JPWO2020071355A1 - Pharmaceutical composition for cancer treatment - Google Patents
Pharmaceutical composition for cancer treatment Download PDFInfo
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- JPWO2020071355A1 JPWO2020071355A1 JP2020550447A JP2020550447A JPWO2020071355A1 JP WO2020071355 A1 JPWO2020071355 A1 JP WO2020071355A1 JP 2020550447 A JP2020550447 A JP 2020550447A JP 2020550447 A JP2020550447 A JP 2020550447A JP WO2020071355 A1 JPWO2020071355 A1 JP WO2020071355A1
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- cancer
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Images
Classifications
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
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- A—HUMAN NECESSITIES
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- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Abstract
本発明の課題は、新規な癌治療用医薬組成物を提供することである。
本発明は、アモロルフィン、フェンチコナゾール、イトラコナゾール、及び、これらの薬理上許容される塩、並びに、ＨＭＧ−ＣｏＡ還元酵素阻害剤からなる群から選択される１以上を含む、癌治療用医薬組成物を提供する。前記ＨＭＧ−ＣｏＡ還元酵素阻害剤は、セリバスタチン、又は、その薬理上許容される塩であってもよい。前記癌は、胆道癌又は膵臓癌であってもよい。An object of the present invention is to provide a novel pharmaceutical composition for treating cancer.
The present invention comprises a pharmaceutical composition for the treatment of cancer comprising amorolfine, fenticonazole, itraconazole, and pharmacologically acceptable salts thereof, and one or more selected from the group consisting of HMG-CoA reductase inhibitors. I will provide a. The HMG-CoA reductase inhibitor may be cerivastatin or a pharmacologically acceptable salt thereof. The cancer may be biliary tract cancer or pancreatic cancer.
Description
本発明は、癌治療用医薬組成物に関する。 The present invention relates to a pharmaceutical composition for treating cancer.
癌は日本人の死因において大きな割合を占める疾患であり、各種の抗癌剤が開発段階にある。他方、抗癌作用を有する物質のなかには、予期せぬ重篤な副作用等を有するものが多く存在する。このような事情を踏まえ、上市される新規抗癌剤の数は年々減少傾向にある。 Cancer is a disease that accounts for a large proportion of the causes of death in Japan, and various anticancer agents are in the development stage. On the other hand, many substances having an anticancer effect have unexpected and serious side effects. Under these circumstances, the number of new anticancer drugs on the market is decreasing year by year.
他方で、特定の疾患に対して有効な既存薬について、別の疾患に対する薬効を発見しようとする、「ドラッグ・リポジショニング」と呼ばれる手法がある（非特許文献１参照。）。この手法によって別の疾患に対する薬効を有することが発見された薬剤は、臨床レベルにおける安全性や体内動態が既に確認されているものである。そのため、この手法には、少ない研究開発コストで、副作用が少ない治療剤を開発し得るというメリットが期待できる。 On the other hand, there is a method called "drug repositioning" that attempts to discover the efficacy of an existing drug that is effective for a specific disease for another disease (see Non-Patent Document 1). Drugs that have been found to have efficacy against other diseases by this method have already been confirmed to be safe and pharmacokinetic at the clinical level. Therefore, this method can be expected to have the merit of being able to develop a therapeutic agent with few side effects at a low research and development cost.
本発明者らは、ドラッグ・リポジショニングを、独自に開発した癌細胞オルガイド培養技術と組み合わせて、新規な抗癌剤（特に、胆道癌又は膵臓癌の治療剤）のスクリーニングのために用いることを着想した。オルガノイドとは、細胞を高密度に集積させることにより自己組織化させた立体的な細胞組織体であり、生体内組織に似た構造を有する。 The present inventors conceived that drug repositioning could be used in combination with a proprietary cancer cell olguide culture technique for screening of novel anticancer agents (particularly therapeutic agents for biliary tract cancer or pancreatic cancer). .. Organoids are three-dimensional cell tissues that are self-assembled by accumulating cells at high density, and have a structure similar to in vivo tissue.
本発明は、以上の実情に鑑みてなされたものであり、新規な癌治療用医薬組成物を提供することを目的とする。 The present invention has been made in view of the above circumstances, and an object of the present invention is to provide a novel pharmaceutical composition for treating cancer.
本発明者らは、スクリーニングの結果、抗真菌剤として知られるアモロルフィン若しくはフェンチコナゾール、又は、脂質異常症治療剤として知られるＨＭＧ−ＣｏＡ還元酵素阻害剤を含む医薬組成物によれば、上記課題を解決できることを見出し、本発明を完成するに至った。より具体的には、本発明は、以下のようなものを提供する。 As a result of screening, the present inventors have described the above-mentioned problems according to a pharmaceutical composition containing amorolfine or fenticonazole known as an antifungal agent or an HMG-CoA reductase inhibitor known as a therapeutic agent for dyslipidemia. We have found that we can solve the problem, and have completed the present invention. More specifically, the present invention provides the following.
（１） アモロルフィン、フェンチコナゾール、イトラコナゾール、及び、これらの薬理上許容される塩、並びに、ＨＭＧ−ＣｏＡ還元酵素阻害剤からなる群から選択される１以上を含む、癌治療用医薬組成物。 (1) A pharmaceutical composition for treating cancer, which comprises amorolfine, fenticonazole, itraconazole, a pharmacologically acceptable salt thereof, and one or more selected from the group consisting of HMG-CoA reductase inhibitors.
（２） 前記ＨＭＧ−ＣｏＡ還元酵素阻害剤がセリバスタチン、又は、その薬理上許容される塩である、（１）に記載の癌治療用医薬組成物。 (2) The pharmaceutical composition for treating cancer according to (1), wherein the HMG-CoA reductase inhibitor is cerivastatin or a pharmacologically acceptable salt thereof.
（３） 前記癌が胆道癌又は膵臓癌である、（１）又は（２）に記載の癌治療用医薬組成物。 (3) The pharmaceutical composition for treating cancer according to (1) or (2), wherein the cancer is biliary tract cancer or pancreatic cancer.
（４） １００〜４００ｍｇのイトラコナゾール又はその薬理上許容される塩を含み、
前記癌が胆道癌又は膵臓癌であり、
ヒトへの経口投与用である、
請求項１に記載の癌治療用医薬組成物。(4) Containing 100 to 400 mg of itraconazole or a pharmacologically acceptable salt thereof,
The cancer is biliary tract cancer or pancreatic cancer,
For oral administration to humans,
The pharmaceutical composition for treating cancer according to
（５） ０．１０〜０．５０ｍｇのセリバスタチン又はその薬理上許容される塩を含み、
前記癌が胆道癌又は膵臓癌であり、
ヒトへの経口投与用である、
請求項１に記載の癌治療用医薬組成物。(5) Containing 0.10 to 0.50 mg of cerivastatin or a pharmacologically acceptable salt thereof,
The cancer is biliary tract cancer or pancreatic cancer,
For oral administration to humans,
The pharmaceutical composition for treating cancer according to
本発明によれば、新規な癌治療用医薬組成物が提供される。 According to the present invention, a novel pharmaceutical composition for treating cancer is provided.
以下、本発明の実施形態について詳細に説明する。なお、本発明は以下の実施形態に限定されない。 Hereinafter, embodiments of the present invention will be described in detail. The present invention is not limited to the following embodiments.
＜癌治療用医薬組成物＞
本発明の癌治療用医薬組成物（以下、「本発明の組成物」ともいう。）は、アモロルフィン、フェンチコナゾール、イトラコナゾール、及び、これらの薬理上許容される塩、並びに、ＨＭＧ−ＣｏＡ還元酵素阻害剤からなる群から選択される１以上を含む。以下、「アモロルフィン、フェンチコナゾール、イトラコナゾール、及び、これらの薬理上許容される塩、並びに、ＨＭＧ−ＣｏＡ還元酵素阻害剤からなる群から選択される１以上」をあわせて「本発明における化合物」ともいう。<Pharmaceutical composition for cancer treatment>
The pharmaceutical composition for treating cancer of the present invention (hereinafter, also referred to as “composition of the present invention”) includes amorolfine, fenticonazole, itraconazole, pharmacologically acceptable salts thereof, and HMG-CoA reduction. Includes one or more selected from the group consisting of enzyme inhibitors. Hereinafter, "a compound in the present invention" is a combination of "one or more selected from the group consisting of amorolfine, fenticonazole, itraconazole, pharmacologically acceptable salts thereof, and HMG-CoA reductase inhibitors". Also called.
本発明における化合物は、いずれも、後述のとおり癌とは全く異なる疾患に対する薬効を有することが知られる既存薬である。本発明者らによる独自のスクリーニングの結果、意外にも、これらの化合物は癌細胞（特に、癌幹細胞）増殖抑制効果を有し、癌（特に、胆道癌や膵臓癌）に対する薬効を有することが見出された。さらに、これらの化合物は、その多くが、安全性が確認された既存薬であることから、副作用の少ない抗癌剤として機能することが期待できる。 All of the compounds in the present invention are existing drugs known to have a medicinal effect on diseases completely different from cancer, as described later. As a result of the original screening by the present inventors, surprisingly, these compounds have a cancer cell (particularly cancer stem cell) growth inhibitory effect and a medicinal effect on cancer (particularly biliary tract cancer and pancreatic cancer). Found. Furthermore, since many of these compounds are existing drugs whose safety has been confirmed, they can be expected to function as anticancer agents with few side effects.
本発明者らが用いたスクリーニングは、癌細胞オルガイド培養技術を用いた系である。この系は、より生体に近い系であるため、該系によって見出された化合物群は、有効な抗癌剤として機能し得る。 The screening used by the present inventors is a system using a cancer cell olguide culture technique. Since this system is closer to the living body, the compound group found by the system can function as an effective anticancer agent.
本発明における「薬理上許容される塩」としては特に限定されず、金属塩（ナトリウム塩、カリウム塩、カルシウム塩、マグネシウム塩等）、有機酸との付加塩（クエン酸塩、シュウ酸塩、酢酸塩、ギ酸塩、プロピオン酸塩、安息香酸塩等）、無機酸との付加塩（塩酸塩、硫酸塩、硝酸塩、リン酸塩等）等が挙げられる。 The "pharmaceutically acceptable salt" in the present invention is not particularly limited, and is not particularly limited, and is an addition salt with a metal salt (sodium salt, potassium salt, calcium salt, magnesium salt, etc.) or an organic acid (citrate, oxalate, etc.). Acetates, formates, propionates, benzoates, etc.), addition salts with inorganic acids (salts, sulfates, nitrates, phosphates, etc.) and the like can be mentioned.
本発明において「癌細胞増殖抑制効果」とは、本発明における化合物が存在しない点以外は同条件の処置を行った場合と比較して、癌細胞の増殖が遅延又は停止等することを意味する。このような癌細胞増殖抑制効果により、本発明の組成物によれば、癌治療効果が期待できる。本発明において「治療」とは、症状の進行の遅延、緩和、軽減、改善、及び治癒等を意味する。 In the present invention, the "cancer cell proliferation inhibitory effect" means that the proliferation of cancer cells is delayed or stopped as compared with the case where the treatment under the same conditions is performed except that the compound in the present invention does not exist. .. Due to such a cancer cell growth inhibitory effect, according to the composition of the present invention, a cancer therapeutic effect can be expected. In the present invention, "treatment" means delaying, alleviating, alleviating, ameliorating, healing, etc. of the progression of symptoms.
本発明の治療対象である癌としては特に限定されず、胆道癌、膵臓癌、肺癌、大腸癌、皮膚癌、肝癌、前立腺癌、乳癌、卵巣癌、脳腫瘍、胃癌等が挙げられる。これらのうち、本発明によれば、胆道癌、膵臓癌を好ましく治療し得る。 The cancer to be treated by the present invention is not particularly limited, and examples thereof include biliary tract cancer, pancreatic cancer, lung cancer, colon cancer, skin cancer, liver cancer, prostate cancer, breast cancer, ovarian cancer, brain cancer, and gastric cancer. Of these, according to the present invention, biliary tract cancer and pancreatic cancer can be preferably treated.
本発明において「胆道癌」とは、胆嚢や胆管に生じる癌の総称を意味する。本発明における「胆道癌」には、任意の発生部位の胆道癌が含まれ、例えば、肝内胆管癌、肝門部胆管癌、上部胆管癌、中部胆管癌、下部胆管癌、神経内分泌癌、十二指腸乳頭部癌（ファーター乳頭部神経内分泌癌等）、胆嚢癌が挙げられる。 In the present invention, "biliary tract cancer" means a general term for cancers that occur in the gallbladder and bile ducts. The "biliary tract cancer" in the present invention includes biliary tract cancer at an arbitrary site of occurrence, for example, intrahepatic cholangiocarcinoma, hilar cholangiocarcinoma, upper cholangiocarcinoma, middle cholangiocarcinoma, lower cholangiocarcinoma, neuroendocrine cancer, etc. Examples include duodenal papilla cancer (Farter papilla nerve endocrine cancer, etc.) and gallbladder cancer.
本発明における「膵臓癌」には、任意の発生部位（例えば、膵頭部、膵体部、及び膵尾部）の膵臓癌が含まれる。また、本発明における「膵臓癌」には、外分泌系癌及び内分泌系癌のいずれもが含まれる。本発明における膵臓癌としては、膵腺癌等が挙げられる。 The "pancreatic cancer" in the present invention includes pancreatic cancer at any site of occurrence (eg, pancreatic head, pancreatic body, and pancreatic tail). In addition, the "pancreatic cancer" in the present invention includes both exocrine cancer and endocrine cancer. Examples of pancreatic cancer in the present invention include pancreatic adenocarcinoma.
（アモロルフィン、フェンチコナゾール、及びイトラコナゾール）
アモロルフィン、フェンチコナゾール、イトラコナゾール、及び、これらの薬理上許容される塩（塩酸塩等）は、抗真菌剤として上市されている。本発明者らによる検討の結果、その作用は明らかではないが、これらの化合物が癌細胞増殖抑制効果を有することが見出された。(Amorolfine, fenticonazole, and itraconazole)
Amorolfine, fenticonazole, itraconazole, and their pharmacologically acceptable salts (hydrochloride, etc.) are marketed as antifungal agents. As a result of the examination by the present inventors, it was found that these compounds have a cancer cell growth inhibitory effect, although the action is not clear.
本発明の組成物におけるアモロルフィン、フェンチコナゾール、イトラコナゾール、及び、これらの薬理上許容される塩（塩酸塩等）の含量は、投与方法、投与期間、その他の諸条件（例えば、患者の症状、年齢、体重）に応じて適宜調整される。例えば、抗真菌剤として使用される場合と同等の量、又は、それよりも少ない量を投与できるようにこれらの化合物の含量を調整してもよい。また、得ようとする効果に応じて、体表面積等に基づき適宜調整してもよい。 The content of amorolfine, fenticonazole, itraconazole, and their pharmacologically acceptable salts (hydrochloride, etc.) in the composition of the present invention includes administration method, administration period, and other conditions (for example, patient's symptoms, etc.). It is adjusted appropriately according to age and weight). For example, the content of these compounds may be adjusted so that an amount equal to or less than that used as an antifungal agent can be administered. Further, it may be appropriately adjusted based on the body surface area or the like according to the effect to be obtained.
本発明の組成物における、アモロルフィン、フェンチコナゾール、イトラコナゾール、及び、これらの薬理上許容される塩（塩酸塩等）の配合量が多いほど、癌細胞増殖抑制効果が高くなることが期待できる。また、これらの化合物は既に安全性が確認されているため、本発明の組成物における配合量が多くとも副作用を生じる可能性が低いことも期待できる。 It is expected that the larger the amount of amorolfine, fenticonazole, itraconazole, and a pharmacologically acceptable salt (hydrochloride, etc.) of these in the composition of the present invention, the higher the effect of suppressing cancer cell growth. Moreover, since the safety of these compounds has already been confirmed, it can be expected that even if the amount of these compounds is large in the composition of the present invention, the possibility of causing side effects is low.
（ＨＭＧ−ＣｏＡ還元酵素阻害剤）
本発明におけるＨＭＧ−ＣｏＡ還元酵素阻害剤は、脂質異常症治療剤として上市されているものである。本発明者らによる検討の結果、その作用は明らかではないが、ＨＭＧ−ＣｏＡ還元酵素阻害剤が癌細胞増殖抑制効果を有することが見出された。(HMG-CoA reductase inhibitor)
The HMG-CoA reductase inhibitor in the present invention is marketed as a therapeutic agent for dyslipidemia. As a result of the examination by the present inventors, it was found that the HMG-CoA reductase inhibitor has a cancer cell growth inhibitory effect, although its action is not clear.
ＨＭＧ−ＣｏＡ還元酵素阻害剤としては、具体的には、スタチン系薬剤、すなわち、セリバスタチン、ロスバスタチン、ピタバスタチン、アトルバスタチン、フルバスタチン、シンバスタチン、プラバスタチン、ロバスタチン、メバスタチン、及びこれらの薬理上許容される塩等が挙げられる。これらのうち、特に癌細胞増殖抑制効果が高いという観点から、セリバスタチン、又は、その薬理上許容される塩が好ましい。 Specific examples of the HMG-CoA reductase inhibitor include statins such as cerivastatin, rosuvastatin, pitavastatin, atorvastatin, fluvastatin, simvastatin, pravastatin, lovastatin, mevastatin, and pharmacologically acceptable salts thereof. Can be mentioned. Of these, cerivastatin or a pharmacologically acceptable salt thereof is preferable from the viewpoint of having a particularly high effect of suppressing cancer cell growth.
本発明の組成物におけるＨＭＧ−ＣｏＡ還元酵素阻害剤の含量は、投与方法、投与期間、その他の諸条件（例えば、患者の症状、年齢、体重）に応じて適宜調整される。例えば、脂質異常症治療剤として使用される場合と同等の量、又は、それよりも少ない量を投与できるようにこれらの化合物の含量を調整してもよい。また、得ようとする効果に応じて、体表面積等に基づき適宜調整してもよい。 The content of the HMG-CoA reductase inhibitor in the composition of the present invention is appropriately adjusted according to the administration method, administration period, and other conditions (for example, patient's symptom, age, body weight). For example, the content of these compounds may be adjusted so that an amount equivalent to or less than that used as a therapeutic agent for dyslipidemia can be administered. Further, it may be appropriately adjusted based on the body surface area or the like according to the effect to be obtained.
本発明の組成物におけるＨＭＧ−ＣｏＡ還元酵素阻害剤（特に、セリバスタチン、又は、その薬理上許容される塩）の配合量が多いほど、癌細胞増殖抑制効果が高くなることが期待できる。 It can be expected that the larger the amount of the HMG-CoA reductase inhibitor (particularly, cerivastatin or a pharmacologically acceptable salt thereof) in the composition of the present invention, the higher the effect of suppressing cancer cell growth.
＜癌治療用医薬組成物の製造方法＞
本発明の組成物は、本発明における化合物が配合されていればよく、任意の剤形として製造できる。本発明の組成物の製造方法は、医薬品の製造分野において採用される任意の方法を、組成物の剤形に応じて選択することができる。<Manufacturing method of pharmaceutical composition for cancer treatment>
The composition of the present invention may be produced in any dosage form as long as the compound of the present invention is blended. As the method for producing the composition of the present invention, any method adopted in the field of manufacturing pharmaceutical products can be selected according to the dosage form of the composition.
本発明の組成物には、アモロルフィン、フェンチコナゾール、イトラコナゾール、及び、これらの薬理上許容される塩、並びに、ＨＭＧ−ＣｏＡ還元酵素阻害剤のうちいずれか１以上が含まれていればよく、これらのうち１種のみが含まれていてもよいし、２種以上が含まれていてもよい。 The composition of the present invention may contain amorolfine, fenticonazole, itraconazole, a pharmacologically acceptable salt thereof, and one or more of HMG-CoA reductase inhibitors. Only one of these may be contained, or two or more of these may be contained.
本発明の組成物の剤形としては特に限定されず、経口剤（錠剤、カプセル剤、丸剤、顆粒剤、散剤、液剤、懸濁剤等）や、非経口剤（注射剤等）等が挙げられる。 The dosage form of the composition of the present invention is not particularly limited, and oral preparations (tablets, capsules, pills, granules, powders, liquids, suspensions, etc.), parenteral preparations (injections, etc.) and the like can be used. Can be mentioned.
本発明の組成物は、その剤形に応じて、薬理上及び製剤上許容し得る添加物を含んでいてもよい。このような添加物としては、通常、製剤分野において担体や賦形剤等として常用され、かつ、本発明の組成物に含まれる有効成分（すなわち、本発明における化合物）と反応しない物質を使用できる。 The composition of the present invention may contain a pharmacologically and pharmaceutically acceptable additive depending on its dosage form. As such an additive, a substance that is usually used as a carrier, an excipient, etc. in the pharmaceutical field and does not react with the active ingredient (that is, the compound in the present invention) contained in the composition of the present invention can be used. ..
＜癌治療用医薬組成物の使用方法＞
本発明の組成物は剤形に応じて、経口的投与、又は、非経口的投与（静脈、皮下、又は筋肉内への投与や、局所的、経直腸的、経皮的又は経鼻的な投与）によって、投与対象に投与される。<How to use the pharmaceutical composition for cancer treatment>
The compositions of the present invention may be administered orally or parenterally (intravenously, subcutaneously, or intramuscularly, or locally, transrectally, percutaneously or nasally, depending on the dosage form. Administration) to the subject.
本発明の組成物の投与対象は特に限定されず、哺乳類等を好ましく挙げることができる。哺乳類としては、ヒト、及び、非ヒト動物（マウス、ラット、ウシ、ブタ、イヌ、ネコ等）のいずれであってもよい。 The administration target of the composition of the present invention is not particularly limited, and mammals and the like can be preferably mentioned. The mammal may be either a human or a non-human animal (mouse, rat, cow, pig, dog, cat, etc.).
本発明の組成物の投与回数や投与間隔は特に限定されず、単回投与であっても複数回投与であってもよい。 The number of administrations and the interval between administrations of the composition of the present invention are not particularly limited, and may be a single administration or a plurality of administrations.
本発明の組成物は、投与目的等に応じて、他の薬剤と併用して投与してもよい。本発明の組成物とともに併用される薬剤の種類や量等は、得ようとする効果等に基づき適宜選択され、本発明の組成物とともに投与してもよく、別々に投与してもよい。 The composition of the present invention may be administered in combination with other drugs depending on the purpose of administration and the like. The type and amount of the drug to be used in combination with the composition of the present invention are appropriately selected based on the effect to be obtained and the like, and may be administered together with the composition of the present invention or separately.
本発明の組成物に、抗真菌剤として知られる成分、すなわち、アモロルフィン、フェンチコナゾール、イトラコナゾール、及び、これらの薬理上許容される塩が含まれる場合、これらの成分は、抗真菌剤として機能する量と同等の量、又は、より少ない量で、癌の治療効果を奏し得る。例えば、抗真菌剤としてイトラコナゾールをヒトへ経口投与する場合、その投与量は、通常、１回あたり２００ｍｇ（１日２回、すなわち１日用量４００ｍｇ）である。他方で、イトラコナゾールを癌治療（特に、胆道癌又は膵臓癌の治療）のためにヒトへ経口投与する場合、その投与量は、好ましくは、１回あたり１００〜４００ｍｇ（好ましくは１日２回投与され、すなわち１日用量が好ましくは２００〜８００ｍｇである。）、より好ましくは、１回あたり１００〜１５０ｍｇ（好ましくは１日２回投与され、すなわち１日用量が好ましくは２００〜３００ｍｇである。）である。 When the composition of the present invention contains components known as antifungal agents, namely amorolfine, fenticonazole, itraconazole, and pharmacologically acceptable salts thereof, these components function as antifungal agents. The therapeutic effect of cancer can be achieved in an amount equal to or smaller than the amount to be used. For example, when itraconazole is orally administered to humans as an antifungal agent, the dose is usually 200 mg (twice a day, that is, a daily dose of 400 mg). On the other hand, when itraconazole is orally administered to humans for cancer treatment (particularly for the treatment of biliary tract cancer or pancreatic cancer), the dose is preferably 100 to 400 mg (preferably twice daily). That is, the daily dose is preferably 200 to 800 mg), more preferably 100 to 150 mg per dose (preferably twice daily, i.e. the daily dose is preferably 200 to 300 mg. ).
本発明の組成物に、脂質異常症治療剤としてしられる成分、すなわち、ＨＭＧ−ＣｏＡ還元酵素阻害剤が含まれる場合、この成分は、脂質異常症治療剤として機能する量と同等の量、又は、より少ない量で、癌の治療効果を奏し得る。例えば、脂質異常症治療剤としてセリバスタチンをヒトへ経口投与する場合、その投与量は、通常、１回あたり０．３０ｍｇ（１日１回）である。他方で、セリバスタチンを癌治療（特に、胆道癌又は膵臓癌の治療）のためにヒトへ経口投与する場合、その投与量は、好ましくは、１回あたり０．１０〜０．５０ｍｇ（好ましくは１日１回投与される。）、より好ましくは、１回あたり０．１０〜０．２０ｍｇ（好ましくは１日１回投与される。）である。 When the composition of the present invention contains a component used as a therapeutic agent for dyslipidemia, that is, an HMG-CoA reductase inhibitor, this component is equal to or equal to an amount that functions as a therapeutic agent for dyslipidemia. , A smaller amount can be effective in treating cancer. For example, when cerivastatin is orally administered to humans as a therapeutic agent for dyslipidemia, the dose is usually 0.30 mg (once a day). On the other hand, when cerivastatin is orally administered to humans for the treatment of cancer (particularly for the treatment of biliary tract cancer or pancreatic cancer), the dose is preferably 0.10 to 0.50 mg (preferably 1) per dose. It is administered once a day), more preferably 0.10 to 0.20 mg (preferably once a day).
以下、実施例を示し、本発明を具体的に説明するが、本発明はこれらの実施例に限定されるものではない。 Hereinafter, the present invention will be specifically described with reference to Examples, but the present invention is not limited to these Examples.
＜癌細胞からのオルガノイドの形成＞
表１に示す由来を有する胆道癌組織若しくは膵臓癌組織から単離した細胞を用いて、以下の方法でオルガノイドを調製した。なお、表及び図面中、「ＩＨＣＣ」とは肝内胆管癌を意味し、「ＰＤＡ」とは膵腺癌を意味し、「ＧＢＣ」とは胆嚢癌を意味し、「ＮＥＣ」とは神経内分泌癌を意味する。<Formation of organoids from cancer cells>
Organoids were prepared by the following methods using cells isolated from biliary tract cancer tissue or pancreatic cancer tissue having the origins shown in Table 1. In the table and drawings, "IFCC" means intrahepatic bile duct cancer, "PDA" means pancreatic adenocarcinoma, "GBC" means gallbladder cancer, and "NEC" means neuroendocrine. Means cancer.
各組織を小片に切り、消化緩衝液中で１時間、３７℃でインキュベートした。消化緩衝液は、ダルベッコ改変イーグル培地（ＤＭＥＭ）（２．５％ ウシ胎児血清、０．０１２５％ ディスパーゼ タイプＩＩ（サーモフィッシャーサイエンティフィック社製）及び０．０１２５％ コラゲナーゼ タイプＸＩ（シグマアルドリッチ社製）を含む。）を用いた。 Each tissue was cut into small pieces and incubated in digestive buffer for 1 hour at 37 ° C. The digestive buffers are Dulbecco's Modified Eagle's Medium (DMEM) (2.5% fetal bovine serum, 0.0125% Dispase Type II (Thermo Fisher Scientific) and 0.0125% Collagenase Type XI (Sigma-Aldrich). ) Is included.) Was used.
インキュベート後、培養物を１分間静置し、培養上清を回収してチューブに入れ、これを８００ｒｐｍで５分間遠心した。得られたペレットをＰＢＳで洗浄した後に、８００ｒｐｍで５分間遠心した（この操作を２度繰り返した。）。単離した各細胞を、氷上でマトリゲル（ｇｒｏｗｔｈ ｆａｃｔｏｒ ｒｅｄｕｃｅｄ， ｐｈｅｎｏｌ ｒｅｄ−ｆｒｅｅ、Ｃｏｒｎｉｎｇ社製）に埋入し、オルガノイド培養用培地（５００μｌ／ウェル）を入れた４８ウェルプレートに播種し、３７℃で培養を開始した。各ウェルにおいて、オルガノイドがコンフルエントな状態となった段階で、オルガノイド培養用培地を用いて継代培養を行った。いずれの組織から得られた細胞について、良好にオルガノイドが形成された。 After incubation, the culture was allowed to stand for 1 minute, the culture supernatant was collected and placed in a tube, which was centrifuged at 800 rpm for 5 minutes. The resulting pellet was washed with PBS and then centrifuged at 800 rpm for 5 minutes (this operation was repeated twice). Each isolated cell was embedded in Matrigel (growth factor red-free, manufactured by Corning) on ice, seeded on a 48-well plate containing a medium for organoid culture (500 μl / well), and seeded at 37 ° C. The culture was started at. In each well, when the organoids were in a confluent state, subculture was performed using an organoid culture medium. Organoids were well formed in cells obtained from any of the tissues.
用いたオルガノイド培養用培地の組成を表２に示す。用いた各成分の詳細は以下のとおりである。
アドバンスト−ＤＭＥＭ／Ｆ１２：サーモフィッシャーサイエンティフィック社製
Ｇｌｕｔａｍａｘ：サーモフィッシャーサイエンティフィック社製
ＨＥＰＥＳ：サーモフィッシャーサイエンティフィック社製
ペニシリン／ストレプトマイシン：サーモフィッシャーサイエンティフィック社製
Ｒ−スポンジン１（Ｒｓｐｏ１）：Ｒｓｐｏ１産生株からの１０％条件培地
Ｎ−２ ｓｕｐｐｌｅｍｅｎｔ：サーモフィッシャーサイエンティフィック社製
Ｂ−２７ ｓｕｐｐｌｅｍｅｎｔ：サーモフィッシャーサイエンティフィック社製
Ｎ−アセチルシステイン（ＮＡＣ）：シグマ アルドリッチ社製
ガストリン：シグマ アルドリッチ社製
ニコチンアミド：シグマ アルドリッチ社製
上皮成長因子（ＥＧＦ）：サーモフィッシャーサイエンティフィック社製
Ｙ−２７６３２：ＷＡＫＯ社製
Ａ８３−０１：Ｔｏｃｒｉｓ社製
フォルスコリン：Ｔｏｃｒｉｓ社製The composition of the organoid culture medium used is shown in Table 2. The details of each component used are as follows.
Advanced-DMEM / F12: Thermo Fisher Scientific Glutamax: Thermo Fisher Scientific HEPES: Thermo Fisher Scientific Penicillin / Streptomycin: Thermo Fisher Scientific R-Spondin 1 (Rspo1): 10% conditional medium from Rspo1 producing strain N-2 supplement: Thermo Fisher Scientific B-27 supplement: Thermo Fisher Scientific N-acetylcysteine (NAC): Sigma Aldrich Gustrin: Sigma Aldrich Nicotinamide: Sigma Aldrich Epithelial Growth Factor (EGF): Thermo Fisher Scientific Y-27632: WAKO A83-01: Tocris Forskolin: Tocris
＜オルガノイドを用いた薬剤スクリーニング＞
上記で得られたオルガノイドを用いて、化合物ライブラリー（東京大学創薬機構より提供）から得られた各種薬剤による癌細胞増殖抑制効果を評価した。なお、スクリーニング対象である薬剤としては、臨床的に用いられているものを３３９種類使用した。<Drug screening using organoids>
Using the organoids obtained above, the cancer cell growth inhibitory effect of various drugs obtained from the compound library (provided by the University of Tokyo Drug Discovery Organization) was evaluated. As the drug to be screened, 339 kinds of clinically used drugs were used.
各オルガノイドから得られた細胞を、１．２×１０３個／ウェルとなるように、オルガノイド培養用培地（５００μｌ／ウェル）を入れた４８ウェルプレートに播種し、３７℃で４日間培養した。培養後、最終濃度が０．１μＭとなるように薬剤を添加し、さらに６日間培養した。また、対照試験として、薬剤の代わりに０．１％ ジメチルスルホキシド（ＤＭＳＯ）の存在下での培養を行った。得られた各培養物を用いて、以下のＷＳＴアッセイを行い、細胞の生存率を測定した。The cells obtained from each organoid were seeded on a 48-well plate containing an organoid culture medium (500 μl / well) so as to have 1.2 × 10 3 cells / well, and cultured at 37 ° C. for 4 days. After culturing, a drug was added so that the final concentration was 0.1 μM, and the cells were further cultured for 6 days. In addition, as a control test, culture was performed in the presence of 0.1% dimethyl sulfoxide (DMSO) instead of the drug. Using each of the obtained cultures, the following WST assay was performed to measure the viability of cells.
（ＷＳＴアッセイ）
市販のキット（商品名「ｔｈｅ Ｃｅｌｌ Ｃｏｕｎｔｉｎｇ Ｋｉｔ−８」、株式会社 同仁化学研究所製）を用いて、各培養物中の細胞の生存率を測定した。対照として、を用いた。測定は各試料につき３回行った。(WST assay)
The viability of cells in each culture was measured using a commercially available kit (trade name "the Cell Counting Kit-8", manufactured by Dojin Chemical Laboratory Co., Ltd.). As a control, was used. The measurement was performed 3 times for each sample.
対照試験における生存率の平均値Ｃに対する、各試料の存在下での細胞の生存率の平均値Ｓの値（Ｓ／Ｃ）が０．５以下である場合、該試料に添加した薬剤の癌細胞増殖抑制効果が顕著であると判定した。 When the average value S (S / C) of the cell survival rate in the presence of each sample is 0.5 or less with respect to the average value C of the survival rate in the control test, the cancer of the drug added to the sample It was determined that the cell growth inhibitory effect was remarkable.
（スクリーニング結果）
上記ＷＳＴアッセイの結果、表３に示す２１種類の薬剤について、癌細胞増殖抑制効果が顕著であると判定された。(Screening result)
As a result of the above WST assay, it was determined that the cancer cell growth inhibitory effect was remarkable for the 21 types of drugs shown in Table 3.
表３に示されるとおり、意外にも、抗真菌剤であるアモロルフィン、フェンチコナゾール、及びイトラコナゾール、並びに、ＨＭＧ−ＣｏＡ還元酵素阻害剤であるセリバスタチンは、既に確立された抗癌剤と同等の癌細胞増殖抑制効果を示した。 As shown in Table 3, surprisingly, the antifungal agents amorolfine, fenticonazole, and itraconazole, and the HMG-CoA reductase inhibitor cerivastatin, have cancer cell proliferation equivalent to those of already established anticancer agents. It showed an inhibitory effect.
アモロルフィン、セリバスタチン、及びイトラコナゾールについて、添加濃度を変えて、上記同様にＷＳＴアッセイを行った。その結果を図１及び２に示す。図１中、（Ａ）はアモロルフィンを用いた結果、（Ｂ）はセリバスタチンを用いた結果を示す。図２中、（Ａ）はイトラコナゾールを用いた結果、（Ｂ）はアモロルフィンを用いた結果を示す。 For amorolfine, cerivastatin, and itraconazole, the WST assay was performed in the same manner as described above with different addition concentrations. The results are shown in FIGS. 1 and 2. In FIG. 1, (A) shows the result of using amorolfine, and (B) shows the result of using cerivastatin. In FIG. 2, (A) shows the result of using itraconazole, and (B) shows the result of using amorolfine.
なお、図１及び２中、「細胞の生存率」は、薬剤の添加濃度が「０μＭ」であるとき、又は「ＤＭＳＯ」を用いたとき（つまり、薬剤が含まれていない場合）の結果を「１」とした場合の相対値として示した。したがって、細胞の生存率の値が低いほど、癌細胞増殖抑制効果が高いことを意味する。 In addition, in FIGS. 1 and 2, the "cell viability" is the result when the drug addition concentration is "0 μM" or when "DMSO" is used (that is, when the drug is not contained). It is shown as a relative value when it is set to "1". Therefore, the lower the cell viability value, the higher the cancer cell growth inhibitory effect.
図１及び２に示されるとおり、アモロルフィン、セリバスタチン、及び、イトラコナゾールのいずれも、濃度依存的に癌細胞増殖抑制効果を示した。この結果から、これらの薬剤が、癌（特に、胆道癌又は膵臓癌）の治療に効果的であることが示唆された。 As shown in FIGS. 1 and 2, all of amorolfine, cerivastatin, and itraconazole showed a concentration-dependent inhibitory effect on cancer cell growth. This result suggests that these agents are effective in treating cancer (particularly biliary tract cancer or pancreatic cancer).
Claims (5)
前記癌が胆道癌又は膵臓癌であり、
ヒトへの経口投与用である、
請求項１に記載の癌治療用医薬組成物。Contains 100-400 mg of itraconazole or a pharmacologically acceptable salt thereof
The cancer is biliary tract cancer or pancreatic cancer,
For oral administration to humans,
The pharmaceutical composition for treating cancer according to claim 1.
前記癌が胆道癌又は膵臓癌であり、
ヒトへの経口投与用である、
請求項１に記載の癌治療用医薬組成物。Contains 0.10 to 0.50 mg of cerivastatin or a pharmacologically acceptable salt thereof.
The cancer is biliary tract cancer or pancreatic cancer,
For oral administration to humans,
The pharmaceutical composition for treating cancer according to claim 1.
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Non-Patent Citations (5)
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| ANTICANCER RESEARCH, vol. 35, JPN6023050956, 2015, pages 4923 - 4928, ISSN: 0005216514 * |
| CHEN K ET AL.: "Itraconazole inhibits invasion and migration of pancreatic cancer cells by suppressing TGF/β/SMAD2/", ONCOLOGY REPORTS, vol. 39, JPN6019046354, April 2018 (2018-04-01), pages 1573 - 1582, XP055700569, ISSN: 0005216510, DOI: 10.3892/or.2018.6281 * |
| GBELCOVA H ET AL.: "Differences in antitumor effects of various statins on human pancreatic cancer", INTERNATIONAL JOURNAL OF CANCER, vol. 122, JPN6019046356, 2008, pages 1214 - 1221, XP055700572, ISSN: 0005216512, DOI: 10.1002/ijc.23242 * |
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| TSUBAMOTO H ET AL.: "Combination Chemotherapy with Itraconazole for Treating Metastatic Pancreatic Cancer in the Second-l", ANTICANCER RESEARCH, vol. 35, JPN6019046355, 2015, pages 4191 - 4196, XP055700571, ISSN: 0005216511 * |
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