JPH0570348A - Multidrug resistance inhibitor - Google Patents
Multidrug resistance inhibitorInfo
- Publication number
- JPH0570348A JPH0570348A JP26323491A JP26323491A JPH0570348A JP H0570348 A JPH0570348 A JP H0570348A JP 26323491 A JP26323491 A JP 26323491A JP 26323491 A JP26323491 A JP 26323491A JP H0570348 A JPH0570348 A JP H0570348A
- Authority
- JP
- Japan
- Prior art keywords
- multidrug resistance
- quercetin
- inhibitor
- mdr1
- gene
- 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.)
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- Pyrane Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は、フラボノイドを含む多
剤耐性抑制剤に関する。本発明の多剤耐性抑制剤は、特
に癌の化学療法分野で用いることができる。TECHNICAL FIELD The present invention relates to a multidrug resistance inhibitor containing flavonoids. The multidrug resistance inhibitor of the present invention can be used particularly in the field of cancer chemotherapy.
【０００２】[0002]
【従来の技術】過去３０年間、癌の化学療法は新しい抗
癌剤を見出すことにより進歩してきた。抗癌剤の併用療
法が確立するのにしたがって、ウィルムス腫瘍や白血病
などの小児癌、婦人の絨毛癌などに対しては有効な治療
法が見出され、これらは治癒可能な癌となっている。バ
ーキットリンパ腫、急性リンパ性白血病、ホジキン病な
どの患者も、かなりの高い割合で社会生活に復帰するこ
とができるようになった。このように化学療法に期待が
寄せられている一方で、化学療法剤に殆ど反応しない肺
癌や大腸癌などの固形癌も依然として存在する。更に、
化学療法剤に反応する前記の癌においても、やがて抗癌
剤が効かなくなる耐性化も問題となっている。癌の化学
療法において最も重要な問題の一つは細胞毒性薬剤に対
する耐性の進行である。BACKGROUND OF THE INVENTION Over the last three decades, cancer chemotherapy has advanced by discovering new anti-cancer agents. With the establishment of combination therapy of anticancer agents, effective treatments have been found for childhood cancers such as Wilms tumor and leukemia, and choriocarcinoma of women, and these are curable cancers. Patients with Burkitt's lymphoma, acute lymphocytic leukemia, Hodgkin's disease, etc. are now able to return to a fairly high rate of social life. While such expectations are high for chemotherapy, there are still solid cancers such as lung cancer and colon cancer that hardly respond to chemotherapeutic agents. Furthermore,
Even in the case of the above-mentioned cancers that respond to chemotherapeutic agents, there is a problem in that the anticancer agents eventually become ineffective and the resistance becomes more effective. One of the most important problems in cancer chemotherapy is the development of resistance to cytotoxic drugs.
【０００３】抗癌剤に対する耐性としては、作用点や構
造にあまり共通点が認められない各種の抗癌剤に対して
同時に耐性を示す性質、即ち多剤耐性が知られている。
この多剤耐性を担う遺伝子はヒト培養細胞から既に単離
されており、ＭＤＲ１（multidrug-resistance）遺伝子
と命名されている。この多剤耐性遺伝子ＭＤＲ１がコー
ドしているヒト膜糖タンパク質（Ｐ−糖タンパク質）は
アミノ酸１，２８０個からなるペプチドであり、エネル
ギーに依存して抗癌剤を細胞外に排出するポンプとして
働いている。As resistance against anti-cancer agents, a property of simultaneously showing resistance to various anti-cancer agents having little commonalities in their action points and structures, that is, multidrug resistance is known.
The gene responsible for this multidrug resistance has already been isolated from human cultured cells and is named MDR1 (multidrug-resistance) gene. The human membrane glycoprotein (P-glycoprotein) encoded by this multidrug resistance gene MDR1 is a peptide consisting of 1,280 amino acids, and acts as a pump that discharges the anticancer drug out of the cell depending on energy. ..
【０００４】Ｐ−糖タンパタ質は、多くの天然物由来の
細胞毒性薬剤、例えばビンクリスチン、ビンブラスチ
ン、アクチノマイシンＤ、グラミシジン、ドキソルビシ
ン、コルヒチン、エポキシド（ＶＰ−１６）及びテニポ
シド（ＶＭ−２６）に対する耐性にも関係している。こ
の多剤耐性を克服するために、Ｃａ2+拮抗薬であるベラ
パミールなどの薬剤を用い、Ｐ−糖タンパタ質による細
胞内薬物の排出を阻害することにより、耐性を減少させ
るという試みがなされている。The P-sugar protein is resistant to many naturally occurring cytotoxic agents such as vincristine, vinblastine, actinomycin D, gramicidin, doxorubicin, colchicine, epoxide (VP-16) and teniposide (VM-26). Is also related to In order to overcome this multidrug resistance, an attempt has been made to reduce resistance by using a drug such as verapamil, which is a Ca 2+ antagonist, and inhibiting the intracellular drug excretion by the P-sugar protein. There is.
【０００５】[0005]
【発明が解決しようとする課題】しかしながら、これら
Ｃａ2+拮抗薬は副作用が多い。即ち、血管拡張作用が強
いので、降圧に伴って交感神経系の活性が高まり、頭
痛、動悸又は顔面紅潮などの副作用がみられ易く、下肢
の浮腫をきたすこともしばしばある。従って、ベラパミ
ールなどのＣａ2+拮抗薬の投与は、低血圧などによりシ
ョックを誘発することがあるので危険である。However, these Ca 2+ antagonists have many side effects. That is, since the vasodilatory action is strong, the activity of the sympathetic nervous system increases with the decrease in blood pressure, side effects such as headache, palpitation or flushing of the face are likely to occur, and edema of the lower limbs is often caused. Therefore, administration of a Ca 2+ antagonist such as verapamil is dangerous because it may induce shock due to hypotension or the like.
【０００６】本発明者は、多剤耐性の発現を遺伝子レベ
ルで制御することのできる物質について探索した結果、
意外にもフラボノイドにはヒト多剤耐性遺伝子ＭＤＲ１
の発現、誘導を抑える作用があることを見出した。本発
明はこうした知見に基づくものである。The present inventor has searched for substances capable of controlling the expression of multidrug resistance at the gene level.
Surprisingly, the human multidrug resistance gene MDR1 is present in flavonoids.
It was found that there is an action of suppressing the expression and induction of The present invention is based on these findings.
【０００７】[0007]
【課題を解決するための手段】従って、本発明は、フラ
ボノイドを含むことを特徴とする、多剤耐性抑制剤に関
する。本発明の多剤耐性抑制剤で有効成分として用いる
フラボノイドとしては、例えば、カルコン類、フラバノ
ン類、フラボン類、フラボノール類、フラバノノール
類、フラバノール類、イソフラボン類及び／又はアント
シアン類に属する各種の化合物を挙げることができる
が、特にはケルセチン〔即ち、２─（３，４─ジヒドロ
キシフェニル）─３，５，７─トリヒドロキシ─４Ｈ─
１─ベンゾピラン─４─オン〕が好ましい。Therefore, the present invention relates to a multidrug resistance inhibitor containing a flavonoid. Examples of flavonoids used as active ingredients in the multidrug resistance inhibitor of the present invention include various compounds belonging to chalcones, flavanones, flavones, flavonols, flavanonols, flavanols, isoflavones and / or anthocyans. Mention may be made especially of quercetin [ie 2- (3,4-dihydroxyphenyl) -3,5,7-trihydroxy-4H-
1-benzopyran-4-one] is preferred.
【０００８】本発明の多剤耐性抑制剤を用いる場合の投
与量は、癌の種類、患者の症状の程度などにより異な
り、特に制限はないが、ケルセチン量として通常成人１
人当り１〜５００mg程度を１日１〜４回程度にわけて、
経口的に又は非経口的に投与する。投与剤型としては、
例えば、散剤、細粒剤、顆粒剤、錠剤、カプセル剤、注
射剤などを挙げることができる。製剤化の際には、通常
の製剤担体を用いて、常法によって製造することができ
る。例えばケルセチン１w/w ％と乳糖９９w/w ％を混合
して充填したカプセル剤などである。本発明の多剤耐性
抑制剤は、フラボノイド又はその医薬上許容される塩を
０．０１〜９９重量％、好ましくは０．１〜８０重量％
の量で含有する。なお、ケルセチンの急性毒性（Ｌ
Ｄ50）をマウスの経口投与によって測定したところ、１
６０mg／kgであった。培地中のケルセチンの濃度として
は２０ないし２００μＭが望ましい。The dose of the multidrug resistance inhibitor of the present invention varies depending on the type of cancer, the degree of symptoms of the patient and the like, and is not particularly limited.
Divide 1 to 500 mg per person into 1 to 4 times a day,
It is administered orally or parenterally. As the dosage form,
For example, powders, fine granules, granules, tablets, capsules, injections and the like can be mentioned. In the case of formulation, it can be produced by a conventional method using a usual formulation carrier. For example, it is a capsule filled with 1 w / w% quercetin and 99 w / w% lactose mixed and filled. The multidrug resistance inhibitor of the present invention contains flavonoid or a pharmaceutically acceptable salt thereof in an amount of 0.01 to 99% by weight, preferably 0.1 to 80% by weight.
Contained in the amount of. The acute toxicity of quercetin (L
D 50 ) was measured by oral administration to mice,
It was 60 mg / kg. The concentration of quercetin in the medium is preferably 20 to 200 μM.
【０００９】[0009]
【作用】多剤耐性遺伝子ＭＤＲ１の転写及び発現は、例
えば熱や亜砒酸によって増強される。多剤耐性遺伝子Ｍ
ＤＲ１の転写及び発現が増強されると、多剤耐性遺伝子
ＭＤＲ１の産物であるＰ−糖タンパク質が多量に産生さ
れ、Ｐ−糖タンパク質が細胞内の抗癌剤などを細胞外へ
排出するので、多剤耐性が現れることになる。しかしな
がら、本発明の多剤耐性抑制剤において有効成分として
用いるフラボノイド、特にケルセチンは、多剤耐性遺伝
子ＭＤＲ１の転写及び発現を誘導又は増強する物質の作
用を阻害し、抑制することができる。従って、本発明の
多剤耐性抑制剤は、抗癌剤が本来的に有する抗癌作用を
維持あるいは増強することができる。また、前記のフラ
ボノイド、特にケルセチンは、多剤耐性を有する腫瘍細
胞に発現する多剤耐性遺伝子ＭＤＲ１を転写レベルで直
接阻害するので、従来から多剤耐性抑制に用いられてき
たＣａ2+拮抗薬のような毒性がない。Transcription and expression of the multidrug resistance gene MDR1 are enhanced by, for example, heat or arsenous acid. Multidrug resistance gene M
When the transcription and expression of DR1 is enhanced, a large amount of P-glycoprotein, which is a product of the multidrug resistance gene MDR1, is produced, and the P-glycoprotein excretes intracellular anticancer drug and the like outside the cell. Tolerance will appear. However, the flavonoid used as an active ingredient in the multidrug resistance inhibitor of the present invention, particularly quercetin, can inhibit and suppress the action of a substance that induces or enhances the transcription and expression of the multidrug resistance gene MDR1. Therefore, the multidrug resistance inhibitor of the present invention can maintain or enhance the anticancer action originally possessed by the anticancer agent. In addition, the flavonoids, especially Quercetin, since the multidrug resistance gene MDR1 expressed in tumor cells with multidrug resistance directly inhibited at the transcriptional level, Ca 2+ antagonists that have been used in multi-drug resistant suppressed conventionally There is no toxicity like.
【００１０】[0010]
【実施例】以下、実施例によって本発明を具体的に説明
するが、これらは本発明の範囲を限定するものではな
い。The present invention will be described in detail below with reference to examples, but these do not limit the scope of the present invention.
【００１１】実施例１：ケルセチンによるＭＤＲ１遺伝
子転写抑制作用 ヒト肝癌由来のＨｅｐＧ２細胞（ＡＴＣＣ−ＨＢ８０６
５）を１０％ウシ胎児血清含有ダルベッコ・モディファ
イド・イーグル培地（Ｄｕｌｂｅｃｃｏ’ｓＭｏｄｉｆ
ｉｅｄ Ｅａｇｌｅ’ｓ Ｍｅｄｉｕｍ）中で培養し
た。この細胞のＭＤＲ１遺伝子の発現に対するケルセチ
ンの効果を調べるため、ＭＤＲ１遺伝子のプロモーター
の下流にＣＡＴ（クロラムフェニコールアセチルトラン
スフェラーゼ）遺伝子を連結し、ＣＡＴアッセイ法
〔「ラボマニュアル 遺伝子工学 増補版」、第３０
章、１９９０年、丸善（株）〕により解析した。具体的
には、ＭＤＲ１下流プロモーターの制御下にＣＡＴ遺伝
子を含んでいるプラスミドｐＭＰ１ＣＡＴ〔ＭＤＲ１の
プロモーター領域（Ueda,K., et al., Jpn. J. Cancer
Res., 80, 1127-1132, (1989) 参照）をエクソヌクレア
ーゼIII （タカラカタログ番号２１７０）とマングビー
ンヌクレアーゼ（タカラカタログ番号２４２０）により
切出した後、プラスミドｐＳＶ００ＣＡＴ（Araki,E.,
et al., Nucleic Acids Res., (1988), 16, 1627参照）
につなぎかえたプラスミドである〕、対照としてＴＫプ
ロモーター（ＭＤＲ１プロモーター不存在）の下流にＣ
ＡＴ遺伝子を連結したプラスミドｐＢＬＣＡＴ２〔Luck
ow,B., et al., Nucleic Acids Res.,15, 5490 (1987)
参照〕を用いた。これらの各プラスミドＤＮＡ１０μｇ
を、内部コントロールプラスミドとしてのｐａｃｔ−β
−ｇａｌ（ニワトリ−β−アクチンプロモーターの制御
下にβ−ガラクトシダーゼ遺伝子を有する）（理化学研
究所分子遺伝学教室石井俊輔氏より入手）５μｇと共
に、リン酸カルシウム共沈澱法によって前記細胞に導入
した。ＤＮＡ導入とグリセロールショックが或る種のス
トレスを引き起こすので、導入処理から４日後の細胞を
使用した。ＣＡＴ酵素活性を測定する前にこれらの細胞
を４群に分け、以下の各種の処理を行なった。即ち、
（１）薬物処理を行なわずそのまま培養〔表１の「コン
トロール」欄〕、（２）亜砒酸ナトリウム（１００μ
Ｍ）処理を４時間実施〔表１の「亜砒酸ナトリウム」
欄〕、（３）ケルセチン（ナカライテスク製：１００μ
Ｍ）処理を４時間実施〔表１の「ケルセチン」欄〕、及
び（４）前項（３）のケルセチン処理を４時間実施した
後、更にケルセチンを入れたまま、亜砒酸ナトリウム
（１００μＭ）処理を４時間実施〔表１の「ケルセチン
＋亜砒酸ナトリウム」欄〕。 Example 1: MDR1 inheritance by quercetin
Inhibition of child transcription HepG2 cells derived from human liver cancer (ATCC-HB806
5) was added to 10% fetal bovine serum in Dulbecco's Modified Eagle Medium (Dulbecco's Modif).
ied Eagle's Medium). In order to investigate the effect of quercetin on the expression of MDR1 gene in these cells, the CAT (chloramphenicol acetyltransferase) gene was ligated downstream of the MDR1 gene promoter, and the CAT assay method [“Labo Manual Genetic Engineering Supplement”, Thirty
Chapter, 1990, Maruzen Co., Ltd.]. Specifically, the plasmid pMP1CAT [MDR1 promoter region (Ueda, K., et al., Jpn. J. Cancer.
Res., 80, 1127-1132, (1989)) was excised with exonuclease III (Takara Catalog No. 2170) and mung bean nuclease (Takara Catalog No. 2420), and then plasmid pSV00CAT (Araki, E.,
et al., Nucleic Acids Res., (1988), 16, 1627)
Plasmid, which was replaced with C.), and C as a control downstream of the TK promoter (absence of MDR1 promoter).
Plasmid pBLCAT2 [Luck in which AT gene is ligated
ow, B., et al., Nucleic Acids Res., 15, 5490 (1987)
Reference] was used. 10 μg of each of these plasmid DNAs
As pact-β as an internal control plasmid
-Gal (having a β-galactosidase gene under the control of the chicken β-actin promoter) (obtained from Shunsuke Ishii, Department of Molecular Genetics, RIKEN) and introduced into the cells by the calcium phosphate coprecipitation method. Cells were used 4 days after the transfection treatment, as DNA transduction and glycerol shock cause some stress. Before measuring the CAT enzyme activity, these cells were divided into 4 groups and subjected to the following various treatments. That is,
(1) Incubation without drug treatment (“Control” column in Table 1), (2) Sodium arsenite (100 μm)
M) Treatment is carried out for 4 hours [“sodium arsenite” in Table 1]
Column], (3) Quercetin (manufactured by Nacalai Tesque: 100μ
M) Treatment for 4 hours [“Quercetin” column of Table 1), and (4) Quercetin treatment of the previous section (3) for 4 hours. Time implementation [Table 1, "Quercetin + sodium arsenite" column].
【００１２】亜砒酸ナトリウムはリン酸緩衝液（ＰＢ
Ｓ）に、ケルセチンは１０mMの濃度でジメチルスルホキ
シド（ＤＭＳＯ）にそれぞれ溶解しておき、培地中で所
定の濃度となるように培地に添加した。続いて、（２）
〜（４）についてはケルセチンを含む新鮮な培養液に交
換してから更に２時間培養して細胞を回復させた。同じ
β−ガラクトシダーゼ活性を示す細胞抽出物をＣＡＴア
ッセイに用いた。以下の表１に、ＣＡＴアッセイの５回
の平均値を示す（コントロールを１００とした相対
値）。Sodium arsenite is a phosphate buffer solution (PB
In S), quercetin was dissolved in dimethylsulfoxide (DMSO) at a concentration of 10 mM, and added to the medium so that the concentration of the quercetin became a predetermined concentration. Then, (2)
Regarding (4) to (4), the cells were recovered by exchanging with a fresh culture medium containing quercetin and further culturing for 2 hours. Cell extracts showing the same β-galactosidase activity were used for the CAT assay. Table 1 below shows the average value of 5 times of the CAT assay (relative value with the control being 100).
【００１３】[0013]
【表１】 処理 ｐＭＰ１ＣＡＴ ｐＢＬＣＡＴ２ (MDR1フ゜ロモータ) (TK フ゜ロモータ) コントロール １００ １００ 亜砒酸ナトリウム ２０８ １０６ ケルセチン １１４ １１３ ケルセチン＋亜砒酸ナトリウム ９４ １０６ Table 1 Treatment pMP1CAT pBLCAT2 (MDR1 promotor) (TK promotor) control 100 100 sodium arsenite 208 106 quercetin 114 113 quercetin + sodium arsenite 94 106
【００１４】実施例２：ケルセチンによるＰ−糖タンパ
ク質生合成抑制作用 Ｐ−糖タンパク質生合成に対する影響を免疫沈降法によ
って調べた。実施例１で用いたＨｅｐＧ２細胞を実施例
１と同様の条件下で培養した後、これらの細胞を４群に
分け、以下の各種の処理を行なった。即ち、（１）薬物
処理を行なわずそのまま培養〔表２の「コントロール」
欄〕、（２）亜砒酸ナトリウム（１００μＭ）処理を４
時間実施〔表２の「亜砒酸ナトリウム」欄〕、（３）ケ
ルセチン（ナカライテスク製：１００μＭ）処理を４時
間実施〔表２の「ケルセチン」欄〕、及び（４）前項
（３）のケルセチン処理を４時間実施した後、更にケル
セチンを入れたまま、亜砒酸ナトリウム（１００μＭ）
処理を４時間実施〔表２の「ケルセチン＋亜砒酸ナトリ
ウム」欄〕。 Example 2: P-sugar tamper with quercetin
Suppression of protein biosynthesis The effect on P-glycoprotein biosynthesis was examined by immunoprecipitation. The HepG2 cells used in Example 1 were cultured under the same conditions as in Example 1, and then these cells were divided into 4 groups and subjected to the following various treatments. That is, (1) culture without treatment with a drug [“control” in Table 2]
Column], (2) treatment with sodium arsenite (100 μM)
Time treatment [“Sodium arsenite” column of Table 2], (3) Quercetin (manufactured by Nacalai Tesque: 100 μM) treatment for 4 hours [“Quercetin” column of Table 2], and (4) Quercetin treatment of the preceding paragraph (3) After 4 hours, sodium arsenite (100 μM) with quercetin added
The treatment was carried out for 4 hours [column of "Quercetin + sodium arsenite" in Table 2].
【００１５】亜砒酸ナトリウムはリン酸緩衝液（ＰＢ
Ｓ）に、ケルセチンは１０mMの濃度でジメチルスルホキ
シド（ＤＭＳＯ）にそれぞれ溶解しておき、培地中で所
定の濃度となるように培地に添加した。続いて、（２）
〜（４）についてはケルセチンを含む新鮮な培養液に交
換してから更に２時間培養して細胞を回復させた。次
に、35Ｓメチオニンで細胞を１時間処理して標識化し
た。細胞の破砕物とＰ−糖タンパク質に対するモノクロ
ナール抗体Ｃ−２１９（セントコア社）を４℃で１時間
混合しプロテインＡ−セファロースで免疫複合体を沈澱
させた。沈澱物を７％ナトリウムドデシルサルフェート
−ポリアクリルアミドゲル（ＳＤＳ−ＰＡＧＥ）で電気
泳動した後、各泳動バンドの濃さをデンシトメーターで
測定した。各処理に対するＰ−糖タンパク質の産生量を
表２に示す（コントロールを１．０とした相対値）。Sodium arsenite is a phosphate buffer solution (PB
In S), quercetin was dissolved in dimethylsulfoxide (DMSO) at a concentration of 10 mM, and added to the medium so that the concentration of the quercetin became a predetermined concentration. Then, (2)
Regarding (4) to (4), the cells were recovered by exchanging with a fresh culture medium containing quercetin and further culturing for 2 hours. The cells were then labeled with 35 S methionine for 1 hour. The cell lysate and the monoclonal antibody C-219 against P-glycoprotein (Centcor) were mixed at 4 ° C for 1 hour, and the immune complex was precipitated with protein A-sepharose. The precipitate was electrophoresed on 7% sodium dodecyl sulfate-polyacrylamide gel (SDS-PAGE), and then the density of each electrophoretic band was measured by a densitometer. The amount of P-glycoprotein produced for each treatment is shown in Table 2 (relative value with control as 1.0).
【００１６】[0016]
【表２】 処理 Ｐ−糖タンパク質の産生量 コントロール １．０ 亜砒酸ナトリウム ２．２ ケルセチン ＜１．０ ケルセチン＋亜砒酸ナトリウム ＜１．０ [Table 2] Treatment P-glycoprotein production control 1.0 Sodium arsenite 2.2 Quercetin <1.0 Quercetin + sodium arsenite <1.0
【００１７】以上のように、ケルセチンは、多剤耐性タ
ンパク質をコードする遺伝子ＭＤＲ１の発現増強を転写
レベルで阻害しＰ−糖タンパク質の生合成を阻害するこ
とが明らかである。As described above, it is clear that quercetin inhibits the enhanced expression of the gene MDR1 encoding a multidrug resistance protein at the transcription level and inhibits the biosynthesis of P-glycoprotein.
【００１８】[0018]
【発明の効果】本発明の多剤耐性抑制剤において有効成
分として用いるフラボノイド、特にケルセチンは、多剤
耐性を有する腫瘍細胞に発現するＭＤＲ１遺伝子を転写
レベルで直接阻害するので、従来、多剤耐性の克服に試
みられてきたＣａ2+拮抗剤に見られた毒性はない。従っ
て、本発明は新規な多剤耐性克服手段を提供するもので
ある。INDUSTRIAL APPLICABILITY The flavonoid used as an active ingredient in the multidrug resistance inhibitor of the present invention, particularly quercetin, directly inhibits the MDR1 gene expressed in tumor cells having multidrug resistance at the transcription level. There is no toxicity seen with Ca 2+ antagonists that have been attempted to overcome. Therefore, the present invention provides a novel means for overcoming multidrug resistance.
Claims (2)
多剤耐性抑制剤。1. A flavonoid is contained,
Multidrug resistance inhibitor.
１記載の多剤耐性抑制剤。2. The multidrug resistance inhibitor according to claim 1, wherein the flavonoid is quercetin.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3263234A JP2514500B2 (en) | 1991-09-14 | 1991-09-14 | Multidrug resistance inhibitor and expression inhibitor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3263234A JP2514500B2 (en) | 1991-09-14 | 1991-09-14 | Multidrug resistance inhibitor and expression inhibitor |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH0570348A true JPH0570348A (en) | 1993-03-23 |
| JP2514500B2 JP2514500B2 (en) | 1996-07-10 |
Family
ID=17386645
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP3263234A Expired - Lifetime JP2514500B2 (en) | 1991-09-14 | 1991-09-14 | Multidrug resistance inhibitor and expression inhibitor |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2514500B2 (en) |
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2781153A1 (en) * | 1998-07-15 | 2000-01-21 | Lafon Labor | Use of flavonoids to prevent proliferation of clonogenic cells in tumors, as a supplement to conventional chemotherapeutic treatment |
| JP2003508524A (en) * | 1999-09-03 | 2003-03-04 | インデナ・ソチエタ・ペル・アツィオーニ | New derivatives of flavones, xanthones and coumarins |
| WO2004069233A1 (en) * | 2003-02-04 | 2004-08-19 | Kabushiki Kaisha Yakult Honsha | Breast cancer-resistant protein inhibitor |
| JP2006504705A (en) * | 2002-10-02 | 2006-02-09 | ノボジェン リサーチ プロプライアタリー リミテッド | Combination chemotherapy compositions and methods |
| JP2007525485A (en) * | 2003-11-19 | 2007-09-06 | ノボゲン リサーチ ピーティーワイ リミテッド | Combined radiotherapy and chemotherapy compositions and methods |
| CN100360670C (en) * | 2005-09-30 | 2008-01-09 | 东北师范大学遗传与细胞研究所 | Human MDR1 gene expression regulator screening system and method for screening gene expression regulator |
| JP2014518274A (en) * | 2011-07-07 | 2014-07-28 | リサーチ キャンサー インスティテュート オブ アメリカ | Systems, methods, and formulations for treating cancer |
| KR20150101436A (en) * | 2015-08-11 | 2015-09-03 | 건국대학교 산학협력단 | A composition inhibiting for anticancer and antibiotic multidrug resisitance comprising quercetin-amino acid conjugates and a method therof |
| US10016392B2 (en) | 2011-07-14 | 2018-07-10 | Research Cancer Institute Of America | Method of treating cancer with combinations of histone deacetylase inhibitors (HDAC1) substances |
| US11369585B2 (en) | 2017-03-17 | 2022-06-28 | Research Cancer Institute Of America | Compositions, methods, systems and/or kits for preventing and/or treating neoplasms |
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-
1991
- 1991-09-14 JP JP3263234A patent/JP2514500B2/en not_active Expired - Lifetime
Non-Patent Citations (3)
| Title |
|---|
| BIOCHEM.BIOPHYS.RES.COMMUN=1991 * |
| CANCER CHEMOTHER.PHARMACOL=1991 * |
| FEMS MICROBIOL.LETT=1989 * |
Cited By (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2781153A1 (en) * | 1998-07-15 | 2000-01-21 | Lafon Labor | Use of flavonoids to prevent proliferation of clonogenic cells in tumors, as a supplement to conventional chemotherapeutic treatment |
| WO2000003706A1 (en) * | 1998-07-15 | 2000-01-27 | Laboratoire L. Lafon | Therapeutic composition based on flavonoids for use in the treatment of tumours with cytotoxic agents |
| JP2003508524A (en) * | 1999-09-03 | 2003-03-04 | インデナ・ソチエタ・ペル・アツィオーニ | New derivatives of flavones, xanthones and coumarins |
| JP4782337B2 (en) * | 1999-09-03 | 2011-09-28 | インデナ・ソチエタ・ペル・アツィオーニ | New derivatives of flavones, xanthones and coumarins |
| JP2006504705A (en) * | 2002-10-02 | 2006-02-09 | ノボジェン リサーチ プロプライアタリー リミテッド | Combination chemotherapy compositions and methods |
| US7906554B2 (en) | 2002-10-02 | 2011-03-15 | Novogen Research Pty Ltd | Combination chemotherapy compositions and methods |
| WO2004069233A1 (en) * | 2003-02-04 | 2004-08-19 | Kabushiki Kaisha Yakult Honsha | Breast cancer-resistant protein inhibitor |
| JP2007525485A (en) * | 2003-11-19 | 2007-09-06 | ノボゲン リサーチ ピーティーワイ リミテッド | Combined radiotherapy and chemotherapy compositions and methods |
| CN100360670C (en) * | 2005-09-30 | 2008-01-09 | 东北师范大学遗传与细胞研究所 | Human MDR1 gene expression regulator screening system and method for screening gene expression regulator |
| JP2014518274A (en) * | 2011-07-07 | 2014-07-28 | リサーチ キャンサー インスティテュート オブ アメリカ | Systems, methods, and formulations for treating cancer |
| JP2017105797A (en) * | 2011-07-07 | 2017-06-15 | リサーチ キャンサー インスティテュート オブ アメリカＲｅｓｅａｒｃｈ Ｃａｎｃｅｒ Ｉｎｓｔｉｔｕｔｅ Ｏｆ Ａｍｅｒｉｃａ | Systems, methods and formulations for treating cancer |
| US10016392B2 (en) | 2011-07-14 | 2018-07-10 | Research Cancer Institute Of America | Method of treating cancer with combinations of histone deacetylase inhibitors (HDAC1) substances |
| US10966957B2 (en) | 2011-07-14 | 2021-04-06 | Research Cancer Institute Of America | Method of treating cancer with combinations of histone deacetylase inhibitors (HDAC1) substances |
| US11890269B2 (en) | 2011-07-14 | 2024-02-06 | Research Cancer Institute Of America | Method of treating cancer with combinations of histone deacetylase inhibitors (HDAC1) substances |
| KR20150101436A (en) * | 2015-08-11 | 2015-09-03 | 건국대학교 산학협력단 | A composition inhibiting for anticancer and antibiotic multidrug resisitance comprising quercetin-amino acid conjugates and a method therof |
| US11890292B2 (en) | 2017-02-27 | 2024-02-06 | Research Cancer Institute Of America | Compositions, methods, systems and/or kits for preventing and/or treating neoplasms |
| US11369585B2 (en) | 2017-03-17 | 2022-06-28 | Research Cancer Institute Of America | Compositions, methods, systems and/or kits for preventing and/or treating neoplasms |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2514500B2 (en) | 1996-07-10 |
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