JPH05201868A - Bufadienolide type differentiation-inducing agent - Google Patents
Bufadienolide type differentiation-inducing agentInfo
- Publication number
- JPH05201868A JPH05201868A JP4011841A JP1184192A JPH05201868A JP H05201868 A JPH05201868 A JP H05201868A JP 4011841 A JP4011841 A JP 4011841A JP 1184192 A JP1184192 A JP 1184192A JP H05201868 A JPH05201868 A JP H05201868A
- Authority
- JP
- Japan
- Prior art keywords
- cells
- differentiation
- bufadienolide
- compound
- inducing
- 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
- 230000001939 inductive effect Effects 0.000 title claims abstract description 19
- 230000004069 differentiation Effects 0.000 title claims description 29
- HAJGVUYNXHQLER-UHFFFAOYSA-N Bufadienolide Natural products O1C(=O)C=CC(C2C3C(C4C(C5CCCCC5CC4)CC3)CC2)=C1 HAJGVUYNXHQLER-UHFFFAOYSA-N 0.000 title abstract description 6
- 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 abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 16
- 208000032839 leukemia Diseases 0.000 claims abstract description 16
- 230000024245 cell differentiation Effects 0.000 claims abstract description 6
- 239000000411 inducer Substances 0.000 claims description 9
- 239000002246 antineoplastic agent Substances 0.000 abstract description 5
- 239000003795 chemical substances by application Substances 0.000 abstract description 3
- 230000002688 persistence Effects 0.000 abstract description 2
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 abstract 1
- 239000002253 acid Substances 0.000 abstract 1
- 125000001931 aliphatic group Chemical group 0.000 abstract 1
- 125000000539 amino acid group Chemical group 0.000 abstract 1
- 150000001720 carbohydrates Chemical group 0.000 abstract 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 36
- 206010028980 Neoplasm Diseases 0.000 description 8
- 201000011510 cancer Diseases 0.000 description 8
- 238000012360 testing method Methods 0.000 description 7
- 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
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 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 description 3
- 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 description 3
- 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
- 210000004881 tumor cell Anatomy 0.000 description 3
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 208000025113 myeloid leukemia Diseases 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000002195 synergetic effect Effects 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 206010029098 Neoplasm skin Diseases 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- GLNADSQYFUSGOU-GPTZEZBUSA-J Trypan blue Chemical compound [Na+].[Na+].[Na+].[Na+].C1=C(S([O-])(=O)=O)C=C2C=C(S([O-])(=O)=O)C(/N=N/C3=CC=C(C=C3C)C=3C=C(C(=CC=3)\N=N\C=3C(=CC4=CC(=CC(N)=C4C=3O)S([O-])(=O)=O)S([O-])(=O)=O)C)=C(O)C2=C1N GLNADSQYFUSGOU-GPTZEZBUSA-J 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- GMRQFYUYWCNGIN-NKMMMXOESA-N calcitriol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCCC(C)(C)O)C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C GMRQFYUYWCNGIN-NKMMMXOESA-N 0.000 description 1
- 239000011612 calcitriol Substances 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
- 239000000496 cardiotonic agent Substances 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 208000029742 colonic neoplasm Diseases 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
- 210000004907 gland Anatomy 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
- 238000011534 incubation Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 231100000225 lethality Toxicity 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229930002330 retinoic acid Natural products 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 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
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
Abstract
Description
【０００１】[0001]
【産業上の利用分野】この発明は、ブファジェノリド型
分化誘導剤に関するものであり、特に白血病などの腫瘍
細胞の分化を促進させる治療薬に関するものである。BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a bufagenolide type differentiation inducer, and more particularly to a therapeutic agent for promoting differentiation of tumor cells such as leukemia.
【０００２】[0002]
【従来の技術】従来から分化誘導作用を有する化合物が
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、例えばオールトラ
ンスレチノイン酸が知られている。2. Description of the Related Art Various compounds having a differentiation inducing action have been studied so far, and an antitumor compound having a differentiation inducing activity for promoting tumor cell differentiation and decancerizing, for example, all-trans retinoic acid is known. ..
【０００３】[0003]
【発明が解決しようとする課題】しかしながら、各種白
血病細胞に共通して分化誘導能を示す化合物は極めて少
ない。However, very few compounds have the ability to induce differentiation commonly in various leukemia cells.
【０００４】[0004]
【発明の目的】そこで、本発明は、各種白血病細胞に共
通して分化誘導能を示す新たな化合物を発見して分化誘
導剤すなわち抗腫瘍剤として提供することを目的として
いる。OBJECTS OF THE INVENTION Therefore, an object of the present invention is to discover a new compound having a differentiation-inducing ability common to various leukemia cells and provide it as a differentiation-inducing agent, that is, an antitumor agent.
【０００５】[0005]
【課題を解決するための手段】この目的を達成するた
め、この発明は、ブファジェノリドの構造式をもった化
合物を細胞分化誘導剤として提供している。また、この
化合物を各種白血病細胞に適用するようにしている。In order to achieve this object, the present invention provides a compound having the structural formula of bufagenolide as a cell differentiation inducer. Moreover, this compound is applied to various leukemia cells.
【０００６】[0006]
【作用】ブファジェノリド型分化誘導剤を癌細胞に適用
すると、癌細胞を分化促進して通常細胞に変化させる。
特に白血病細胞に抗腫瘍剤として働かせると分化誘導能
を発揮して脱癌させる。When a bufagenolide type differentiation inducer is applied to cancer cells, they promote the differentiation of cancer cells and change them into normal cells.
In particular, when it acts on leukemia cells as an antitumor agent, it exerts differentiation-inducing ability to decancerize.
【０００７】[0007]
【実施例】本発明者は、永年の研究の結果、従来より家
庭薬や漢方薬として利用されているセンソに着目した。
センソはシ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で、強心剤、局所麻酔薬や皮膚腫瘍
の治療薬として使用されたものである。EXAMPLES As a result of many years of research, the present inventor has focused on Senso, which has been conventionally used as a home remedy or a herbal medicine.
Senso is a collection of dried secretions of the venom glands of the toad or related species, dried, and used as a cardiotonic agent, local anesthetic and as a therapeutic agent for skin tumors.
【０００８】[0008]
【化１】 [Chemical 1]
【０００９】[0009]
【化２】 [Chemical 2]
【００１０】このセンソから１４β−ヒドロキシ−５β
−ブファジエノリドで示される一般式(Ｉ)および１４
β，１５β−エポキシ−５β−ブファジエノリドで示さ
れる一般式(II)のブファジエノリドの構造式をもった化
合物（ブファリン、シノブファギンおよびこれらの誘導
体）の強心性ステロイドをM.Komatsu and S.Okano（分
析化学，１５， １１１５頁（１９６６））の方法によ
り抽出精製した。この構造式をもった化合物が白血病
（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（すなわちブファジエノリド型分
化誘導剤）を知見した（L.Zhang, K.Nakaya, T.Yoshid
a, and Y.Kuroiwa(Biochem. Biophys. Res. Commun.,１
７８， ６８６頁（１９９１））。From this senso, 14β-hydroxy-5β
-The general formula (I) and 14 represented by bufadienolide
M. Komatsu and S. Okano (analytical chemistry) of cardiotonic steroids of compounds having the structural formula of bufadienolide of general formula (II) represented by β, 15β-epoxy-5β-bufadienolide (bufaline, cinobufagin and their derivatives) , 15, 1115 (1966)). It was discovered that a compound having this structural formula is a new compound having a differentiation-inducing ability to promote differentiation (decanceration) of leukemia (cancer) cells (that is, a bufadienolide-type differentiation inducer) (L. Zhang, K. Nakaya, T. Yoshid
a, and Y. Kuroiwa (Biochem. Biophys. Res. Commun., 1
78, 686 (1991)).
【００１１】特にブファリンは、発生段階の異なる４種
のヒトの骨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。ブファリンはまた、
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
力な細胞毒性を示し、たとえばヒトメラノーマＭＥＷＯ
細胞に対しても１０ｎＭの濃度で５０パーセント致死作
用を有し、ヒト大腸癌ＨＣＴ−１１６細胞に対しても２
００ｎＭで５０パーセント致死作用を有することも知見
した。In particular, bufarin has a common differentiation-inducing ability for four human myeloid leukemia cells at different developmental stages, and can be used as an antitumor agent. Bufarin is also
It also shows strong cytotoxicity against various human-derived tumor cells other than leukemia cells. For example, human melanoma MEWO
It also has a 50% lethal effect on cells at a concentration of 10 nM, and 2 even on human colon cancer HCT-116 cells.
It was also found to have 50 percent lethality at 00 nM.
【００１２】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、軟膏、座
剤等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、例えば錠剤、カプセル剤、顆粒剤お
よ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１α，２５−ジヒドロキシビタミ
ンＤ3、ｒ−ＴＮＦαあるいはインターフェロン等と相
加ないし相乗的な分化誘導作用を示し（中谷一泰、張麗
莎、亀井英夫、吉田武美、黒岩幸雄（第５０回日本癌学
会総会講演要旨集および発表））、より有効な治療効果
を期待することができる。The bufarin 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 injection, an ointment, a suppository, etc. according to a conventional method. Preferred dosage forms for oral administration include tablets, capsules, granules and solutions. Furthermore, bufarin shows an additive or synergistic differentiation-inducing action with known differentiation inducers 1α, 25-dihydroxyvitamin D 3 , r-TNFα, interferon, etc. (Kazuyasu Nakatani, Rei Zhang, Hideo Kamei, Takemi Yoshida). , Yukio Kuroiwa (Abstracts and Presentations at the 50th Annual Meeting of the Japanese Cancer Society), and more effective therapeutic effects can be expected.
【００１３】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更にこれらの誘導体の
薬理作用を具体的な試験例によって説明する。ここに誘
導体は、生体内への吸収、持続性、増強性等を目的とし
て決定されるものである。The pharmacological action of bufarin and cinobufagin represented by the general formulas (I) and (II) of the present invention, and the pharmacological action of these derivatives will be described with reference to specific test examples. Here, the derivative is determined for the purpose of absorption in the living body, persistence, enhancement, and the like.
【００１４】[0014]
【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なった。この
測定は、K.Tanakaら（CancerRes., ４２，５１５２（１
９８２））記載の方法によった。Test Example 1 A test for determining the cancer cell differentiation-inducing activity of the compound of the present invention was carried out based on the cytotoxicity (viable cell rate) and the nitroblue tetrazolium (NBT) reducing ability of the compound of the present invention on human myeloid leukemia cell K562. .. This measurement is performed by K. Tanaka et al. (Cancer Res., 42, 5152 (1
982)).
【００１５】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ＲＰＭＩ１６４０＋１０パーセント
牛胎児血清（５６°Ｃ、３０分間熱処理を行なって不活
性化した）を用い、５パーセント二酸化炭素／９５パー
セント空気の気相比で培養した。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パーセントになるように調製して添加した。The compound of the present invention and K562 leukemia cells (1 ×
(10 5 cells / ml) for 4 days, and RPMI1640 + 10% fetal bovine serum (inactivated by heat treatment at 56 ° C. for 30 minutes) was used as a medium and 5% carbon dioxide / 95% air. Cultured in phase ratio. 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.
【００１６】図１はＫ５６２細胞の分化に対する種々の
濃度のブファリンの影響を示すものである。Ｋ５６２細
胞は種々の濃度の存在下で、３７°Ｃで４日間培養され
た。分化誘導活性はＮＢＴを還元する能力で測り、生き
ている細胞の割合はトリパンブルー染色で調べた。各点
は３回の測定の平均値±標準偏差である。FIG. 1 shows the effect of various concentrations of bufarin on the differentiation of K562 cells. K562 cells were cultured for 4 days at 37 ° C in the presence of various concentrations. The differentiation-inducing activity was measured by the ability to reduce NBT, and the ratio of living cells was examined by trypan blue staining. Each point is the average value ± standard deviation of three measurements.
【００１７】図１によれば、Ｋ５６２細胞を２．５から
１００ｎＭのブファリンとインキュベーションするとＮ
ＢＴ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パーセントのＫ
５６２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。According to FIG. 1, incubation of K562 cells with 2.5 to 100 nM bufarin resulted in N
Differentiated into cells having BT reducing ability. 10 nM bufarin gives about 80 percent K without cytotoxicity
The 562 cells were differentiated into cells having NBT reducing ability. K562 at 50 nM to 100 nM bufarin
The cell viability decreased in a dose-dependent manner, and most of the remaining cells had NBT reducing ability.
【００１８】ブファリンにより分化誘導された細胞を形
態学的および生化学的に調べたところ顆粒球様細胞に分
化していることが示された。次にブファリン、シノブフ
ァギンおよび他の強心性ステロイドを添加すると顆粒球
様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。The cells differentiated by bufarin were examined morphologically and biochemically to show that they were differentiated into granulocyte-like cells. Subsequent addition of bufarin, cinobufagin and other cardiotonic steroids also morphologically observed differentiation into granulocyte-like cells. Among these cardiotonic steroids used, the differentiation-inducing action of bufarin was particularly strong.
【００１９】その試験結果を表１、表２に要約して示
す。The test results are summarized in Tables 1 and 2.
【００２０】[0020]
【表１】 [Table 1]
【００２１】[0021]
【表２】 [Table 2]
【００２２】[0022]
【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、発生段階の異なる他の３種の白血病細胞に対する効
果を検討した結果を表３に要約して示す。試験例１と同
様な方法で、ＨＬ６０細胞は５ｎＭブファリン、ＭＬ１
およびＵ９３７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、Ｈ
Ｌ６０、ＭＬ１およびＵ９３７の各白血病細胞をいずれ
もＮＢＴ還元能を有し、かつ形態学的には単球ないしマ
クロファージ様細胞へと分化誘導（脱癌）した。[Test Example 2] As a result of Test Example 1, since the differentiation-inducing activity of bufarin against K562 leukemia cells was the strongest, the results of examining the effects on 3 other leukemia cells at different developmental stages are summarized in Table 3. And show it. In the same manner as in Test Example 1, HL60 cells contained 5 nM bufarin and ML1.
And U937 cells were incubated with 10 nM bufarin for 4 days, and as with K562 cells, H
Each of the L60, ML1 and U937 leukemia cells had an NBT reducing ability, and morphologically induced differentiation into monocytes or macrophage-like cells (decanceration).
【００２３】[0023]
【表３】 [Table 3]
【００２４】[0024]
【発明の効果】本発明のブファジエノリド型分化誘導剤
は白血病（癌）細胞の分化誘導活性（脱癌作用）が強
く、しかも種々の白血病（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
ないし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 bufadienolide type differentiation inducer of the present invention has a strong leukemia (cancer) cell differentiation-inducing activity (carcinogenic effect), and exhibits a differentiation-inducing activity common to various leukemia (cancer) cells. Since it exhibits an additive or synergistic action with a conventionally known differentiation inducer, it can be expected to be used as an excellent cancer chemotherapeutic agent.
【図１】Ｋ５６２細胞の分化に対する種々の濃度のブフ
ァリンの影響を示す図である。FIG. 1 shows the effect of various concentrations of bufarin on the differentiation of K562 cells.
───────────────────────────────────────────────────── フロントページの続き (72)発明者 吉田 武美 東京都品川区旗の台１丁目５番８号学校法 人昭和大学内 ─────────────────────────────────────────────────── ─── Continued Front Page (72) Inventor Takemi Yoshida 1-5-8 Hatanodai, Shinagawa-ku, Tokyo School Hojin Showa University
Claims (2)
が細胞の分化誘導能を有していることを特徴とするブフ
ァジェノリド型分化誘導剤。1. A bufagenolide-type differentiation inducer, wherein a compound having a bufagenolide structural formula has a cell differentiation-inducing ability.
胞であることを特徴とするブファジェノリド型分化誘導
剤。2. The bufagenolide type differentiation inducer according to claim 1, wherein the cells are various leukemia cells.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP4011841A JP2515074B2 (en) | 1992-01-27 | 1992-01-27 | Bufagenolide type differentiation inducer |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP4011841A JP2515074B2 (en) | 1992-01-27 | 1992-01-27 | Bufagenolide type differentiation inducer |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH05201868A true JPH05201868A (en) | 1993-08-10 |
| JP2515074B2 JP2515074B2 (en) | 1996-07-10 |
Family
ID=11788957
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP4011841A Expired - Lifetime JP2515074B2 (en) | 1992-01-27 | 1992-01-27 | Bufagenolide type differentiation inducer |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2515074B2 (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 |
| CN106265693A (en) * | 2015-05-20 | 2017-01-04 | 中国科学院大连化学物理研究所 | The application in preparing cancer therapy drug of the bufadienolide compound with amino acid chain |
-
1992
- 1992-01-27 JP JP4011841A patent/JP2515074B2/en not_active Expired - Lifetime
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 |
| CN106265693A (en) * | 2015-05-20 | 2017-01-04 | 中国科学院大连化学物理研究所 | The application in preparing cancer therapy drug of the bufadienolide compound with amino acid chain |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2515074B2 (en) | 1996-07-10 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Goldstein et al. | Stimulation of human polymorphonuclear leukocyte superoxide anion radical production by tumor promoters | |
| Grotte et al. | Fluorescent, physiological and pharmacokinetic properties of fluorescein glucuronide | |
| Thomsen et al. | Evidence for the production of nitric oxide by activated macrophages treated with the antitumor agents flavone-8-acetic acid and xanthenone-4-acetic acid | |
| US4708952A (en) | Method of treatment of the infectious and viral diseases by one time interference | |
| JPH03500643A (en) | 13-trans-retinoic acid ester | |
| RU95107892A (en) | Derivatives of 11,21-bisphenyl-19-norpregnane, method of their synthesis, pharmaceutical composition based on thereof and method of its preparing | |
| Noris et al. | Increased nitric oxide formation in recurrent thrombotic microangiopathies: a possible mediator of microvascular injury | |
| DeChatelet et al. | Chemiluminescence of human neutrophils induced by soluble stimuli: effect of divalent cations | |
| Freeman et al. | Effect of sulfhydryl-containing compounds on the antitumor effects of adriamycin | |
| Emery et al. | Retrohydroxamate ferrichrome, a biomimetic analogue of ferrichrome | |
| JPH0296523A (en) | Platinum chemical remedy product | |
| Froelich et al. | 5-heptyl-2-thiohydantion, a new antitubercular agent | |
| Krause et al. | ItaCORMs: conjugation with a CO-releasing unit greatly enhances the anti-inflammatory activity of itaconates | |
| JPH05201868A (en) | Bufadienolide type differentiation-inducing agent | |
| EP0005346B1 (en) | Enterochelin complexes, pharmaceutical compositions containing them and a process for preparing them | |
| Kappas et al. | The occurrence of substances in human plasma capable of inducing the enzyme δ-aminolevulinate synthetase in liver cells | |
| Spizizen et al. | Biochemical studies on the phenomenon of virus reproduction: III. The inhibition of coliphage T2r+ multiplication by sodium salicylate and sodium gentisate | |
| US5414015A (en) | Anti-skin tumor promoting composition | |
| Sadar et al. | Trace analysis of pesticides using cholinesterase from human serum, rat liver, electric eel, bean leaf beetle, and white fringe beetle | |
| Roberts et al. | Arginase activity and nitrogen content in epidermal carcinogenesis in mice | |
| Sullivan et al. | Effects of recombinant human granulocyte-macrophage colony-stimulating factor on intracellular pH in mature granulocytes | |
| Kohl et al. | Inhibitory studies of DNA, RNA and protein synthesis in Escherichia coli by platinum containing complexes | |
| Hecht et al. | Sphingosine as an inhibitor of blood clotting | |
| Parmar et al. | Selective inhibition of nicotinamide adenine dinucleotide dependent oxidation by 2-methyl-3-o-tolyl-4-quinazolone | |
| McKinney et al. | Non-specificity of Thioflavine-T as an Amyloid Stain |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20080430 Year of fee payment: 12 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20090430 Year of fee payment: 13 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20120430 Year of fee payment: 16 |
|
| EXPY | Cancellation because of completion of term | ||
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20120430 Year of fee payment: 16 |