JPH05112596A - Medicine containing bufalin and bufadienolide as effective components - Google Patents
Medicine containing bufalin and bufadienolide as effective componentsInfo
- Publication number
- JPH05112596A JPH05112596A JP33637791A JP33637791A JPH05112596A JP H05112596 A JPH05112596 A JP H05112596A JP 33637791 A JP33637791 A JP 33637791A JP 33637791 A JP33637791 A JP 33637791A JP H05112596 A JPH05112596 A JP H05112596A
- Authority
- JP
- Japan
- Prior art keywords
- cells
- differentiation
- bufalin
- bufarin
- compds
- 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
- 239000003814 drug Substances 0.000 title claims abstract description 6
- 229940079593 drug Drugs 0.000 title claims abstract description 4
- QEEBRPGZBVVINN-UHFFFAOYSA-N Desacetyl-bufotalin Natural products CC12CCC(C3(CCC(O)CC3CC3)C)C3C1(O)CCC2C=1C=CC(=O)OC=1 QEEBRPGZBVVINN-UHFFFAOYSA-N 0.000 title abstract description 3
- QEEBRPGZBVVINN-BMPKRDENSA-N bufalin Chemical compound C=1([C@H]2CC[C@]3(O)[C@H]4[C@@H]([C@]5(CC[C@H](O)C[C@H]5CC4)C)CC[C@@]32C)C=CC(=O)OC=1 QEEBRPGZBVVINN-BMPKRDENSA-N 0.000 title abstract description 3
- HAJGVUYNXHQLER-UHFFFAOYSA-N Bufadienolide Natural products O1C(=O)C=CC(C2C3C(C4C(C5CCCCC5CC4)CC3)CC2)=C1 HAJGVUYNXHQLER-UHFFFAOYSA-N 0.000 title 1
- YBPMPRDOWHIVNA-XTBIJCDISA-N bufadienolide Chemical compound C=1([C@H]2CC[C@@H]3[C@H]4[C@@H]([C@]5(CCCCC5CC4)C)CC[C@@]32C)C=CC(=O)OC=1 YBPMPRDOWHIVNA-XTBIJCDISA-N 0.000 title 1
- 230000004069 differentiation Effects 0.000 claims abstract description 17
- 210000004027 cell Anatomy 0.000 claims description 23
- 210000004881 tumor cell Anatomy 0.000 claims description 6
- 230000024245 cell differentiation Effects 0.000 claims description 5
- 239000002246 antineoplastic agent Substances 0.000 claims description 4
- 239000000411 inducer Substances 0.000 claims 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims 1
- 206010028980 Neoplasm Diseases 0.000 abstract description 7
- 208000032839 leukemia Diseases 0.000 abstract description 7
- SCULJPGYOQQXTK-OLRINKBESA-N Cinobufagin Chemical compound C=1([C@@H]2[C@@]3(C)CC[C@@H]4[C@@]5(C)CC[C@H](O)C[C@H]5CC[C@H]4[C@@]43O[C@@H]4[C@@H]2OC(=O)C)C=CC(=O)OC=1 SCULJPGYOQQXTK-OLRINKBESA-N 0.000 abstract description 4
- SCULJPGYOQQXTK-UHFFFAOYSA-N Cinobufagin Natural products CC(=O)OC1C2OC22C3CCC4CC(O)CCC4(C)C3CCC2(C)C1C=1C=CC(=O)OC=1 SCULJPGYOQQXTK-UHFFFAOYSA-N 0.000 abstract description 3
- 239000003795 chemical substances by application Substances 0.000 abstract description 3
- 210000004907 gland Anatomy 0.000 abstract description 2
- 241000269417 Bufo Species 0.000 abstract 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 abstract 1
- 230000002622 anti-tumorigenesis Effects 0.000 abstract 1
- 238000001035 drying Methods 0.000 abstract 1
- 238000000605 extraction Methods 0.000 abstract 1
- 210000003608 fece Anatomy 0.000 abstract 1
- 238000000034 method Methods 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 description 14
- 230000001939 inductive effect Effects 0.000 description 11
- JPXMTWWFLBLUCD-UHFFFAOYSA-N nitro blue tetrazolium(2+) Chemical compound COC1=CC(C=2C=C(OC)C(=CC=2)[N+]=2N(N=C(N=2)C=2C=CC=CC=2)C=2C=CC(=CC=2)[N+]([O-])=O)=CC=C1[N+]1=NC(C=2C=CC=CC=2)=NN1C1=CC=C([N+]([O-])=O)C=C1 JPXMTWWFLBLUCD-UHFFFAOYSA-N 0.000 description 6
- 201000011510 cancer Diseases 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 230000003177 cardiotonic effect Effects 0.000 description 3
- 230000003013 cytotoxicity Effects 0.000 description 3
- 231100000135 cytotoxicity Toxicity 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 150000003431 steroids Chemical class 0.000 description 3
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 210000000265 leukocyte Anatomy 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 230000002195 synergetic effect Effects 0.000 description 2
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 241000269435 Rana <genus> Species 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 229940057344 bufferin Drugs 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 241000411851 herbal medicine Species 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 208000025113 myeloid leukemia Diseases 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 239000002435 venom Substances 0.000 description 1
- 210000001048 venom Anatomy 0.000 description 1
- 231100000611 venom Toxicity 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 230000001018 virulence Effects 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
Abstract
Description
【産業上の利用分野】本発明は腫瘍細胞などの細胞の分
化誘導作用をゆうするブファジニノリドであるブファリ
ン、シノブファギン及びそれら関連化合物を有効成分と
する医薬、具体的には、白血病などの腫瘍の治療薬に関
する。FIELD OF THE INVENTION The present invention relates to a drug containing bufadininolide bufalininolide, which has an effect of inducing differentiation of cells such as tumor cells, cinobufagine and related compounds thereof, specifically, treatment of tumors such as leukemia. Regarding medicine.
【従来の技術及び発明が解明しようとする課題】従来か
ら、分化誘導作用を有する化合物は種々研究されてお
り、腫瘍細胞の分化を促進して脱癌させる分化誘導活性
を示す制癌化合物が知られている。しかしながら、腫瘍
細胞に共通して分化誘導能を示す化合物はきわめて少な
い。本発明者らは、腫瘍細胞に共通して分化誘導を示す
新たな化合物を発見して抗腫瘍剤として提供することを
目的として研究を行っている。BACKGROUND OF THE INVENTION Various compounds having a differentiation-inducing action have been studied in the past, and an anti-cancer compound having a differentiation-inducing activity of promoting tumor cell differentiation and decanceration is known. Has been. However, very few compounds have the ability to induce differentiation commonly in tumor cells. The present inventors have conducted research for the purpose of discovering a new compound commonly showing differentiation induction in tumor cells and providing it as an antitumor agent.
【課題を解決させるための手段及び作用】本発明者ら
は、研究の結果、従来より家庭薬や漢方生薬として利用
されているセンソ（ツナヒキガエルまたは近縁種の毒腺
の分泌物を集めて乾燥したもの）より、一般式（Ｉ）
（ＩＩ）および（ＩＩＩ）で示されるブファリン、シノ
ブファギン及び類似化合物の強心性ステロイドをＭ．Ｋ
ｏｍａｔｓｕ ａｎｄ Ｓ．Ｏｋａｎｏ（分析化学，１
５，１１１５（１９６６））の方法により抽出精製し、
これらの化合物が癌細胞の分化（脱癌）を促す分化誘導
能を有する新たな化合物であることを知見した。（Ｌ．
Ｚｈａｎｇ，Ｋ．Ｎａｋａｙａ，Ｔ．Ｙｏｓｈｉｄａ
ａｎｄ Ｙ．Ｋｕｒｏｉｗａ（Ｂｉｏｃｈｅｍ．Ｂｉｏ
ｐｈｙｓ．Ｒｅｓ．Ｃｏｍｍｕｎ．，１７８ ６８６
（１９９１））。ブファリンは、白血病細胞以外の種々
のヒト由来腫瘍細胞に対しても強力な細胞毒性を示すこ
とも知見した。特にブファリンは、発生段階の子となる
４種のヒトの脊髄性白血病細胞に対して共通して分化誘
導能を有し、抗腫瘍剤として用い得る。本発明の一般式
（Ｉ）で示されるブファリンは、常法に従い、例えば経
口剤または注射剤の形に製剤化されて投与され得る。経
口投与に好ましい剤型としては、たとえば錠剤カプセル
剤、顆粒剤及び液剤を挙げることができる。更にブファ
リンは、既知の分化誘導剤であるオールトランスレチノ
イドアシド、インターフェロン等と相加あるいは相乗的
な分化誘導作用を示し、より有効な治療効果を期待する
ことができる。本発明の一般式（Ｉ）および（ＩＩ）で
示されるブファリンおよびシノブファギンとさらに類似
化合物の薬理作用を具体的な試験例によって説明する。 試験例１ ヒト骨髄性白血病細胞Ｋ５６２に対する本発明化合物の
細胞毒性（生細胞率）お よびニトロブルーテトラゾリウム（ＮＢＴ）還元能によ
って、本発明化合物の癌細胞の分化誘導活性の判定試験
を行った。この測定は、Ｋ．Ｔａｎａｋａ ら（Ｃａｎ
ｃｅｒ Ｒｅｓ．，４２，５１５２（１９８２））記載
の方法によった。本発明化合物とＫ５６２白血病細胞
（１×１０５ｃｅｌｌｓ／ｍｌ）とのインキュベーショ
ンは４日間とし、培地としてＲＰＨＩ−１６４０＋１０
％牛胎児血清（５６℃、３０分間熱処理を行って不活性
化した）を用い、５％二酸化炭素９５％空気の気相下で
培養した。この培地に本発明化合物をエタノールに溶解
し、培養液中のエタノールの濃度が０．１％になるよう
に調節して添加した。 Ｋ５６２細胞を２．５から１０
０ｎＭのブファリンとインキュベーションするとＮＢＴ
還元能を有する細胞へと分化した。１０ｎＭのブファリ
ンは細胞毒性を示すことなく約８０％のＫ５６２細胞を
ＮＢＴ還元能を有する細胞へと分化させた。５０ｎＭか
ら１００ｎＭのブファリンではＫ５６２細胞の生存率が
用量依存的に低下し、残存細胞のほとんどはＮＢＴ還元
能を有していた。ブファリンにより分化誘導された細胞
を形態学的及び生化学的に調べたところ成熟した白血球
細胞に分化していることが示された。次にブファリンお
よび強心性ステロイドを添加すると上記と同様な白血球
細胞への分化が形態学的にも観察された。これら使用し
た強心性ステロイドのうち、ブファリンの分化誘導作用
は特に強力であった。その実験結果を表１に要約して示
す。 試験例２ 試験例１の結果、ブファリンのＫ５６２白血病細胞に対
する分化誘導活性が最も強力であったので、発生段階の
異なる３種の白血病細胞に対する効果を検討した結果を
表２に要約して示す。 試験例１と同様な方法で、ＨＬ
−６０細胞は５ｎＭのブファリン、ＭＬ−１およびＵ９
３７細胞は１０ｎＭのブファリンと４日間インキュベー
トすると、Ｋ５６２細胞の場合と同様に、ＨＬ−６０、
ＭＬ１およびＵ９３７の各白血病細胞をいずれもＮＢＴ
元能を有するマクロファージ様細胞へと分化誘導（脱
癌）した。[Means and Actions for Solving the Problems] As a result of research, the present inventors have collected and dried the secretions of venom glands of Senso (Rana toad or related species), which have been conventionally used as home remedies and herbal medicines. From the general formula (I)
Bufferin, cinobufagin and similar compounds cardiotonic steroids represented by (II) and (III) are described in M. K
omatsu and S.M. Okano (Analytical Chemistry, 1
5,1115 (1966)),
It was discovered that these compounds are new compounds having a differentiation-inducing ability to promote the differentiation (decanceration) of cancer cells. (L.
Zhang, K .; Nakaya, T .; Yoshida
and Y. Kuroiwa (Biochem. Bio
phys. Res. Commun. , 178 686
(1991)). It was also found that bufarin also shows strong cytotoxicity against various human-derived tumor cells other than leukemia cells. In particular, bufarin has a common differentiation-inducing ability for four human spinal leukemia cells that are developmental offspring, and can be used as an antitumor agent. The bufalin represented by the general formula (I) of the present invention can be administered by formulating it in the form of, for example, an oral preparation or an injectable preparation according to a conventional method. Preferred dosage forms for oral administration include, for example, tablet capsules, granules and solutions. Furthermore, bufarin exhibits an additive or synergistic differentiation-inducing action with known transduction agents such as all-trans-retinoid acid and interferon, and a more effective therapeutic effect can be expected. The pharmacological actions of bufarin and cinobufagin represented by the general formulas (I) and (II) of the present invention and further similar compounds will be described by way of specific test examples. Test Example 1 Cytotoxicity (viability rate) of the compound of the present invention to human myeloid leukemia cells K562 And the ability to reduce nitroblue tetrazolium (NBT) were used to evaluate the activity of the compound of the present invention to induce differentiation of cancer cells. This measurement is based on the K. Tanaka et al. (Can
cer Res. , 42, 5152 (1982)). The compound of the present invention and K562 leukemia cells (1 × 10 5 cells / ml) were incubated for 4 days, and RPHI-1640 + 10 was used as a medium.
% Fetal bovine serum (inactivated by heat treatment at 56 ° C. for 30 minutes) was used and cultured in the gas phase of 5% carbon dioxide and 95% air. The compound of the present invention was dissolved in ethanol in this medium, and the concentration of ethanol in the culture solution was adjusted to 0.1% and added. 2.5 to 10 K562 cells
NBT when incubated with 0 nM bufarin
Differentiated into cells having reducing ability. 10 nM bufarin differentiated about 80% of K562 cells into cells having NBT reducing ability without showing cytotoxicity. From 50 nM to 100 nM bufarin, the survival rate of K562 cells decreased in a dose-dependent manner, and most of the remaining cells had NBT reducing ability. The morphological and biochemical examination of the cells induced to differentiate by bufarin showed that they were differentiated into mature white blood cells. Then, when bufarin and cardiotonic steroid were added, the same differentiation into white blood cells as above was morphologically observed. Among these cardiotonic steroids used, the differentiation-inducing action of bufarin was particularly strong. The experimental results are summarized in Table 1. Test Example 2 As a result of Test Example 1, since the differentiation-inducing activity of bufarin against K562 leukemia cells was the most potent, the results of examining the effects on three types of leukemia cells at different developmental stages are summarized in Table 2. In the same manner as in Test Example 1, HL
-60 cells contain 5 nM bufarin, ML-1 and U9
When 37 cells were incubated with 10 nM bufarin for 4 days, HL-60, similar to K562 cells,
Both ML1 and U937 leukemic cells were NBT
Differentiation was induced (de-cancerous) into macrophage-like cells having virulence.
【発明の効果】本発明化合物は癌細胞の分化誘導活性
（脱癌作用）が強く、しかも種々の癌細胞に対し共通し
て分化誘導活性を示し、従来知られている分化誘導剤と
も相加あるいは相乗作用を示すことから、優れた癌化学
療法剤としての用途が期待できる。INDUSTRIAL APPLICABILITY The compound of the present invention has a strong cancer cell differentiation-inducing activity (carcinogenic effect), and also shows a common differentiation-inducing activity for various cancer cells, and is added to conventionally known differentiation-inducing agents. Alternatively, since they show a synergistic effect, they can be expected to be used as excellent cancer chemotherapeutic agents.
Claims (4)
原子水酸基または、アセチル基である。1. A general formula In the formula, R1 is a hydrogen atom or a hydroxyl group, and R2 is a hydrogen atom hydroxyl group or an acetyl group.
第１項記載の医薬2. The medicine according to claim 1, which is a cell differentiation inducer.
２項記載の分化誘導剤3. The differentiation inducer according to claim 2, wherein the cells are tumor cells.
請求の範囲第２項または第３項記載の医薬4. The drug according to claim 2 or 3, wherein the cell differentiation inducer is an antitumor agent.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP33637791A JPH05112596A (en) | 1991-10-20 | 1991-10-20 | Medicine containing bufalin and bufadienolide as effective components |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP33637791A JPH05112596A (en) | 1991-10-20 | 1991-10-20 | Medicine containing bufalin and bufadienolide as effective components |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH05112596A true JPH05112596A (en) | 1993-05-07 |
Family
ID=18298511
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP33637791A Pending JPH05112596A (en) | 1991-10-20 | 1991-10-20 | Medicine containing bufalin and bufadienolide as effective components |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH05112596A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002014343A1 (en) * | 2000-08-17 | 2002-02-21 | Terness, Peter | Bufadienolide derivatives and use as immunosuppressive, antiinflammatory and analgesic agents |
| JP2013525403A (en) * | 2010-04-27 | 2013-06-20 | ファルマ、マール、ソシエダード、アノニマ | Unsaturated anticancer steroidal lactone at position 7 (8) |
-
1991
- 1991-10-20 JP JP33637791A patent/JPH05112596A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002014343A1 (en) * | 2000-08-17 | 2002-02-21 | Terness, Peter | Bufadienolide derivatives and use as immunosuppressive, antiinflammatory and analgesic agents |
| JP2013525403A (en) * | 2010-04-27 | 2013-06-20 | ファルマ、マール、ソシエダード、アノニマ | Unsaturated anticancer steroidal lactone at position 7 (8) |
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