JP2007302609A - Agent for reinforcing radiation-sensitizing ability in hypoxic cell radiation sensitizer - Google Patents
Agent for reinforcing radiation-sensitizing ability in hypoxic cell radiation sensitizer Download PDFInfo
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- JP2007302609A JP2007302609A JP2006133154A JP2006133154A JP2007302609A JP 2007302609 A JP2007302609 A JP 2007302609A JP 2006133154 A JP2006133154 A JP 2006133154A JP 2006133154 A JP2006133154 A JP 2006133154A JP 2007302609 A JP2007302609 A JP 2007302609A
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Abstract
Description
本発明は、低酸素性細胞放射線増感剤において、その放射線増感能を増強する技術に関する。 The present invention relates to a technique for enhancing the radiosensitizing ability of a hypoxic cell radiosensitizer.
２−ニトロイミダゾール誘導体は、癌放射線療法において、放射線抵抗性を有する、低酸素性の癌細胞の、放射線感受性を高め、放射線療法の効果を高める有用な薬剤であることが既に知られている。この様な２−ニトロイミダゾール誘導体の内でも、１−（１−ヒドロキシメチル−２，３−ジヒドロキシプロピル）オキシメチル−２−ニトロイミダゾールは、親水性が高く、神経細胞への移行性が殆ど存しないため、中枢毒性のない放射線増感剤として現在臨床試験中である。（例えば、特許文献１、特許文献２、特許文献３を参照）又、かかる物質においては、この様な低酸素性細胞に対する放射線増感効果以外にも、核酸水酸化物消去作用（例えば、特許文献４を参照）、アポトーシス・シグナル保持作用（例えば、特許文献５を参照）などが存し、癌治療においては有用な薬剤であると言える。
2-Nitroimidazole derivatives are already known to be useful drugs for enhancing the radiosensitivity and the effect of radiotherapy of cancer cells with radioresistance and hypoxic cancer in cancer radiotherapy. Among such 2-nitroimidazole derivatives, 1- (1-hydroxymethyl-2,3-dihydroxypropyl) oxymethyl-2-nitroimidazole is highly hydrophilic and has almost no migration to nerve cells. Therefore, it is currently in clinical trials as a radiosensitizer without central toxicity. (See, for example,
かかる１−（１−ヒドロキシメチル−２，３−ジヒドロキシプロピル）オキシメチル−２−ニトロイミダゾールを低酸素性癌細胞に対する放射線増感剤として用いる場合、前記放射線の線源としては、通常用いられるＸ線に加えて、コバルトの放射性同位体を線源とするγ線、電子線を直線型加速装置で加速した粒子線や、サイクロトロンなどより取り出されるα線などの重粒子線等が使用されており、癌治療効果としては重粒子線、粒子線、ガンマ線の順であるが、装置の規模もこの順で非常に大型化するため、治療用に汎用されているのはＸ線であり、大規模な病院でのみ直線加速型の粒子線が使用されている。この為、通常でも放射線に対する感受性の低い腺ガン、特に肺ガンの腺ガンなどにおいては、前記放射線増感剤を使用しても、良好な治療効果を得るには、照射回数を大幅に増やさなければならない状況が存しているし、加えて、転移の問題については対策が存しないと言える。転移という点について言及するならば、放射線感受性が良好であるとされている偏平上皮ガンにおいても、初回治療効果は確かに著しいものの、従来の放射線治療では再発、転移の可能性が高く残っており、この様な再発後転移した癌の処置は非常に困難であると言われている。即ち、癌放射線療法では、再発或いは転移と言った点について、更なる治療効果の向上手段の開発が望まれていたと言える。 When such 1- (1-hydroxymethyl-2,3-dihydroxypropyl) oxymethyl-2-nitroimidazole is used as a radiosensitizer for hypoxic cancer cells, X-rays usually used as the radiation source are used. In addition to rays, gamma rays using cobalt radioisotopes as a source, particle rays obtained by accelerating electron beams with a linear accelerator, and heavy particle rays such as alpha rays extracted from cyclotrons are used. The effect of cancer treatment is heavy particle beam, particle beam, and gamma ray in this order, but the scale of the device is also very large in this order. Therefore, X-ray is widely used for treatment. The linear acceleration type particle beam is used only in hospitals. For this reason, even in the case of adenocarcinomas that are usually less sensitive to radiation, especially adenocarcinoma of lung cancer, the number of irradiations must be significantly increased in order to obtain a good therapeutic effect even if the radiosensitizer is used. It can be said that there is a situation that must be done, and in addition, there is no countermeasure for the transfer problem. In terms of metastasis, even in squamous cell carcinoma, which is considered to have good radiosensitivity, the effect of initial treatment is certainly remarkable, but the possibility of recurrence and metastasis remains high with conventional radiation therapy. It is said that the treatment of cancer that has metastasized after recurrence is very difficult. In other words, in cancer radiotherapy, it can be said that the development of a means for further improving the therapeutic effect was desired in terms of recurrence or metastasis.
一方、シスプラチン、カルボプラチンなどの白金系抗がん剤は、優れた抗がん作用と、放射線との併用効果の存することから、放射線治療時に用いられる機会の多い抗がん剤であった。（例えば、非特許文献１を参照）前記放射線との併用効果は、メトロニダゾール、ニモダゾールなどの４−ニトロイミダゾール誘導体乃至は５−ニトロイミダゾール誘導体に匹敵するほどのものであると言われている。（例えば、非特許文献２を参照）又、白金系抗がん剤は、頭頸部癌などの放射線感受性の高い癌の放射線治療においては、チラパザミンなどの増感剤と相加効果の存することも知られている。（例えば、非特許文献３を参照）しかしながら、シスプラチン等の白金系抗がん剤と１−（１−ヒドロキシメチル−２，３−ジヒドロキシプロピル）オキシメチル−２−ニトロイミダゾールとを併用して、放射線治療において使用することも、この様な併用により放射線治療を著しく高め、放射線抵抗性の存する肺ガンのＸ線による治療においても、その有効性が高められることは全く知られていなかったし、その様な効果が存すると言う想像すらされていなかった。 On the other hand, platinum anticancer agents such as cisplatin and carboplatin are anticancer agents that have many opportunities to be used during radiotherapy because of their excellent anticancer activity and combined use effect with radiation. (For example, refer nonpatent literature 1) It is said that the combined effect with the said radiation is comparable to 4-nitroimidazole derivatives or 5-nitroimidazole derivatives, such as metronidazole and nimodazole. (For example, see Non-Patent Document 2) In addition, platinum-based anticancer agents may have an additive effect with sensitizers such as tirapazamine in radiotherapy of highly sensitive cancers such as head and neck cancer. Are known. (For example, refer nonpatent literature 3) However, platinum-type anticancer agents, such as cisplatin, and 1- (1-hydroxymethyl-2,3-dihydroxypropyl) oxymethyl-2-nitroimidazole are used together, It has not been known at all that it can be used in radiotherapy, and the radiotherapy can be remarkably enhanced by such a combination, and the effectiveness of radiotherapy for lung cancer with X-rays can be enhanced. It was not even imagined that such an effect would exist.
本発明は、この様な状況下為されたものであり、１−（１−ヒドロキシメチル−２，３−ジヒドロキシプロピル）オキシメチル−２−ニトロイミダゾールを放射線増感剤として用いた、低酸素性癌細胞の放射線療法において、再発、転移を抑制しその効果を更に高める手段を提供することを課題とする。 The present invention has been made under such circumstances, and is hypoxic using 1- (1-hydroxymethyl-2,3-dihydroxypropyl) oxymethyl-2-nitroimidazole as a radiosensitizer. It is an object of the present invention to provide means for suppressing recurrence and metastasis and further enhancing the effect in radiotherapy of cancer cells.
この様な状況に鑑みて、本発明者らは、１−（１−ヒドロキシメチル−２，３−ジヒドロキシプロピル）オキシメチル−２−ニトロイミダゾールの放射線増感剤としての作用を更に高める手段を求めて、鋭意研究努力を重ねた結果、シスプラチンなどの白金系抗がん剤にその様な作用が存することを見出し、発明を完成させるに至った。即ち、本発明は以下に示すとおりである。
（１）白金系抗がん剤からなる、次の化学式１に構造を示す１−（１−ヒドロキシメチル−２，３−ジヒドロキシプロピル）オキシメチル−２−ニトロイミダゾールの癌に対する放射線増感能の増強剤。
In view of such circumstances, the present inventors have sought a means for further enhancing the action of 1- (1-hydroxymethyl-2,3-dihydroxypropyl) oxymethyl-2-nitroimidazole as a radiosensitizer. As a result of intensive research efforts, the inventors have found that such an action exists in platinum-based anticancer agents such as cisplatin, and have completed the invention. That is, the present invention is as follows.
(1) The radiosensitizing ability of 1- (1-hydroxymethyl-2,3-dihydroxypropyl) oxymethyl-2-nitroimidazole having a structure represented by the following
（２）前記白金系抗がん剤が、シスプラチンであることを特徴とする、（１）に記載の放射線増感能の増強剤。
（３）前記１−（１−ヒドロキシメチル−２，３−ジヒドロキシプロピル）オキシメチル−２−ニトロイミダゾールが、光学活性体乃至はラセミ体であることを特徴とする、（１）又は（２）に記載の放射線増感能の増強剤。
（４）前記１−（１−ヒドロキシメチル−２，３−ジヒドロキシプロピル）オキシメチル−２−ニトロイミダゾールを癌に対する放射線増感剤として使用する条件において、放射線が、Ｘ線又はγ線であることを特徴とする、（１）〜（３）何れか１項に記載の放射線増感能の増強剤。
（５）治療すべき癌が腺ガン又は偏平上皮ガンであることを特徴とする、（１）〜（４）何れか１項に記載の放射線増感能の増強剤。
(2) The enhancer of radiosensitizing ability according to (1), wherein the platinum-based anticancer agent is cisplatin.
(3) The 1- (1-hydroxymethyl-2,3-dihydroxypropyl) oxymethyl-2-nitroimidazole is an optically active substance or a racemate, (1) or (2) The agent for enhancing radiosensitivity described in 1.
(4) In the condition where 1- (1-hydroxymethyl-2,3-dihydroxypropyl) oxymethyl-2-nitroimidazole is used as a radiosensitizer for cancer, the radiation is X-ray or γ-ray. The enhancer of radiosensitizing ability according to any one of (1) to (3), wherein:
(5) The agent for enhancing radiosensitivity according to any one of (1) to (4), wherein the cancer to be treated is adenocarcinoma or squamous cell carcinoma.
本発明によれば、１−（１−ヒドロキシメチル−２，３−ジヒドロキシプロピル）オキシメチル−２−ニトロイミダゾールを放射線増感剤として用いた、低酸素性癌細胞の放射線療法において、再発、転移を抑制し、その効果を更に高める手段を提供することができる。 According to the present invention, recurrence and metastasis in radiotherapy of hypoxic cancer cells using 1- (1-hydroxymethyl-2,3-dihydroxypropyl) oxymethyl-2-nitroimidazole as a radiosensitizer. It is possible to provide means for suppressing the above and further enhancing the effect.
（１）本発明の放射線増感能の増強剤
本発明の放射線増感能の増強剤は、白金系抗がん剤からなり、癌放射線治療において、１−（１−ヒドロキシメチル−２，３−ジヒドロキシプロピル）オキシメチル−２−ニトロイミダゾールの放射線増感剤としての作用を更に高める作用を有することを特徴とする。放射線増感剤としての作用を高める作用としては、治療期間を短縮する効果、治療しきれない癌を治療で出来るようにする効果、癌の再発を抑制する効果、再発後の転移を抑制する効果などが挙げられ、中でも、放射線治療後に時としておこる、癌の再発を抑制する作用が好ましく例示できる。本発明で言う白金系抗がん剤とは、その構造に白金原子を含み、臨床的に抗がん剤として使用されているものであれば特段の限定無く適用でき、例えば、シスプラチン、カルボプラチン或いはアクプラなどが特に好適に例示できる。かかる成分の用量は、これらの薬剤を癌治療の目的で臨床で、この薬剤単独で使用する用量に対して、同量乃至はその８割程度が好ましい。その投与は、放射線治療に先立って、数日、具体的には２乃至３日〜３０分前に行っても良いし、照射後３０分〜数日、具体的には２乃至３日に後処理として行っても良い。より好ましい形態は、放射線照射前１時間から３０分に投与する形態である。この時、後記に示す放射線増感剤の投与と重ならないようにすることが好ましい。これは、放射線増感剤と本発明の放射線増感剤の増強剤を同時に投与した場合に、時として、お互いの副作用を増強する場合が存するためである。この様に、放射線増感剤と投与のタイミングをずらす場合には、先に本発明の放射線増感剤の増強剤を投与し、しかる後に放射線増感剤を投与することが好ましい。この様な順にした方が癌を抑制する作用に優れるためである。本発明の放射線増感剤の増強剤は、前記放射線増感剤の存在下においては、他の抗がん剤を併用しても、放射線増感剤の効果増強作用を奏するため、白金系抗がん剤以外の抗がん剤を更に併用して条件下でも使用できる。この様な抗がん剤としては、例えば、ビンオルビン、ビンクリスチン、ビンデシン、ビンブラスチン、タキソテール、タキソール等の植物性抗がん剤、５−フルオロウラシル、フトラフール、カペシタビン、フルツロン、メソトレキセート、ロイコボリン、アラＣ、ジェムザール、フルダラ、ロイスタチン、ロイナーゼ、ハイドレア等の代謝拮抗剤系抗がん剤、イリノテカン、エトポシド、ハイカムチン、ペラゾリン等のトポイソメラーゼ阻害剤系抗がん剤、マイトマイシン、カルセド、ファルモルビシン、アドリアシン、ダウノルビシン、ピラルビシン、ノバントロン、ブレオマイシン等の抗生物質系抗がん剤などが好適に例示できる。これらは、併用する場合に於いては、単独使用時の用量乃至はその用量の８割の用量で用いることが好ましい。この様な本発明の放射線増感剤の増強剤は、製剤化のための任意成分ととももに、常法に従って、散剤、顆粒剤、錠剤、座剤、注射剤に加工することが出来る。前記任意成分としては、乳化剤、可溶化剤、分散剤、賦形剤、結合剤、崩壊剤、滑沢剤、被覆剤、糖衣剤、矯味矯臭剤、安定剤などが好ましく例示できる。
(1) The radiosensitizing ability enhancer of the present invention The radiosensitizing capacity enhancer of the present invention comprises a platinum-based anticancer agent, and is used in cancer radiotherapy as 1- (1-hydroxymethyl-2,3). -Dihydroxypropyl) oxymethyl-2-nitroimidazole has the effect of further enhancing the action as a radiosensitizer. The effect of enhancing the action as a radiosensitizer is the effect of shortening the treatment period, the effect of enabling treatment of cancer that cannot be treated, the effect of suppressing recurrence of cancer, the effect of suppressing metastasis after recurrence Among them, the action of suppressing the recurrence of cancer, which sometimes occurs after radiotherapy, can be preferably exemplified. The platinum-based anticancer agent referred to in the present invention can be applied without particular limitation as long as it contains a platinum atom in its structure and is clinically used as an anticancer agent. For example, cisplatin, carboplatin or An example of ACPLA is particularly preferable. The dosage of these components is preferably the same or about 80% of the dosage of these drugs used clinically for the purpose of cancer treatment and the drug alone. The administration may be performed several days prior to radiation treatment, specifically 2 to 3 days to 30 minutes before, or 30 minutes to several days after irradiation, specifically 2 to 3 days later. It may be performed as a process. A more preferable form is a form administered from 1 hour to 30 minutes before irradiation. At this time, it is preferable not to overlap with administration of the radiosensitizer described later. This is because when the radiosensitizer and the enhancer of the radiosensitizer of the present invention are administered at the same time, sometimes the side effects of each other are enhanced. Thus, when the administration timing of the radiosensitizer is shifted, it is preferable to administer the enhancer of the radiosensitizer of the present invention first and then administer the radiosensitizer. This is because such an order is superior in suppressing cancer. In the presence of the radiosensitizer, the enhancer of the radiosensitizer of the present invention exhibits the effect of enhancing the effect of the radiosensitizer even when used in combination with other anticancer agents. It can also be used under conditions by further using an anticancer agent other than a cancer agent. Examples of such anticancer agents include plant anticancer agents such as vinolvin, vincristine, vindesine, vinblastine, taxotere, taxol, 5-fluorouracil, ftorafur, capecitabine, flutulon, methotrexate, leucovorin, ala C, gemzar. Anti-metabolite anticancer drugs such as fludara, leustatin, leunin, hydrarea, topoisomerase inhibitor anticancer drugs such as irinotecan, etoposide, hicamchin, and perazoline, mitomycin, chalced, farmorubicin, adriacin, daunorubicin, pirarubicin, novantrone An antibiotic anticancer agent such as bleomycin can be preferably exemplified. When these are used in combination, it is preferable to use a single dose or 80% of the dose. Such a radiosensitizer enhancer of the present invention can be processed into powders, granules, tablets, suppositories, and injections in accordance with conventional methods together with optional components for formulation. Preferred examples of the optional component include emulsifiers, solubilizers, dispersants, excipients, binders, disintegrants, lubricants, coating agents, sugar-coating agents, flavoring agents, and stabilizers.
（２）本発明の放射線増感剤の増強剤が増強すべき放射線増感剤
本発明の放射線増感剤の増強剤は、前記化学式１の構造を有する放射線増感剤の低酸素性癌細胞放射線増感効果を増強し、放射線治療後の再発を抑制する。前記化学式１の構造の化合物は不整炭素を２個有しており、その立体異性体はＳＳ体、ＲＳ体、ＳＲ体、ＲＳ体の４種が存在するがこれらの何れの作用をも、本発明の増強剤は増強することが出来る。勿論、光学活性体の効果を増強することも出来るし、ラセミ体のような等量混合物の効果を増強することも出来る。特に好ましいものは、ＳＲ体とＲＳ体の体であり、これは、臨床試験において、実際に有効性が確かめられているためである。かかる化合物は、特許文献１或いは特許文献２に記載された方法に従って製造することが出来、例えば、２−ニトロ−１−トリメチルシリルイミダゾールと２−アセトキシメトキシ−１，３，４−トリアセトキシブタンとをルイス酸の存在下縮合させ、しかる後に、ナトリウムメトキシドなどを反応させて脱アセチル化することにより、製造することが出来る。この時、２−アセトキシメトキシ−１，３，４−トリアセトキシブタンの立体特性が、最終生成物の１−（１−ヒドロキシメチル−２，３−ジヒドロキシプロピル）オキシメチル−２−ニトロイミダゾールにも反映される。かかる放射線増感剤は、放射線増感効果を有しながら、中枢への配向が制限されており、神経毒性を極めて誘起しにくい放射線増感剤であり、これは非環状糖部分の水溶性による。しかしながら、この様な構造のために代謝により、速やかに腫瘍部位から排出されてしまうことを意味し、その投与は放射線照射３０分前〜直前に行うことが好ましい。その用量も成人１人あたり、１〜５ｇを照射前に投与することが好ましい。又、この様な放射線増感剤と放射線増感剤の増強剤を用いて治療するにあたり、対象として好ましい癌腫は、腺ガン又は偏平上皮癌、特に腺ガンの内の肺癌が、偏平上皮癌の内の皮膚癌、頭頸部ガン又は乳ガンが例示できる。これは、この様な癌腫においては放射線抵抗性或いは転移による再発と、再発可能性が著しいためである。放射線療法に於ける、化学式１の構造の放射線増感剤と、本発明の放射線増感剤の増強剤の併用により、かかる放射線抵抗性と再発可能性を低下せしめることが出来る。
(2) The radiosensitizer that the radiosensitizer enhancer of the present invention should enhance The radiosensitizer enhancer of the present invention is a hypoxic cancer cell of the radiosensitizer having the structure of Formula 1 It enhances the radiosensitizing effect and suppresses recurrence after radiotherapy. The compound of the structure of the
以下に、実施例を挙げて本発明について更に詳細に説明を加えるが、本発明がかかる実施例にのみに限定されるものではない。 Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to such examples.
以下に示す処方に従って、本発明の放射線増感剤の増強剤である、シスプラチンについて、in vivoでその増強効果を確かめた。即ち、Ｃ３Ｈマウス（雌性、５週齢）１群５匹を４群用い、右後ろ足太股部に扁平上皮癌（ＳＣＣＶＩＩ）由来細胞を１０５個移植し、１週間予飼育した。移植した部分に生じた腫瘍の大きさを計測した後、治療を開始した。治療は１群が２０Ｇｙの放射線照射のみ（第１群；放射線照射群）、１群はシスプラチンを８ｍｇ／Ｋｇ腹腔内投与し、その２４時間後に２０Ｇｙの放射線照射を行い（第２群；シスプラチン投与群）、１群は２００ｍｇ／Ｋｇの１−（１−ヒドロキシメチル−２，３−ジヒドロキシプロピル）オキシメチル−２−ニトロイミダゾール（第３群；ＳＲ・ＲＳラセミ体）を静脈内投与し、その１５分後に２０Ｇｙの放射線照射を行い（放射線増感剤投与群）、残る１群はシスプラチンを８ｍｇ／Ｋｇ腹腔内投与し、２４時間後に放射線を照射するが、その１５分前に２００ｍｇ／Ｋｇの１−（１−ヒドロキシメチル−２，３−ジヒドロキシプロピル）オキシメチル−２−ニトロイミダゾール（ＳＲ・ＲＳラセミ体）を静脈内投与した。（第４群；放射線増感・増強群） 放射線はX線を用いた。その２日後、７日後、９日後、１０日後に腫瘍体積を計測した。これらの結果より、開始時の腫瘍体積を１とした場合の相対体積値を求めた。結果をこの相対体積値の遷移として、表1及び図１に示す。これより、本発明の増強剤を用いると、９日後から観察される癌の再発を防止できることが判る。再発を防止することにより、転移も抑制できる。
According to the formulation shown below, the enhancement effect of cisplatin, which is an enhancer of the radiosensitizer of the present invention, was confirmed in vivo. That is, 4 groups of 5 C3H mice (female, 5 weeks old) were used, and 10 5 squamous cell carcinoma (SCCVII) -derived cells were transplanted into the right hind leg crotch and pre-bred for 1 week. Treatment was started after measuring the size of the tumor in the transplanted area. For treatment, 1 group only received 20 Gy irradiation (
ヒト肺ガン由来細胞ＲＥＬＦ−ＬＣ−ＡＩ細胞を用いたＭＴＴ法で、本発明の放射線増感剤の増強剤であるシスプラチン（０．３μｇ／ｍｌ）の存在下又は非存在下での１−（１−ヒドロキシメチル−２，３−ジヒドロキシプロピル；ＰＲ３５０）オキシメチル−２−ニトロイミダゾールの用量反応性を調べた。まず、細胞は８００個をシャーレに播種し、１７時間前培養した後、シスプラチンを０．３μmol/L添加して２４時間インキュベーションした。その後、培地を交換し、PR-３５０を１〜４mmol/L添加し、低酸素条件下放射線を３Gy照射した。照射４８時間後に発色液を加え、２時間３７℃でインキュベーションした後、吸光度を測定し、細胞の増殖率を測定した。結果を図２に示す。これより、本発明の増強剤の存在下、ＰＲ３５０の濃度依存的に細胞増殖率が減少しており（図２、第６群〜第８群）、本発明の放射線増感剤の増強剤の効果が確認された。 1- (1) in the presence or absence of cisplatin (0.3 μg / ml), which is a potentiator of the radiosensitizer of the present invention, in the MTT method using human lung cancer-derived cells RELF-LC-AI cells. The dose response of 1-hydroxymethyl-2,3-dihydroxypropyl; PR350) oxymethyl-2-nitroimidazole was investigated. First, 800 cells were seeded in a petri dish and pre-cultured for 17 hours, and then cisplatin was added at 0.3 μmol / L and incubated for 24 hours. Thereafter, the medium was changed, PR-350 was added at 1 to 4 mmol / L, and radiation was applied at 3 Gy under hypoxic conditions. After 48 hours of irradiation, a coloring solution was added and incubated at 37 ° C. for 2 hours, and then the absorbance was measured to determine the cell growth rate. The results are shown in FIG. As a result, in the presence of the enhancer of the present invention, the cell growth rate decreased depending on the concentration of PR350 (FIG. 2, Group 6 to Group 8), and the radiosensitizer enhancer of the present invention The effect was confirmed.
本発明は、癌放射線治療の向上に利用できる。 The present invention can be used to improve cancer radiotherapy.
Claims (5)
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| JP2006133154A JP2007302609A (en) | 2006-05-12 | 2006-05-12 | Agent for reinforcing radiation-sensitizing ability in hypoxic cell radiation sensitizer |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2014185133A (en) * | 2013-03-22 | 2014-10-02 | Pola Pharma Inc | Inhibitor of abc transporter |
| JP2017206538A (en) * | 2017-06-29 | 2017-11-24 | 株式会社ポーラファルマ | ABC transporter inhibitor |
| JPWO2017122743A1 (en) * | 2016-01-14 | 2018-11-01 | Ａｇｃ株式会社 | Curable composition, cured product, prepreg and fiber reinforced molded product |
| WO2020179125A1 (en) | 2019-03-05 | 2020-09-10 | 株式会社エム・ティー・スリー | Radiosensitizer |
| EP4353224A1 (en) | 2022-10-11 | 2024-04-17 | M.T.3, Inc. | Pharmaceutical composition comprising a sulfoquinovosylacylpropanediol derivate for treating cancer |
-
2006
- 2006-05-12 JP JP2006133154A patent/JP2007302609A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2014185133A (en) * | 2013-03-22 | 2014-10-02 | Pola Pharma Inc | Inhibitor of abc transporter |
| JPWO2017122743A1 (en) * | 2016-01-14 | 2018-11-01 | Ａｇｃ株式会社 | Curable composition, cured product, prepreg and fiber reinforced molded product |
| JP2017206538A (en) * | 2017-06-29 | 2017-11-24 | 株式会社ポーラファルマ | ABC transporter inhibitor |
| WO2020179125A1 (en) | 2019-03-05 | 2020-09-10 | 株式会社エム・ティー・スリー | Radiosensitizer |
| EP4353224A1 (en) | 2022-10-11 | 2024-04-17 | M.T.3, Inc. | Pharmaceutical composition comprising a sulfoquinovosylacylpropanediol derivate for treating cancer |
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