip and/or oral cavity cancer Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 208000003445 Mouth Neoplasms Diseases 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 239000004264 Petrolatum Substances 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 206010043515 Throat cancer Diseases 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- PYMYPHUHKUWMLA-WDCZJNDASA-N arabinose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)C=O PYMYPHUHKUWMLA-WDCZJNDASA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000012888 bovine serum Substances 0.000 description 1
- 239000002021 butanolic extract Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000012531 culture fluid Substances 0.000 description 1
- 210000004748 cultured cell Anatomy 0.000 description 1
- 231100000599 cytotoxic agent Toxicity 0.000 description 1
- 239000002619 cytotoxin Substances 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 235000021050 feed intake Nutrition 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- DOUGLYJWNNDEQP-UHFFFAOYSA-N gypenoside XXVIII Natural products CC(=CCCC(C)(O)C1CCC2(C)C1CCC3C2(C)CCC4C(C)(C)C(CCC34C=O)OC5OC(CO)C(O)C(O)C5OC6OC(CO)C(O)C(O)C6O)C DOUGLYJWNNDEQP-UHFFFAOYSA-N 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000037451 immune surveillance Effects 0.000 description 1
- 229960001438 immunostimulant agent Drugs 0.000 description 1
- 239000003022 immunostimulating agent Substances 0.000 description 1
- 230000003308 immunostimulating effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229940039717 lanolin Drugs 0.000 description 1
- 235000019388 lanolin Nutrition 0.000 description 1
- -1 liquid paraffin Substances 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- HCWCAKKEBCNQJP-UHFFFAOYSA-N magnesium orthosilicate Chemical compound [Mg+2].[Mg+2].[O-][Si]([O-])([O-])[O-] HCWCAKKEBCNQJP-UHFFFAOYSA-N 0.000 description 1
- 239000000391 magnesium silicate Substances 0.000 description 1
- 235000019792 magnesium silicate Nutrition 0.000 description 1
- 229910052919 magnesium silicate Inorganic materials 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 229940066842 petrolatum Drugs 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Plant Substances (AREA)
- Steroid Compounds (AREA)
Description
本発明は抗癌作用を有する医薬的製剤、更に詳
しくはダンマラン骨格の20位あるいは21位の炭素
原子に遊離の水酸基を有するギペノサイド類を有
効成分とする抗癌剤組成物に関する。
従来の抗癌剤は主として癌細胞を阻害するいわ
ゆる細胞毒と宿主の免疫監視機構に作用する免疫
促進物質に大別されている。しかし、前者は癌細
胞と正常細胞との間における毒性の差が少なく、
副作用が非常に強い欠点がある。後者において
は、副作用の少ない、作用の緩和なものも見出さ
れているが、未だ適格な効果を示すものは得られ
ていない。本発明者等は、副作用の少ないすぐれ
た抗癌剤を得る目的で種々検討を重ねた結果、ダ
ンマラン骨格の20位あるいは21位の炭素原子に遊
離の水酸基を有するギペノサイド類（アマチヤヅ
ルに含まれるサポニンの総称）にすぐれた抗癌作
用のあることを発見し、本発明を完成するに至つ
た。
即ち、本発明はダンマラン骨核の20位または21
位の炭素原子に遊離の水酸基を有するギペノサイ
ド類を有効成分とする抗癌剤、特に一般式：
〔式中、R1およびR4はそれぞれ独立してＨま
たは糖残基、R2はCH3、CHOまたはCH2OH、
R3はＨまたはOH、R5はCH3、CH2OHまたは
CH2O―糖残基、R6はＨまたはOH、波線（〓）
はα結合またはβ結合を表わす。ただし、(1)R4
がＨでない場合はR5はCH2OHを表わし、(2)R1が
糖残基、R2がCH3、R3がOH、R4がＨ、R6がＨ
の場合はR5はα―メチルではない。〕
で示されるギペノサイド類を有効成分として含
有する抗癌剤を提供するものである。
ダンマラン骨格の20位または21位の炭素原子に
遊離の水酸基を有するギペノサイド類（以下活性
ギペノサイド類ともいう）は、主として兵庫県に
産するアマチヤヅル（Gynostemma
pentaphyllum Makino、ウリ科
（Cucurbitaceae）植物）に多量含まれている。
活性ギペノサイド類は、上記植物の全草を、通常
のサポニン抽出法によつて抽出することにより得
ることができ、得られた全サポニンは適当な分離
法によつて個々のギペノサイドに分離することが
できる。アマチヤヅルは我国をはじめとして、朝
鮮、中国、台湾、インドなどの山野に広く分布す
る雑草であるが、我国に関する限り、そして本発
明者らの知る限り、兵庫県産以外のアマチヤヅル
には、ダンマラン骨核の20位または21位の炭素原
子に遊離の水酸基を有するギペノサイド類は少量
しか、あるいはほとんど含まれていない。
ダンマラン骨核の20位の炭素原子に遊離の水酸
基を持つ活性ギペノサイドの具体例としては、ギ
ペノサイドXXIII（R1＝−glc2−glc，R2＝
CH2OH，R3＝Ｈ，R4＝Ｈ，R5＝CH2Oglc，R6
＝Ｈ）、ギペノサイドXXIV（R1＝−glc2−glc，
R2＝CHO，R3＝Ｈ，R4＝Ｈ，R5＝CH2Oglc，
R6＝Ｈ）、ギペノサイドXXV（R1＝−ara2−glc，
R2＝CHO，R3＝Ｈ，R4＝Ｈ，R5＝CH2Oglc，
R6＝Ｈ）、ギペノサイドXXVII（R1＝−glc2−
glc，R2＝CH2OH，R3＝Ｈ，R4＝Ｈ，R5＝CH3，
R6＝Ｈ）、ギペノサイドXXVIII（R1＝−glc2−
glc，R2＝CHO，R3＝Ｈ，R4＝Ｈ，R5＝CH3，
R6＝Ｈ）、ギペノサイドXXIX（R1＝glc2−glc，
R2＝CHO，R3＝Ｈ，R4＝Ｈ，R5＝CH3，R6＝
Ｈ）等があり、また21位の炭素に遊離の水酸基を
持つ具体例としては、ギペノサイドXXII（R1＝
−glc2−glc，R2＝CH2OH，R3＝Ｈ，R4＝−glc2
−xyl，R5＝CH2OH，R6＝Ｈ）、ギペノサイド
XXVI（R1＝−ara2−glc，R2＝CHO，R3＝Ｈ，
R4＝−glc，R5＝CH2OH，R6＝Ｈ）等があげら
れる（但し、glc＝グルコース，ara＝アラビノー
ス，xyl＝キシロース）。
20位または21位の炭素原子に遊離の水酸基を有
するギペノサイド類は、後述する如く、癌細胞、
例えば肝癌、黒色腫瘍、子宮癌、肺癌等の細胞の
増殖を顕著に抑制する（第１図〜第４図参照）
が、正常細胞には何等の影響を与えず（第５図参
照）、治療薬としてはすぐれた特性を有するもの
である。また動物の腹水癌に対する投与実験で
は、対照群に対して明らかに延命効果を示す（第
６図参照）。
実際の治療に用いるには、前記の個々のギペノ
サイドを含む製剤を用いることも可能ではある
が、それらの混合物、あるいはそれらの混合物を
多量含有しているアマチヤヅルの抽出エキスを用
いる方がより経済的である。後者の場合は、前記
した理由で、兵庫県産のアマチヤヅルを用いなけ
ればならず、それ以外のアマチヤヅルを用いた場
合は、得られるエキスが後述の実施例１に示した
20位または21位の炭素原子に遊離の水酸基を持た
ないギペノサイド類、即ち非活性ギペノサイド類
を主成分とするため、その薬効をほとんど期待す
ることができない。兵庫県産アマチヤヅルの乾燥
全草には約１〜２％、その水性乾燥エキスには２
〜10％程度の活性ギペノサイドが含まれている。
この抽出エキスの高速液体クロマトグラムを第７
図に示した（図中の符号XXII〜XXIXはそれぞ
れ前記の活性ギペノサイドXXII〜XXIXを表わ
す。第１図〜第５図、第７図および第８図におい
ても同じ）。
アマチヤヅルは、且つて、アマチヤの代用とし
て、あるいは野菜としても用いられたこともあ
り、その毒性はきわめて低く、その乾燥エキスの
急性毒性をラツトを用いた実験結果では、10ｇ／
Kgを経口投与しても、何等の影響を示さず、
LD50の測定の限界を越えている。また腹腔内投
与においてもLD501.85ｇ／Kgときわめて低い毒性
を示した。また８ｇ／Kg／dayを１ケ月間連続経
口投与して、一般症状、体重、飼料摂取量、飲水
量、尿、血液、組織重量、病理学的所見等をしら
べたが、何等の異常も認められなかつた。
活性ギペノサイド類、あるいはそれらの混合物
を含有するアマチヤヅル水性エキスは、水溶性
で、かつ安定であるので、経口的あるいは非経口
的のいかんを問わず、種々の剤型に製剤化するこ
とが可能である。すなわち、錠剤、丸剤、カプセ
ル剤、散剤、顆粒剤、シロツプ剤、注射剤、軟膏
剤などの剤型をとることができる。これ等の製剤
を製造するには、有効成分を乳糖、ブドウ糖、デ
ンプン、庶糖、水飴、デキストリン、セルロース
類、カンテン、ステアリン酸マグネシウム、ケイ
酸マグネシウム、ケイ酸アルミニウム、タルク、
アラビアゴム、ゼラチン、トガラント、水、ベジ
タブルオイル、ポリアルキレングリコール、流動
パラフイン、ラノリン、ワセリン等の常用される
医薬的担体と混合し、適宜の剤形にすればよい。
必要に応じて、保存剤、安定化剤、乳化剤などを
使用することも考慮されてよい。本発明の抗癌剤
組成物の用量は、これを用いる患者の年令、疾病
の状態、あるいは体重等によつて左右されるが、
通常の成人に対して経口投与する場合、サポニン
換算量として、50〜500mgを１日に投与すればよ
い。また、腫瘍部位、筋肉内、腹腔内に同様の用
量を投与してもよい。適応範囲としては、皮膚
癌、子宮癌、肝癌、肺癌、胃癌、口喉癌、膵癌等
が挙げられる。
以下に本発明の実施例を挙げるが、本発明がこ
れらの実施例に限定されるものと解釈してはなら
ない。
実施例 １
ギペノサイド類の肝癌細胞に対する作用
試料（ギペノサイド類）の調製：兵庫県産の新
鮮なアマチヤヅルの全草1.3トンを大型抽出釜に
入れ、熱湯で抽出した。抽出液を減圧下で濃縮し
た後スプレードライヤーで乾燥し、乾燥エキス26
Kgを得た。
乾燥エキス500ｇを水1.5に溶解し、ｎ―ブタ
ノールで抽出し、抽出液を減圧下で濃縮し、ブタ
ノールエキス65ｇを得た。このエキスを80％メタ
ノール150mlに溶解し、クロマト用活性炭100ｇを
入れたカラムに吸着させ、80％メタノール７で
洗浄した後酢酸エチルとエタノールの混液（８：
２）10で溶出する画分を集め、溶媒を留去して
淡黄色の粉末としてギペノサイド混合物19.2ｇを
得た。この混合物の薄層クロマドグラム（シリカ
ゲルの厚さ：0.25mm、展開溶剤：クロロホルム／
メタノール／水（65／35／10）、発色：10％硫酸
発色、100℃で加熱）を第８図に示した。
上で得たギペノサイド混合物を同量のシリカゲ
ルと混合し、50倍量のシリカゲルカラムの上部に
置き、クロロホルム／メタノール／水（65：35：
10）混液で溶出し、薄層クロマトグラフイーで溶
出物をモニターしながら同一成分を含む画分を集
めることにより各成分に分離した。この操作を繰
り返し、ギペノサイド混合物20ｇからギペノサイ
ドXXIX（m.p.＝170〜172℃、〔α〕D（MeOH）＝
＋36.9）、XXVIII（m.p.＝181〜183℃、〔α〕D
（MeOH）＝＋26.1）、XXVII（m.p.＝165〜167℃、
〔α〕D（MeOH）＝＋10.8）、XXVI（m.p.＝212〜
213℃、〔α〕D（MeOH）＝＋21.5）、XXV（m.p.＝
165〜167℃、〔α〕D（MeOH）＝＋23.1）、XXIV
（m.p.＝180〜182℃、〔α〕D（MeOH）＝＋21.6）、
XXIII（m.p.＝182〜184℃、〔α〕D（MeOH）＝＋
4.6）およびXXII（m.p.＝192〜194℃、〔α〕D
（MeOH）＝＋4.4）をそれぞれ600mg、340mg、500
mg、300mg、1400mg、300mg、300mgおよび240mgの
収量で得た。
上記と同様の操作により、石川県産アマチヤヅ
ルから下記の表１に示すギペノサイド類（対照化
合物）を得た。
The present invention relates to a pharmaceutical preparation having an anticancer effect, and more particularly to an anticancer composition containing as an active ingredient a gypenoside having a free hydroxyl group at the 20th or 21st carbon atom of the dammarane skeleton. Conventional anticancer drugs are broadly classified into so-called cytotoxins, which mainly inhibit cancer cells, and immunostimulants, which act on the host's immune surveillance mechanism. However, the former has little difference in toxicity between cancer cells and normal cells;
The drawback is that it has very strong side effects. Among the latter, some have been found that have fewer side effects and have milder effects, but none have yet been found to exhibit adequate efficacy. As a result of various studies with the aim of obtaining an excellent anticancer drug with few side effects, the present inventors discovered that gypenosides (a general term for saponins contained in Jiaogulan) have a free hydroxyl group at the 20th or 21st carbon atom of the dammarane skeleton. ) has an excellent anticancer effect, leading to the completion of the present invention. That is, the present invention is directed to the 20th or 21st position of the Dammaran bone nucleus.
An anticancer agent containing a gypenoside as an active ingredient having a free hydroxyl group at the carbon atom, especially the general formula: [In the formula, R 1 and R 4 are each independently H or a sugar residue, R 2 is CH 3 , CHO or CH 2 OH,
R 3 is H or OH, R 5 is CH 3 , CH 2 OH or
CH 2 O - sugar residue, R 6 is H or OH, wavy line (〓)
represents an α bond or a β bond. However, (1) R 4
is not H, R 5 represents CH 2 OH, (2) R 1 is a sugar residue, R 2 is CH 3 , R 3 is OH, R 4 is H, R 6 is H
In this case, R 5 is not α-methyl. ] The present invention provides an anticancer agent containing the gypenosides shown below as an active ingredient. Gypenosides (hereinafter also referred to as active gypenosides), which have a free hydroxyl group at the 20th or 21st carbon atom of the dammarane skeleton, are mainly found in the Gynostema
Pentaphyllum Makino, a plant in the Cucurbitaceae family, contains large amounts.
Active gypenosides can be obtained by extracting the whole plant of the above plant using a conventional saponin extraction method, and the obtained total saponin can be separated into individual gypenosides using an appropriate separation method. can. Gypsophila is a weed that is widely distributed in the mountains and fields of Japan, Korea, China, Taiwan, India, etc. However, as far as Japan is concerned and as far as the present inventors know, Gypsophila that does not grow in Hyogo Prefecture does not have Dammaran bones. Gypenosides, which have a free hydroxyl group at the 20th or 21st carbon atom of the nucleus, are present in small amounts or almost exclusively. A specific example of an active gypenoside having a free hydroxyl group at the 20th carbon atom of the dammaran bone core is gypenoside XXIII (R 1 = -glc 2 -glc, R 2 =
CH 2 OH, R 3 = H, R 4 = H, R 5 = CH 2 Oglc, R 6
= H), gypenoside XXIV (R 1 = −glc 2 −glc,
R 2 = CHO, R 3 = H, R 4 = H, R 5 = CH 2 Oglc,
R 6 = H), gypenocide XXV (R 1 = −ara 2 −glc,
R 2 = CHO, R 3 = H, R 4 = H, R 5 = CH 2 Oglc,
R 6 = H), gypenoside XXVII (R 1 = −glc 2 −
glc, R 2 = CH 2 OH, R 3 = H, R 4 = H, R 5 = CH 3 ,
R 6 = H), gypenoside XXVIII (R 1 = −glc 2 −
glc, R 2 = CHO, R 3 = H, R 4 = H, R 5 = CH 3 ,
R 6 = H), gypenoside XXIX (R 1 = glc 2 −glc,
R 2 = CHO, R 3 = H, R 4 = H, R 5 = CH 3 , R 6 =
H), etc., and a specific example with a free hydroxyl group at carbon position 21 is gypenoside XXII (R 1 =
-glc 2 -glc, R 2 = CH 2 OH, R 3 = H, R 4 = -glc 2
-xyl, R 5 = CH 2 OH, R 6 = H), gypenoside
XXVI (R 1 = −ara 2 −glc, R 2 = CHO, R 3 = H,
R 4 = -glc, R 5 = CH 2 OH, R 6 = H), etc. (however, glc = glucose, ara = arabinose, xyl = xylose). Gypenosides having a free hydroxyl group on the carbon atom at the 20th or 21st position can cause cancer cells,
For example, it significantly suppresses the proliferation of cells such as liver cancer, melanoma, uterine cancer, and lung cancer (see Figures 1 to 4).
However, it has no effect on normal cells (see Figure 5) and has excellent properties as a therapeutic agent. Furthermore, in experiments on administration of the drug to ascites cancer in animals, it clearly showed a survival effect compared to the control group (see Figure 6). For actual treatment, it is possible to use preparations containing each of the individual gypenosides mentioned above, but it is more economical to use a mixture of them, or a Jiaogulan extract containing a large amount of the mixture. It is. In the latter case, for the reason mentioned above, it is necessary to use Gyododendron from Hyogo Prefecture, and if other Gynecology is used, the resulting extract will be the same as that shown in Example 1 below.
Since the main component is gypenosides that do not have a free hydroxyl group at the 20th or 21st carbon atom, that is, inactive gypenosides, little medicinal efficacy can be expected. The dried whole plant of Jiaogulan from Hyogo Prefecture contains about 1-2%, and its aqueous dry extract contains about 2%.
Contains ~10% active gypenoside.
The high-performance liquid chromatogram of this extract is shown in the seventh column.
(The symbols XXII to XXIX in the figure represent the active gypenosides XXII to XXIX, respectively. The same applies to FIGS. 1 to 5, FIG. 7, and FIG. 8). Jiaogulan was once used as a substitute for Amachia or as a vegetable, and its toxicity is extremely low.Acute toxicity of its dried extract was determined to be 10g/
Oral administration of Kg showed no effect;
The measurement limit of LD 50 is exceeded. Also, when administered intraperitoneally, it showed extremely low toxicity with an LD 50 of 1.85 g/Kg. In addition, 8g/Kg/day was orally administered continuously for one month, and general symptoms, body weight, feed intake, water intake, urine, blood, tissue weight, pathological findings, etc. were examined, but no abnormalities were found. I couldn't help it. The aqueous Jiaogulan extract containing active gypenosides or mixtures thereof is water-soluble and stable, so it can be formulated into various dosage forms for oral or parenteral administration. be. That is, it can take the form of tablets, pills, capsules, powders, granules, syrups, injections, ointments, and the like. To manufacture these preparations, active ingredients such as lactose, glucose, starch, sucrose, starch syrup, dextrin, celluloses, agar, magnesium stearate, magnesium silicate, aluminum silicate, talc,
It may be mixed with commonly used pharmaceutical carriers such as gum arabic, gelatin, togalant, water, vegetable oil, polyalkylene glycol, liquid paraffin, lanolin, petrolatum, etc., and prepared into an appropriate dosage form.
The use of preservatives, stabilizers, emulsifiers, etc. may also be considered, if necessary. The dose of the anticancer composition of the present invention depends on the age, disease state, body weight, etc. of the patient receiving it;
When orally administered to normal adults, 50 to 500 mg per day may be administered in terms of saponin. Similar doses may also be administered at the tumor site, intramuscularly, or intraperitoneally. The applicable range includes skin cancer, uterine cancer, liver cancer, lung cancer, stomach cancer, mouth and throat cancer, and pancreatic cancer. Examples of the present invention are listed below, but the present invention should not be construed as being limited to these Examples. Example 1 Effect of gypenosides on liver cancer cells Preparation of sample (gypenosides): 1.3 tons of fresh whole plants of Gypenosides from Hyogo Prefecture were placed in a large extraction pot and extracted with boiling water. After concentrating the extract under reduced pressure, it was dried with a spray dryer to obtain a dry extract of 26
Got Kg. 500 g of the dry extract was dissolved in 1.5 g of water, extracted with n-butanol, and the extract was concentrated under reduced pressure to obtain 65 g of butanol extract. This extract was dissolved in 150 ml of 80% methanol, adsorbed on a column containing 100 g of activated carbon for chromatography, washed with 80% methanol 7, and then mixed with ethyl acetate and ethanol (8:
2) The fractions eluted at 10 were collected and the solvent was distilled off to obtain 19.2 g of a gypenoside mixture as a pale yellow powder. Thin layer chromatogram of this mixture (silica gel thickness: 0.25 mm, developing solvent: chloroform/
Methanol/water (65/35/10), color development: 10% sulfuric acid color development, heating at 100°C) is shown in Figure 8. The gypenoside mixture obtained above was mixed with the same amount of silica gel, placed on top of a 50-fold volume silica gel column, and mixed with chloroform/methanol/water (65:35:
10) Elute with a mixed solution, monitor the eluate using thin layer chromatography, and collect fractions containing the same component to separate each component. Repeat this operation and add 20 g of gypenoside mixture to gypenoside XXIX (mp=170-172℃, [α] D (MeOH)=
+36.9), XXVIII (mp=181-183℃, [α] D
(MeOH) = +26.1), XXVII (mp = 165-167℃,
[α] D (MeOH) = +10.8), XXVI (mp = 212 ~
213℃, [α] D (MeOH) = +21.5), XXV (mp =
165-167℃, [α] D (MeOH) = +23.1), XXIV
(mp=180-182℃, [α] D (MeOH)=+21.6),
XXIII (mp=182-184℃, [α] D (MeOH)=+
4.6) and XXII (mp=192-194℃, [α] D
(MeOH) = +4.4) at 600 mg, 340 mg, and 500 mg, respectively.
Yields of mg, 300mg, 1400mg, 300mg, 300mg and 240mg were obtained. By the same operation as above, the gypenosides (control compounds) shown in Table 1 below were obtained from Jiaogulan from Ishikawa Prefecture.
【表】
これらの試料は下記の培養液に10μｇ／mlの濃
度となる様に溶解した。
培養液：培養液は、HAMの合成培地Ｆ―10お
よびＬ―15の３：１の混液に牛胎児血清を加えて
用いた。血清濃度は、培養細胞数が最大値の1/2
になるように予め検討し、濃度を設定した。
操作法：試料の培養液溶液4.5mlを径60mmの培
養皿に取り、これにモーリス肝癌細胞（MH1C1）
培養液懸濁液0.5ml（細胞数１×105個を含む）を
加え、５日間、37゜で、５％CO2―インキユベー
ターで培養し、培養液を吸引して除き、生理食塩
水で洗浄後、0.125％トリプシンHank′s溶液およ
び0.01％EDTA生理食塩水溶液の１：１の混合溶
液を剥離溶液として0.5mlを加え、培養皿に付着
した細胞を剥離し、更に9.5mlの生理食塩水を加
えて細胞を懸濁させ、コールターカウンターで細
胞数を測定した。
結果を第１図に示す。第１図から明らかな様
に、対照に用いた石川県産ギペノサイド類と比べ
て、活性ギペノサイド類XXII〜XXIXは、いづ
れも癌細胞の増殖を顕著に抑制した。
実施例１で得たギペノサイド類を用いて以下の
実験を行なつた。
実施例 ２
黒色腫瘍細胞に対する作用
黒色腫瘍細胞（B16）を用い、血清はPHM（15
％馬血清、2.5％牛新生児血清）を用いた。細胞
剥離液は、0.125％トリプシンHank′s溶液を用い
た。培養期間は、４日間とした。他は、実施例１
と同様に行なつた（第２図）。この場合も実施例
１と同様、顕著な抑制作用がみられた。なお、図
中MIXは、活性ギペノサイド混合物を表わす。
実施例 ３
子宮癌細胞に対する作用
子宮癌細胞（Hela S3）を用いるほかは、実施
例２と同様にして実験した。結果を第３図に示
す。
実施例 ４
肺癌細胞に対する作用
肺癌細胞（3LL）を用いた。血清は10％牛胎児
血清を用いた。他は実施例２と同様に行なつた
（第４図）。
実施例 ５
正常細胞に対する作用
Wister系ラツトの肝臓から単離した正常細胞
を用いた。他は実施例４と同様に行なつた（第５
図）。図から明らかな様に、活性ギペノサイドは
正常細胞には作用しない。
実施例 ６
腹水癌に対する作用
２―メチルコランスレンを用いて白色マウス
（BALB／Ｃ）に誘導した腫瘍の腹水懸濁液0.5ml
（１×106個の腫瘍細胞を含む）を白色マウス
（BALB／CSrCL、６週令、雄）の腹腔内に注入
し、翌日より隔日に試料（ギペノサイドXXVII）
の生理食塩水溶液（濃度：40mg／50mlまたは80
mg／50ml）0.5mlを腹腔内に注入し（投与量：20
mg／Kgおよび40mg／Kg）、マウスの生存日数を調
べた。対照群には生理食塩水を同様に注入した。
結果を第６図に示す。図中、１は対照群、２は20
mg／Kg投与群、３は40mg／Kg投与群を表わす。図
から明らかな様に、活性ギペノサイド投与群には
明らかな延命効果が認められた。
以下に本発明の抗癌剤の処方例を挙げる。
実施例 ７
ギペノサイドXXVII 20.0ｇ
乳 糖 49.6ｇ
微結晶セルロース 49.6ｇ
コーンスターチ 0.4ｇ
ステアリン酸マグネシウム 0.4ｇ
上記の薬剤の処方量をＶ型混合機でよく混合
し、JIS32メツシユ篩にて篩過後、打錠機にてス
ラツグ錠を製し、オツシレーターで粗砕、選粒し
て顆粒化する。当該顆粒120.0ｇを用い、常法に
従つて打錠し、裸錠400錠を製する。１錠（300
mg）当りギペノサイドXXVII50mgを含有する。
実施例 ８
ギペノサイドXXV 25.0ｇ
微結晶セルロース 37.5ｇ
コーンスターチ 18.5ｇ
重質ケイ酸アルミニウム 18.5ｇ
ステアリン酸マグネシウム 0.5ｇ
上記の薬剤の処方量をよく混合し、直接打錠機
により裸錠500錠を製する。１錠（200mg）当りギ
ペノサイドXXV50mgを含有する。
実施例 ９
実施例１で得た粉末ギペノサイド混合物
25.0ｇ
乳 糖 75.0ｇ
上記の薬剤の処方量をよく混合し、カプセル充
填機によりカプセル500個を製する。カプセル１
個当り、当該ギペノサイド混合物50mgを含有す
る。
実施例 10
主として活性ギペノサイドを含有する
アマチヤヅル乾燥エキス 50.0ｇ
乳 糖 25.0ｇ
上記の薬剤の処方量をよく混合し、カプセル充
填機によりカプセル250個を製する。カプセル１
個当り当該エキス200mgを含有する。
実施例 11
主として活性ギペノサイドを含有する
アマチヤヅル乾燥エキス 50.0ｇ
乳 糖 99.0ｇ
ステアリン酸マグネシウム 1.0ｇ
上記の薬剤の処方量をよく混合し、乾式顆粒機
により顆粒150ｇを製造する。顆粒３ｇ当り当該
エキス１ｇを含有する。
実施例 12
ギペノサイドXXVII 0.2ｇ
生理食塩水 全量10.0ml
ギペノサイドXXVIIを生理食塩水に溶解し、
ミリポアフイルターで過し、加熱滅菌して注射
剤とする。[Table] These samples were dissolved in the following culture solution to a concentration of 10 μg/ml. Culture solution: The culture solution was a 3:1 mixture of HAM's synthetic media F-10 and L-15 with fetal bovine serum added. Serum concentration is 1/2 of the maximum number of cultured cells.
The concentration was determined in advance by considering the following. Procedure: Take 4.5 ml of the sample culture solution into a culture dish with a diameter of 60 mm, and add Morris liver cancer cells (MH 1 C 1 ) to it.
Add 0.5 ml of culture suspension (containing 1 x 10 5 cells) and culture for 5 days at 37° in a 5% CO 2 -incubator, remove the culture fluid by suction, and add physiological saline. After washing with water, add 0.5 ml of a 1:1 mixed solution of 0.125% trypsin Hank's solution and 0.01% EDTA physiological saline solution as a detachment solution to detach the cells attached to the culture dish, and add 9.5 ml of physiological saline solution. Saline was added to suspend the cells, and the number of cells was measured using a Coulter counter. The results are shown in Figure 1. As is clear from FIG. 1, all of the active gypenosides XXII to XXIX significantly suppressed the proliferation of cancer cells, compared to the gypenosides produced in Ishikawa Prefecture used as a control. The following experiment was conducted using the gypenosides obtained in Example 1. Example 2 Effect on black tumor cells Black tumor cells (B16) were used, and the serum was PHM (15
% horse serum, 2.5% neonatal bovine serum). As the cell detachment solution, 0.125% trypsin Hank's solution was used. The culture period was 4 days. Others are Example 1
I did the same thing as (Figure 2). In this case as well, similar to Example 1, a significant inhibitory effect was observed. Note that MIX in the figure represents an active gypenoside mixture. Example 3 Effect on Uterine Cancer Cells Experiments were conducted in the same manner as in Example 2, except that uterine cancer cells (Hela S3) were used. The results are shown in Figure 3. Example 4 Effect on lung cancer cells Lung cancer cells (3LL) were used. The serum used was 10% fetal bovine serum. The rest was carried out in the same manner as in Example 2 (FIG. 4). Example 5 Effect on normal cells Normal cells isolated from the liver of Wistar rats were used. The rest was carried out in the same manner as in Example 4 (5th
figure). As is clear from the figure, active gypenosides do not act on normal cells. Example 6 Effect on ascites cancer 0.5 ml of ascites suspension of tumor induced in white mice (BALB/C) using 2-methylcholanthrene
(containing 1 × 10 6 tumor cells) was injected intraperitoneally into a white mouse (BALB/CSrCL, 6 weeks old, male), and samples (gypenocide XXVII) were injected every other day from the next day.
saline solution (concentration: 40 mg/50 ml or 80
mg/50ml) 0.5ml was injected intraperitoneally (dose: 20
mg/Kg and 40 mg/Kg), and the survival days of the mice were investigated. The control group was similarly injected with physiological saline.
The results are shown in Figure 6. In the figure, 1 is the control group, 2 is the 20
mg/Kg administration group, 3 represents the 40 mg/Kg administration group. As is clear from the figure, a clear survival effect was observed in the active gypenoside administration group. Prescription examples of the anticancer agent of the present invention are listed below. Example 7 Gypenocide XXVII 20.0g Lactose 49.6g Microcrystalline cellulose 49.6g Corn starch 0.4g Magnesium stearate 0.4g The prescribed amounts of the above drugs were thoroughly mixed in a V-type mixer, passed through a JIS32 mesh sieve, and then tableted. A slug tablet is made using a machine, then coarsely crushed using an oscillator, and then granulated by sorting. Using 120.0 g of the granules, tablet according to a conventional method to produce 400 plain tablets. 1 tablet (300
Contains 50 mg of gypenoside XXVII per mg). Example 8 Gypenocide XXV 25.0g Microcrystalline cellulose 37.5g Cornstarch 18.5g Heavy aluminum silicate 18.5g Magnesium stearate 0.5g The prescribed amounts of the above drugs are thoroughly mixed and 500 plain tablets are made using a direct tablet machine. . Contains 50mg of gypenoside XXV per tablet (200mg). Example 9 Powdered gypenoside mixture obtained in Example 1 25.0g Lactose 75.0g The prescribed amounts of the above drugs were thoroughly mixed and 500 capsules were manufactured using a capsule filling machine. capsule 1
Each container contains 50 mg of the gypenoside mixture. Example 10 Dry extract of Jiaogulan, mainly containing active gypenosides 50.0g Lactose 25.0g The prescribed amounts of the above drugs are mixed well and 250 capsules are made using a capsule filling machine. capsule 1
Each piece contains 200mg of the extract. Example 11 50.0 g of dry extract of Jiaogulan containing mainly active gypenosides, 99.0 g of lactose, 1.0 g of magnesium stearate, and the prescribed amounts of the above drugs are thoroughly mixed and 150 g of granules are produced using a dry granulator. Contains 1 g of the extract per 3 g of granules. Example 12 Gypenocide XXVII 0.2g Physiological saline Total volume 10.0ml Gypenocide XXVII was dissolved in physiological saline,
Pass through a Millipore filter and heat sterilize to make an injection.
第１図は活性ギペノサイド類およびその他の非
活性ギペノサイド類の肝癌細胞に対する作用を表
わすグラフ、第２図〜第５図は活性ギペノサイド
類のそれぞれ皮膚癌細胞、子宮癌細胞、肺癌細胞
および正常細胞に対する作用を表わすグラフ、第
６図はギペノサイドXXIIの、腹水癌マウスに対
する延命効果を表わすグラフ、第７図は兵庫県産
アマチヤヅルの抽出エキスの高速液体クロマトグ
ラム、第８図は活性ギペノサイド混合物の薄層ク
ロマトグラムである。
１…対照群、２…20mg／Kg投与群、３…40mg／
Kg投与群、MIX…活性ギペノサイド混合物。
Figure 1 is a graph showing the effects of active gypenosides and other inactive gypenosides on liver cancer cells, and Figures 2 to 5 are graphs showing the effects of active gypenosides on skin cancer cells, uterine cancer cells, lung cancer cells, and normal cells, respectively. Graph showing the action. Figure 6 is a graph showing the survival effect of gypenoside XXII on mice with ascites cancer. Figure 7 is a high-performance liquid chromatogram of extract of Gypenosides from Hyogo Prefecture. Figure 8 is a thin layer of active gypenoside mixture. This is a chromatogram. 1...Control group, 2...20mg/Kg administration group, 3...40mg/
Kg administration group, MIX...Active gypenoside mixture.
Claims (1)
たは21位の炭素原子に遊離の水酸基を有するギベ
ノサイド類を有効成分として含有する抗癌剤： ［式中、R1およびR4はそれぞれ独立してＨま
たは糖残基、R2はCH3、CHOまたはCH2OH、
R3はＨまたはOH、R5はCH3、CH2OHまたは
CH2O―糖残基、R6はＨまたはOH、波線（〓）
はα結合またはβ結合を表わす。ただし、(1)R4
がＨでない場合はR5はCH2OHを表わし、(2)R1が
糖残基、R2がCH3、R3がOH、R4がＨ、R6がＨ
の場合はR5はα―メチルではない。］。[Claims] 1. An anticancer agent containing as an active ingredient a gibenocide having a free hydroxyl group at the 20th or 21st carbon atom of the dammaran bone nucleus represented by the following formula: [In the formula, R 1 and R 4 are each independently H or a sugar residue, R 2 is CH 3 , CHO or CH 2 OH,
R 3 is H or OH, R 5 is CH 3 , CH 2 OH or
CH 2 O - sugar residue, R 6 is H or OH, wavy line (〓)
represents an α bond or a β bond. However, (1) R 4
is not H, R 5 represents CH 2 OH, (2) R 1 is a sugar residue, R 2 is CH 3 , R 3 is OH, R 4 is H, R 6 is H
In this case, R 5 is not α-methyl. ].
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP56157925A JPS5859921A (en) | 1981-10-02 | 1981-10-02 | Carcinostatic agent containing amachazuru saponin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP56157925A JPS5859921A (en) | 1981-10-02 | 1981-10-02 | Carcinostatic agent containing amachazuru saponin |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5859921A JPS5859921A (en) | 1983-04-09 |
| JPS6312445B2 true JPS6312445B2 (en) | 1988-03-18 |
Family
ID=15660457
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP56157925A Granted JPS5859921A (en) | 1981-10-02 | 1981-10-02 | Carcinostatic agent containing amachazuru saponin |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS5859921A (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0436682B1 (en) * | 1989-07-21 | 1994-01-19 | Marigen S.A. | Sterols, esters with fatty acids and glucosides of such sterols; a method of preparation thereof; spontaneously dispersable agents containing these compounds; and the use of such agents to treat tumours |
| GB9518883D0 (en) * | 1995-09-15 | 1995-11-15 | Leo Pharm Prod Ltd | Chemical compounds |
| KR101128920B1 (en) | 2009-12-15 | 2012-04-23 | 충남대학교산학협력단 | Gypenoside, Method for Preparing the Same and Use Thereof |
| CN102579471B (en) * | 2012-01-16 | 2013-12-11 | 中央民族大学 | Applications of four gypenoside compounds in preparation of medicament for treating tumors |
| CN103012537B (en) * | 2012-12-20 | 2014-10-29 | 上海交通大学 | Dammarane type triterpene compound and preparation method and application thereof |
| CN105153271B (en) * | 2015-09-17 | 2018-03-02 | 沈阳农业大学 | Two new Dammarane type triterpene compounds and its production and use |
| EP3501296A1 (en) * | 2017-12-22 | 2019-06-26 | Analyticon Discovery GmbH | Novel triterpene-glycosides as sweeteners or sweetener enhancer |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5857399A (en) * | 1981-10-01 | 1983-04-05 | Osaka Chem Lab | Ginseng saponin, its separation, preparation and use |
-
1981
- 1981-10-02 JP JP56157925A patent/JPS5859921A/en active Granted
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5857399A (en) * | 1981-10-01 | 1983-04-05 | Osaka Chem Lab | Ginseng saponin, its separation, preparation and use |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5859921A (en) | 1983-04-09 |
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