JP3175832B2 - Antitumor agent - Google Patents
Antitumor agentInfo
- Publication number
- JP3175832B2 JP3175832B2 JP33045290A JP33045290A JP3175832B2 JP 3175832 B2 JP3175832 B2 JP 3175832B2 JP 33045290 A JP33045290 A JP 33045290A JP 33045290 A JP33045290 A JP 33045290A JP 3175832 B2 JP3175832 B2 JP 3175832B2
- Authority
- JP
- Japan
- Prior art keywords
- piperidino
- human
- camptothecin
- ethyl
- carboniloxy
- 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 - Fee Related
Links
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
【発明の詳細な説明】 〔産業上の利用分野〕 本発明は、優れた抗腫瘍効果を有する薬剤に関し、更
に詳しくは、生物反応修飾物質（BRM）の一つであるヒ
トインターフェロン（ヒトIFN）と、強い抗腫瘍効果を
有するカンプトテシン誘導体である７−エチル−10−ピ
ペリジノ−ピペリジノ−カルボニロキシ−カンプトテシ
ンもしくはその塩を組み合わせた癌治療に有効な薬剤に
関する。Description: TECHNICAL FIELD The present invention relates to a drug having an excellent antitumor effect, and more specifically, human interferon (human IFN) which is one of biological response modifiers (BRM) And 7-ethyl-10-piperidino-piperidino-carboniloxy-camptothecin, which is a camptothecin derivative having a strong antitumor effect, or a salt thereof, which is effective for treating cancer.
７−エチル−10−ピペリジノ−ピペリジノ−カルボニ
ロキシ−カンプトテシンは、中国原産の植物である喜樹
（Camptotheca acuminata）などに含有されるアルカロ
イドの一種であるカンプトテシンから誘導された半合成
誘導体である。7-Ethyl-10-piperidino-piperidino-carboniloxy-camptothecin is a semi-synthetic derivative derived from camptothecin, a kind of alkaloid contained in plants such as Camptotheca acuminata, a plant native to China.
カンプトテシンの臨床研究は、1970年代に米国NCIに
よって行われたが、強い副作用の発現などがみられるた
め、カンプトテシンそのものについての研究は中止され
ている。Clinical research on camptothecin was conducted by the US NCI in the 1970s, but research on camptothecin itself has been discontinued due to strong side effects.
その後、種々のカンプトテシン誘導体について合成研
究が行われた結果、宮坂、沢田らにより水溶性でかつ優
れた抗腫瘍効果を有し、さらに毒性も軽減された７−エ
チル−10−ピペリジノ−ピペリジノ−カルボニロキシ−
カンプトテシンが合成され、抗腫瘍剤として提供された
（特開昭60−19790号公報、特開昭61−85319号公報参
照）。Thereafter, as a result of conducting synthetic studies on various camptothecin derivatives, 7-ethyl-10-piperidino-piperidino-carboniloxy which was soluble in water and had an excellent antitumor effect by Miyasaka and Sawada et al. −
Camptothecin was synthesized and provided as an antitumor agent (see JP-A-60-19790 and JP-A-61-85319).
７−エチル−10−ピペリジノ−ピペリジノ−カルボニ
ロキシ−カンプトテシンは、各種実験腫瘍に対して優れ
た抗腫瘍効果を示し、スペクトルも広く治療係数も高い
という特徴を有する。その作用機作は、トポイソメラー
ゼＩへの阻害に基づく核酸合成阻害作用であるとされて
おり、他に類をみない新しいタイプの癌化学療法剤とし
て注目されている。本国においては、現在第II相臨床試
験中であり、肺癌、婦人科癌、乳癌等に対してその有効
性が確認されている。7-ethyl-10-piperidino-piperidino-carboniloxy-camptothecin has an excellent antitumor effect against various experimental tumors, and is characterized by a broad spectrum and a high therapeutic index. Its mode of action is said to be a nucleic acid synthesis inhibitory action based on inhibition of topoisomerase I, and has attracted attention as a unique new type of cancer chemotherapeutic agent. In its home country, it is currently undergoing phase II clinical trials, and its efficacy has been confirmed for lung cancer, gynecological cancer, breast cancer, and the like.
しかし、癌の種類によっては、効果が発現しにくいも
のもあり、他の薬剤との併用療法の検討も行われてい
る。However, depending on the type of cancer, some of the effects are unlikely to be exhibited, and combination therapy with other drugs is being studied.
一方で、近年癌治療の分野では、各種インターフェロ
ン（α、β、γ等）、各種インターロイキン（IL−１〜
IL−８等）、腫瘍細胞壊死因子（TNF）といった生物反
応修飾物質（BRM）と称される物質群が生物工学的手法
による大量生産の技術の進歩もあいまって、脚光をあび
ている。これらの物質は、腫瘍細胞に対する宿主の生物
学的応答を調節することにより治療効果を発揮させるも
のである。このうちのいくつかは単独で効果を発揮する
が、その効果は必ずしも充分なものではなく用法の工夫
が望まれている。On the other hand, in recent years, in the field of cancer treatment, various interferons (α, β, γ, etc.), various interleukins (IL-1 to IL-1)
A group of substances called biological response modifiers (BRMs), such as IL-8) and tumor cell necrosis factor (TNF), have been spotlighted along with the progress of mass-production technology using biotechnological techniques. These substances exert a therapeutic effect by modulating the biological response of the host to tumor cells. Some of them exert their own effects, but their effects are not always sufficient, and a method of using them is desired.
本発明者らは、強力な抗腫瘍活性を有する７−エチル
−10−ピペリジノ−ピペリジノ−カルボニロキシ−カン
プトテシンの癌治療薬としての有用性を広げることを目
的として、７−エチル−10−ピペリジノ−ピペリジノ−
カルボニロキシ−カンプトテシンとヒトインターフェロ
ン（以下、ヒトIFNと略記する）またはヒト腫瘍細胞壊
死因子（以下、ヒトTNFと略記する）との併用効果の検
討を行ったところ、ヒト腎細胞癌を用いたin vivoアッ
セイ系で強い併用効果が得られることが確認された。本
発明は、かかる知見に基づいて完成するに至ったもので
ある。The present inventors aimed to expand the usefulness of 7-ethyl-10-piperidino-piperidino-carboniloxy-camptothecin, which has potent antitumor activity, as a therapeutic agent for cancer, by using 7-ethyl-10-piperidino-piperidino. −
Examination of the combined effect of carboniloxy-camptothecin and human interferon (hereinafter abbreviated as human IFN) or human tumor cell necrosis factor (hereinafter abbreviated as human TNF) was performed. It was confirmed that a strong combination effect was obtained in the assay system. The present invention has been completed based on such findings.
すなわち、本発明は、ヒトインターフェロンまたはヒ
ト腫瘍細胞壊死因子と下記構造式（Ｉ）で表される７−
エチル−10−ピペリジノ−ピペリジノ−カルボニロキシ
−カンプトテシンもしくはその塩 とを併用することにより、個々の物質が示す抗腫瘍効果
より一層高い抗腫瘍効果を示す抗腫瘍剤を提供するもの
である。That is, the present invention relates to human interferon or human tumor cell necrosis factor, which is represented by the following structural formula (I):
Ethyl-10-piperidino-piperidino-carboniloxy-camptothecin or a salt thereof In combination, the present invention provides an antitumor agent exhibiting a higher antitumor effect than the antitumor effect exhibited by an individual substance.
本発明に係る抗腫瘍剤のうち、上記式（Ｉ）の化合物
は、さきに引用した公報に記載された方法により製造す
ることができる。Among the antitumor agents according to the present invention, the compound of the above formula (I) can be produced by the method described in the publication cited above.
すなわち、例えば天然から単離されたカンプトテシ
ン、もしくは全合成法で得られたカンプトテシンから、
ラジカルアルキル化反応、光照射ヒドロキシ転移反応を
経て合成された７−エチル−10−ヒドロキシカンプトテ
シンにピペリジノピペリジノクロルカーボネートを反応
させて製造することができる。That is, for example, from camptothecin isolated from nature or camptothecin obtained by a total synthesis method,
It can be produced by reacting 7-ethyl-10-hydroxycamptothecin synthesized via a radical alkylation reaction and a light irradiation hydroxylation reaction with piperidinopiperidinochlorocarbonate.
本発明に係る式（Ｉ）の化合物は、そのまま用いても
よいが、各種酸との塩（塩酸塩、硫酸塩等）とし、水溶
性を上げて使用するとよい。The compound of the formula (I) according to the present invention may be used as it is, or may be used in the form of salts with various acids (hydrochloride, sulfate, etc.) to increase the water solubility.
また、本発明に係る抗腫瘍剤に用いられる、ヒトIFN
は、IFNα、β、及びγの３種が知られており、ヒト末
梢血白血球、リンパ芽球細胞、線維芽細胞、または末梢
血リンパ球等をウィルス、合成poly IC（２重鎖RNA）、
またはマイトージエン等で刺激することにより生産され
るものを単離・精製して得ることができる。例えば、パ
ーキットリンパ腫由来のナマルバ細胞に、センダイウィ
ルスにより刺激して抽出することによりIFNαが得られ
る。またヒトインターフェロンの産生遺伝子を利用して
大腸菌を宿主とする遺伝子工学の手法によっても製造す
ることができる。Further, human IFN used in the antitumor agent according to the present invention.
Are known to be three kinds of IFNα, β, and γ, and can be used for human peripheral blood leukocytes, lymphoblast cells, fibroblasts, or peripheral blood lymphocytes, etc. as viruses, synthetic poly IC (double-stranded RNA),
Alternatively, those produced by stimulating with mitogen or the like can be obtained by isolation and purification. For example, IFNα can be obtained by extracting and stimulating Namalba cells derived from Parkit lymphoma with Sendai virus. It can also be produced by a genetic engineering technique using Escherichia coli as a host using a human interferon production gene.
また、本発明に係る抗腫瘍剤に用いられる、ヒトTNF
例えばヒトTNFαは、in vivoもしくはin vitroでヒトの
白血球もしくはマクロファージをBCG、コリネバクテリ
ア、インターフェロンγ等で感作し、ついでバクテリア
のエンドトキシンで刺激することにより生産されるもの
を単離・精製して得られる。またヒトTNFを産生遺伝子
を利用して大腸菌を宿主とする遺伝子工学の手法によっ
ても製造することができる。Further, human TNF used in the antitumor agent according to the present invention.
For example, human TNFα is isolated and purified by sensitizing human leukocytes or macrophages in vivo or in vitro with BCG, corynebacterium, interferon γ, etc., and then stimulating with bacterial endotoxin. can get. Human TNF can also be produced by a genetic engineering technique using Escherichia coli as a host using a gene for production.
本発明に係る成分の安全性については、式（Ｉ）の化
合物は先の引例においては、通常の投与量の範囲で安全
であることが確認されており、ヒトIFN並びにヒトTNFに
ついても通常の投与の範囲では、重篤な副作用を発現し
ない。すなわち、ヌードマウスを用いたin vivoの系に
おいて、ヒトIFNは１×105〜１×106IUの投与量で全く
体重変化が見られず、ヒトTNFは1000〜20000JRUの投与
量で全く体重変化が見られない。With respect to the safety of the components according to the present invention, the compounds of formula (I) have been confirmed in the above references to be safe in the usual dosage range, and the human IFN and human TNF are also known to be safe. No serious side effects occur in the range of administration. That is, in an in vivo system using nude mice, human IFN showed no change in body weight at a dose of 1 × 10 5 to 1 × 10 6 IU, and human TNF showed no weight change at a dose of 1000 to 20000 JRU. No change is seen.
本発明に係る抗腫瘍剤は、各薬剤の有効適応量の範囲
で腫瘍の種類や症状などにより適宜の量で併用される
が、式（Ｉ）の化合物対ヒトIFNの使用割合としては、
体重1kgあたり10〜1000mg対１×104〜１×106IUが適当
であり、更に好ましくは10〜500mg対１×104〜３×105I
Uの使用割合がよい。また、ヒトTNFとの使用割合として
は体重1kgあたり10〜1000mg対1000〜50000JRUが適当で
あり、更に好ましくは10〜500mg対1000〜10000JRUの使
用割合がよい。The antitumor agent according to the present invention is used in an appropriate amount depending on the type and symptom of the tumor within the range of the effective adaptation amount of each drug, and the use ratio of the compound of formula (I) to human IFN is as follows:
10-1000 mg / kg body weight to 1 × 10 4 -1 × 10 6 IU is suitable, more preferably 10-500 mg to 1 × 10 4 -3 × 10 5 IU.
U use ratio is good. The ratio of use with human TNF is suitably from 10 to 1000 mg / kg to 1,000 to 50,000 JRU / kg of body weight, and more preferably from 10 to 500 mg / 1000 to 10,000 JRU / kg.
各薬剤はいずれも水溶性であるから、医薬上許容され
る安定剤、浸透圧調整剤、pH調節剤等の助剤とともに適
宜水溶液として注射剤等に製剤化される。また、各薬剤
をそれぞれ、単独に含む単位製剤の形にしておき、それ
らを用時に混合して使用する形態をとってもよい。ま
た、それぞれの単独製剤を、独立して、異なる投与方法
（例えば、皮下投与、静脈投与、筋肉注射）で投与して
もよい。Since each drug is water-soluble, it is formulated into an injection or the like as an appropriate aqueous solution together with pharmaceutically acceptable auxiliaries such as a stabilizer, an osmotic pressure regulator, and a pH regulator. In addition, a form may be used in which each drug is individually contained in the form of a unit preparation, and they are mixed when used. In addition, each of the single preparations may be independently administered by different administration methods (for example, subcutaneous administration, intravenous administration, intramuscular injection).
以下に、本発明の内容、効果について実施例をもって
説明するが、本発明は本実施例に限定されるものではな
い。Hereinafter, the contents and effects of the present invention will be described with reference to examples, but the present invention is not limited to the examples.
７−エチル−10−ピペリジノ−ピペリジノ−カルボニ
ロキシ−カンプトテシンは、引例の方法により製造し、
それを塩酸塩の水溶液として使用した。7-ethyl-10-piperidino-piperidino-carboniloxy-camptothecin was prepared by the method of the reference,
It was used as an aqueous solution of the hydrochloride.
ヒトIFNは、ヒトIFNαの注射剤スミフェロン（商品
名：住友製薬者製）を使用した。As the human IFN, human IFNα injection Sumiferon (trade name, manufactured by Sumitomo Pharmaceutical Co., Ltd.) was used.
ヒトTNFは、特開昭61−50923号公報に記載の方法に従
って製造したヒトTNFαを使用した。As human TNF, human TNFα produced according to the method described in JP-A-61-50923 was used.
実験株として、可移植性ヒト腎細胞癌株（JRC11:anap
lastic and alveolar pattern,grade IV）を用いた。ヌ
ードマウスの両側腹部皮下に2mm角に細切した腫瘍細胞
を移植し、移植腫瘍が100mg〜300mgに増殖した時点で薬
剤の投与を開始した。As an experimental strain, a transplantable human renal cell carcinoma strain (JRC11: anap
lastic and alveolar pattern, grade IV). Tumor cells cut into 2 mm squares were implanted subcutaneously in both abdominal regions of nude mice, and drug administration was started when the transplanted tumor grew to 100 to 300 mg.
投与薬剤は、７−エチル−10−ピペリジノ−ピペリジ
ノ−カルボニロキシ−カンプトテシン塩酸塩（以下、CP
T−11と略記する）が50mg/kgと100mg/kgの２群につい
て、４日に１回腹腔内投与を行った。ヒトTNFαは3000J
RU/kgと10000JRU/kgの２群については連日腹腔内投与を
行た。ヒトINFαは１×105IU/kgと３×105IU/kgの２群
について連日皮下投与を行った。The administered drug was 7-ethyl-10-piperidino-piperidino-carboniloxy-camptothecin hydrochloride (hereinafter referred to as CP).
T-11) was administered intraperitoneally once every four days for two groups, 50 mg / kg and 100 mg / kg. Human TNFα is 3000J
The two groups of RU / kg and 10,000 JRU / kg were administered intraperitoneally every day. Human INFα was subcutaneously administered daily for two groups, 1 × 10 5 IU / kg and 3 × 10 5 IU / kg.
効果判定は、各群５匹として各薬剤についての単独投
与群と、併用投与群について、薬剤非投与のコントロー
ル群に対する相対的平均腫瘍重量比（T/C値）、病理組
織学的変性の程度（下里分類）、マウスの延命効果の３
項目で行った。腫瘍増殖に対する薬剤の併用による効果
の結果を単独投与群の場合（表１）とともに表２〜表４
に示す。The effect was evaluated by determining the relative average tumor weight ratio (T / C value) and the degree of histopathological degeneration of the single administration group for each drug and the combination administration group as compared to the control group not administered with the drug as 5 animals per group. (Shimosato classification), 3
Made with items. Table 2 to Table 4 show the results of the effects of the combined use of the agents on tumor growth, together with the case of the single administration group (Table 1)
Shown in
〔発明の効果〕 抗腫瘍効果試験の結果から明らかなとおり、本発明に
係る、７−エチル−10−ピペリジノ−ピペリジノ−カル
ボニロキシ−カンプトテシンとヒトIFNもしくはヒトIFN
との組合せ使用による薬剤によれば、７−エチル−10−
ピペリジノ−ピペリジノ−カルボニロキシ−カンプトテ
シン単独では、顕著な効果が見られない腫瘍に対して
も、顕著な腫瘍阻止活性および延命効果が得られ、優れ
た抗腫瘍剤である７−エチル−10−ピペリジノ−ピペリ
ジノ−カルボニロキシ−カンプトテシンの用途をさらに
拡大するものである。 [Effects of the Invention] As is clear from the results of the antitumor effect test, 7-ethyl-10-piperidino-piperidino-carboniloxy-camptothecin according to the present invention and human IFN or human IFN
According to the drug used in combination with 7-ethyl-10-
With piperidino-piperidino-carboniloxy-camptothecin alone, a remarkable tumor-inhibiting activity and a prolonged survival effect are obtained even for tumors in which a remarkable effect is not seen, and 7-ethyl-10-piperidino- The use of piperidino-carboniloxy-camptothecin is further expanded.
フロントページの続き (72)発明者 町田 豊平 東京都港区西新橋３―25―８ 東京慈恵 会医科大学内 (72)発明者 萩原 久男 東京都港区東新橋１丁目１番19号 株式 会社ヤクルト本社内 (56)参考文献 特開 昭60−19790（ＪＰ，Ａ) 特開 昭61−85319（ＪＰ，Ａ) Ｂｉｏｃｈｅｍ．Ｂｉｏｐｈｙｓ．Ｒ ｅｓ．Ｃｏｍｍｕｎ．，Ｖｏｌ．166, Ｎｏ．１，（Ｊａｎ．1990）ｐ．160− 167 Ｃａｎｃｅｒ Ｒｅｓｅａｒｃｈ，Ｖ ｏｌ．50，Ｎｏ．９（Ｍａｙ 1990) ｐ．2636−2640 Ｊ．Ｉｍｍｕｎｏｌ．，Ｖｏｌ．145, Ｎｏ．９，（Ｎｏｖ．1990）ｐ．2908− 0913 (58)調査した分野(Int.Cl.7，ＤＢ名) A61K 31/4745 A61K 38/21 A61P 35/00 A61P 43/00 ＣＡ（ＳＴＮ) ＥＭＢＡＳＥ（ＳＴＮ) ＭＥＤＬＩＮＥ（ＳＴＮ)Continued on the front page (72) Inventor Toyohira Machida 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo Inside Jikei University Medical University (72) Inventor Hisao Hagiwara 1-1-1 Higashi-Shimbashi, Minato-ku, Tokyo Yakult Co., Ltd. In-house (56) References JP-A-60-19790 (JP, A) JP-A-61-85319 (JP, A) Biochem. Biophys. Res. Commun. , Vol. 166, no. 1, (Jan. 1990) p. 160-167 Cancer Research, Vol. 50, No. 9 (May 1990) p. 2636-2640 J.P. Immunol. , Vol. 145, no. 9, (Nov. 1990) p. 2908-0913 (58) Fields investigated (Int. Cl. 7 , DB name) A61K 31/4745 A61K 38/21 A61P 35/00 A61P 43/00 CA (STN) EMBASE (STN) MEDLINE (STN)
Claims (1)
（Ｉ）で表される７−エチル−10−ピペリジノ−ピペリ
ジノ−カルボニロキシ−カンプトテシンもしくはその塩 とを併用することを特徴とする抗腫瘍剤。1. Human interferon α and 7-ethyl-10-piperidino-piperidino-carboniloxy-camptothecin represented by the following structural formula (I) or a salt thereof: An antitumor agent, which is used in combination with
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP33045290A JP3175832B2 (en) | 1990-11-30 | 1990-11-30 | Antitumor agent |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP33045290A JP3175832B2 (en) | 1990-11-30 | 1990-11-30 | Antitumor agent |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH04208224A JPH04208224A (en) | 1992-07-29 |
| JP3175832B2 true JP3175832B2 (en) | 2001-06-11 |
Family
ID=18232779
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP33045290A Expired - Fee Related JP3175832B2 (en) | 1990-11-30 | 1990-11-30 | Antitumor agent |
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| Country | Link |
|---|---|
| JP (1) | JP3175832B2 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPWO2004083186A1 (en) * | 2003-03-18 | 2006-06-22 | 大日本住友製薬株式会社 | Viral hepatitis therapeutic agent and anticancer agent |
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1990
- 1990-11-30 JP JP33045290A patent/JP3175832B2/en not_active Expired - Fee Related
Non-Patent Citations (3)
| Title |
|---|
| Ｂｉｏｃｈｅｍ．Ｂｉｏｐｈｙｓ．Ｒｅｓ．Ｃｏｍｍｕｎ．，Ｖｏｌ．１６６，Ｎｏ．１，（Ｊａｎ．１９９０）ｐ．１６０−１６７ |
| Ｃａｎｃｅｒ Ｒｅｓｅａｒｃｈ，Ｖｏｌ．５０，Ｎｏ．９（Ｍａｙ １９９０）ｐ．２６３６−２６４０ |
| Ｊ．Ｉｍｍｕｎｏｌ．，Ｖｏｌ．１４５，Ｎｏ．９，（Ｎｏｖ．１９９０）ｐ．２９０８−０９１３ |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH04208224A (en) | 1992-07-29 |
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