JP7414230B2 - Antihematologic malignant tumor drug - Google Patents
Antihematologic malignant tumor drug Download PDFInfo
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- JP7414230B2 JP7414230B2 JP2018211066A JP2018211066A JP7414230B2 JP 7414230 B2 JP7414230 B2 JP 7414230B2 JP 2018211066 A JP2018211066 A JP 2018211066A JP 2018211066 A JP2018211066 A JP 2018211066A JP 7414230 B2 JP7414230 B2 JP 7414230B2
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- tofogliflozin
- malignant tumor
- drug
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Description
特許法第３０条第２項適用 １．学会抄録集（日本内分泌学会雑誌）の発行による公開 学会名：第９１回日本内分泌学会学術総会 発行者：一般社団法人日本内分泌学会事務局 発行日：平成３０年４月１日 ２．学会発表による公開 学会名：第９１回日本内分泌学会学術総会 公開日：平成３０年４月２６日 開催日：平成３０年４月２６～２８日Application of Article 30, Paragraph 2 of the Patent Act 1. Publication through publication of academic conference abstracts (Journal of the Japanese Endocrine Society) Society name: 91st Academic Meeting of the Japanese Endocrine Society Publisher: Japan Endocrine Society Secretariat Publication date: April 1, 2018 2. Publication through conference presentations Conference name: 91st Academic Meeting of the Japanese Endocrine Society Publication date: April 26, 2018 Event date: April 26-28, 2018
本発明は、トホグリフロジンを有効成分として含有することを特徴とする抗血液悪性腫瘍薬に関する。 The present invention relates to an antihematologic malignant tumor drug characterized by containing tofogliflozin as an active ingredient.
悪性腫瘍は、年間、日本人の２人に１人が罹患する疾病といわれている。そのため、悪性腫瘍の治療、管理、予防をすることが求められている。
また、種々の抗悪性腫瘍剤が、市販、開発されているが、未だ発展途上といえる。すなわち、現在の抗悪性腫瘍剤は、完治することが難しい、効果に個体差がある、副作用が大きい等の課題を有しており、さらなる抗悪性腫瘍剤の開発ないし改良が求められている。
Malignant tumors are said to be a disease that affects one in two Japanese people every year. Therefore, there is a need to treat, manage, and prevent malignant tumors.
In addition, various anti-malignant tumor agents are commercially available and have been developed, but they are still under development. That is, current anti-malignant tumor agents have problems such as difficulty in completely curing the disease, individual differences in effectiveness, and large side effects, and there is a need for further development or improvement of anti-malignant tumor agents.
悪性腫瘍細胞は、増殖・転移に有利になる環境を自ら作り出し、低栄養、低酸素という劣悪な環境下でも生き延びる形質を獲得する。悪性腫瘍細胞において知られるワールブルグ効果は、悪性腫瘍細胞が有酸素環境下においてすらミトコンドリアによる酸化的リン酸化よりも解糖系によるアデノシン三リン酸（ATP）産生に依存する現象である。このワールブルグ効果は、90年以上前に提唱された分子メカニズムにも関わらず、その詳細は、未だ充分に解明されていない。
悪性腫瘍細胞では、ミトコンドリアの機能低下も相俟って、エネルギー産生効率の悪い解糖系に糖代謝がシフトしている。そのため、悪性腫瘍細胞では、糖の取り込みが正常細胞よりも盛んになる。この特性を利用したFDG-PET検査が、悪性腫瘍の局在診断・転移診断に汎用されている（非特許文献１）。また、極めて難治性の高い血液悪性腫瘍である成人T細胞白血病の悪性度の階層化に、PET検査が有用であることも報告されている(非特許文献２)。
Malignant tumor cells create an environment that is favorable for their proliferation and metastasis, and acquire characteristics that allow them to survive even in poor environments such as low nutrition and low oxygen. The Warburg effect known in malignant tumor cells is a phenomenon in which malignant tumor cells rely on adenosine triphosphate (ATP) production by glycolysis rather than oxidative phosphorylation by mitochondria even under an aerobic environment. Although the molecular mechanism of the Warburg effect was proposed more than 90 years ago, its details have not yet been fully elucidated.
In malignant tumor cells, combined with decreased mitochondrial function, sugar metabolism shifts to glycolysis, which is less efficient in energy production. Therefore, malignant tumor cells take up more sugar than normal cells. FDG-PET testing that utilizes this characteristic is widely used for localization and metastasis diagnosis of malignant tumors (Non-Patent Document 1). It has also been reported that PET examination is useful for stratifying the malignancy of adult T-cell leukemia, which is an extremely refractory hematological malignancy (Non-Patent Document 2).
成人Ｔ細胞白血病（Adult T-cell Leukemia。以下「ATL」とも表示する。）は、ウイルスの一種であるHTLV-1の感染によって発症する。HTLV-1感染者は、世界の中でも日本の西南部（九州・沖縄地方）に多い。日本におけるHTLV-1感染者は、西南日本沿岸部を中心に110万人ほど存在し、感染者の発症率は年間1,000人に0.6～0.7人である。HTLV-1感染は、感染から発症までの潜伏期間が長いことから、HTLV-1感染者が生涯に発症する確率は約5％程度といわれている。また、HTLV-1感染において急性型やリンパ腫型では、高カルシウム血症や免疫低下に伴う感染症により、予後が悪いのが特徴である。 Adult T-cell leukemia (hereinafter also referred to as "ATL") is caused by infection with HTLV-1, a type of virus. The number of people infected with HTLV-1 is higher in the southwestern part of Japan (Kyushu and Okinawa regions) than in the world. There are approximately 1.1 million people infected with HTLV-1 in Japan, mainly in the coastal areas of southwestern Japan, and the incidence of infection is 0.6 to 0.7 per 1,000 people per year. Because HTLV-1 infection has a long incubation period from infection to onset of symptoms, it is said that the probability that a person infected with HTLV-1 will develop symptoms during their lifetime is approximately 5%. In addition, the acute type and lymphoma type of HTLV-1 infection are characterized by poor prognosis due to infection associated with hypercalcemia and decreased immunity.
解糖系をターゲットとした悪性腫瘍治療薬の開発は、これまでにも試みが知られており、2-Deoxyglucose、Lonidamine、3-Bromopyruvate(3 BrPA)、Imatinib、Oxythiamineなど、臨床試験まで行われている薬剤もあるが(非特許文献１)、未だ実地臨床には応用されていない。 Attempts have been made in the past to develop drugs to treat malignant tumors that target the glycolytic system, and clinical trials have been conducted for drugs such as 2-Deoxyglucose, Lonidamine, 3-Bromopyruvate (3 BrPA), Imatinib, and Oxythiamine. Although there are some drugs that have been used for this purpose (Non-Patent Document 1), they have not yet been applied in clinical practice.
一方、sodium-glucose cotransporter 2（以下「SGLT2」とも表示する。）阻害剤は、糖尿病治療薬であり、近位尿細管からの糖の再吸収を阻害して尿糖***を促進することで血糖値を低下させるメカニズムを有する。SGLT2阻害剤は、副作用が少なく、インスリン分泌に作用する薬剤とは異なる作用の治療薬である。
SGLT2阻害剤には、ある種の悪性腫瘍に対する抗腫瘍効果が知られており（非特許文献３）、ダパグリフロジン、カナグリフロジン、トホグリフロジンにおいては、がん移植モデルマウスや幾つかの悪性腫瘍細胞に対する効果が報告されている（非特許文献４から８）。
On the other hand, sodium-glucose cotransporter 2 (hereinafter also referred to as "SGLT2") inhibitors are antidiabetic drugs that inhibit sugar reabsorption from the proximal renal tubule and promote urinary glucose excretion, thereby reducing blood sugar levels. It has a mechanism to reduce the value. SGLT2 inhibitors are therapeutic agents that have few side effects and have a different action from drugs that act on insulin secretion.
SGLT2 inhibitors are known to have antitumor effects against certain types of malignant tumors (Non-Patent Document 3), and dapagliflozin, canagliflozin, and tofogliflozin have antitumor effects against cancer-transplanted model mice and some malignant tumor cells. Effects have been reported (Non-Patent Documents 4 to 8).
例えば、非特許文献４では、ダパグリフロジンやカナグリフロジンに関して、すい臓がん、前立腺がんのがん移植モデルマウスにおける抗がん作用が報告されている。
非特許文献５では、ダパグリフロジンに関して、ヒト腎がん細胞株、及び腎がん細胞株由来マウスゼノグラフトモデルにおける抗がん作用が報告されている。
非特許文献６では、カナグリフロジンに関して、ヒト肝がん細胞株、及びヒト肝がん細胞株由来マウスゼノグラフトモデルにおける抗がん作用が報告されている。
非特許文献７では、カナグリフロジンに関して、ヒトの前立腺がん細胞株、肺がん細胞株、肝臓がん細胞株、乳がん細胞株における抗がん作用が報告されている。加えて、その作用は弱いが、大腸がん細胞株、卵巣がん細胞株における抗がん作用、並びに、ヒト前立腺がん細胞株由来マウスゼノグラフトモデルにおける抗がん作用についても報告されている。
非特許文献８では、トホグリフロジンに関して、糖尿病マウスにおける肝がん発生予防作用が報告されている。
これら文献には、SGLT2阻害剤が種々の癌に作用することが報告されているものの、血液悪性腫瘍に対する報告はない。
For example, Non-Patent Document 4 reports the anticancer effects of dapagliflozin and canagliflozin in cancer-transplanted model mice of pancreatic cancer and prostate cancer.
Non-Patent Document 5 reports the anticancer effects of dapagliflozin in a human renal cancer cell line and a mouse xenograft model derived from a renal cancer cell line.
Non-Patent Document 6 reports the anticancer effect of canagliflozin in a human liver cancer cell line and a mouse xenograft model derived from a human liver cancer cell line.
Non-Patent Document 7 reports the anticancer effects of canagliflozin on human prostate cancer cell lines, lung cancer cell lines, liver cancer cell lines, and breast cancer cell lines. In addition, although the effect is weak, anticancer effects have been reported in colon cancer cell lines, ovarian cancer cell lines, and in mouse xenograft models derived from human prostate cancer cell lines. .
Non-Patent Document 8 reports that tofogliflozin has a preventive effect on the development of liver cancer in diabetic mice.
Although these documents report that SGLT2 inhibitors act on various cancers, there are no reports on hematological malignancies.
また、SGLT2阻害剤と抗悪性腫瘍剤との併用に関して、非特許文献４には、カナグリフロジンとゲムシタビン併用によるすい臓がんへの作用が報告されている。
非特許文献７には、カナグリフロジンとドセタキセルまたは放射線治療併用による前立腺がんへの作用が報告されている。
特許文献１には、カナグリフロジンとドセタキセル、シスプラチンまたは放射線治療併用による前立腺がんや肺がんへの作用が報告されている。
特許文献２には、ダパグリフロジンとグルフォスファミドによる併用療法が報告されている。
しかしながら、これら文献には、トホグリフロジンと抗癌剤との併用に関する報告はなく、血液悪性腫瘍に関する併用療法の報告もない。
Regarding the combination of an SGLT2 inhibitor and an antineoplastic agent, Non-Patent Document 4 reports the effect of a combination of canagliflozin and gemcitabine on pancreatic cancer.
Non-Patent Document 7 reports the effect of combined use of canagliflozin and docetaxel or radiotherapy on prostate cancer.
Patent Document 1 reports the effects of canagliflozin in combination with docetaxel, cisplatin, or radiotherapy on prostate cancer and lung cancer.
Patent Document 2 reports combination therapy using dapagliflozin and glufosfamide.
However, in these literatures, there are no reports on the combination of tofogliflozin and anticancer drugs, and there are no reports on combination therapy for hematological malignancies.
本発明は、血液悪性腫瘍に対する予防・治療効果を有する新たな薬剤の提供を課題とする。 An object of the present invention is to provide a new drug that has preventive and therapeutic effects on hematological malignancies.
本発明者らは、鋭意検討を行った結果、トホグリフロジンが、血液悪性腫瘍細胞に関し、細胞増殖を抑制する効果を発揮することを明らかとし、トホグリフロジンが血液悪性腫瘍の予防・治療に有用なことを見出し、本発明を完成させたものである。 As a result of extensive studies, the present inventors have clarified that tofogliflozin exhibits the effect of suppressing cell proliferation regarding hematological malignant tumor cells, and has demonstrated that tofogliflozin is useful for the prevention and treatment of hematological malignant tumors. The heading completes the invention.
すなわち、本発明は、
（１）トホグリフロジンを有効成分として含有することを特徴とする抗血液悪性腫瘍薬、
（２）トホグリフロジン水和物を含有することを特徴とする抗血液悪性腫瘍薬、
（３）血液悪性腫瘍が、悪性リンパ腫、白血病及び多発性骨髄腫からなる群より選ばれる（１）又は（２）に記載の抗血液悪性腫瘍薬、
（４）血液悪性腫瘍が、成人Ｔ細胞白血病である（１）又は（２）に記載の抗血液悪性腫瘍薬、
である。
That is, the present invention
(1) An antihematologic malignant tumor drug characterized by containing tofogliflozin as an active ingredient;
(2) an anti-hematologic malignant tumor drug characterized by containing tofogliflozin hydrate;
(3) the antihematological malignant tumor drug according to (1) or (2), wherein the hematological malignant tumor is selected from the group consisting of malignant lymphoma, leukemia, and multiple myeloma;
(4) the anti-hematological malignant tumor drug according to (1) or (2), wherein the hematological malignant tumor is adult T-cell leukemia;
It is.
本発明により、血液悪性腫瘍に対する予防・治療効果を有する新たな薬剤の提供が可能となった。
トホグリフロジンは血液悪性腫瘍細胞の増殖を抑制することができる。トホグリフロジンを血液悪性腫瘍の予防及び／又は治療に用いることで、がん治療の選択の幅を広げることが可能となる。
さらに、従来から用いられている抗がん剤とトホグリフロジンを併用することで、治療効果を増強させることが可能となり、新たな治療方法を提供可能な点で、非常に有用である。
The present invention has made it possible to provide a new drug that has preventive and therapeutic effects on hematological malignancies.
Tofogliflozin can inhibit the proliferation of hematological malignant tumor cells. By using tofogliflozin for the prevention and/or treatment of hematological malignancies, it becomes possible to expand the range of cancer treatment options.
Furthermore, by using tofogliflozin in combination with a conventionally used anticancer drug, it is possible to enhance the therapeutic effect, and it is extremely useful in that it can provide a new treatment method.
本発明の抗血液悪性腫瘍薬は、トホグリフロジンを含有することを特徴とする。
トホグリフロジンは、化学名を(1S,3'R,4'S,5'S,6'R)-6-[(4-Ethylphenyl)methyl]-6'-(hydroxymethyl)-3',4',5',6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran]-3',4',5'-triolとするものであり、本発明の抗血液悪性腫瘍薬に含有されるトホグリフロジンは、フリー体でもよく、薬理学的に許容な塩の形態でもよく、また溶媒和物等の種々の形態のものを用いることができる。本発明の抗血液悪性腫瘍薬においては、例えば、トホグリフロジンのフリー体、トホグリフロジン水和物を用いるのが好ましい。
The antihematologic malignant tumor drug of the present invention is characterized by containing tofogliflozin.
Tofogliflozin has the chemical name (1S,3'R,4'S,5'S,6'R)-6-[(4-Ethylphenyl)methyl]-6'-(hydroxymethyl)-3',4',5',6 '-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran]-3',4',5'-triol, and tofogliflozin contained in the antihematologic malignant tumor drug of the present invention is , may be in the free form, may be in the form of a pharmacologically acceptable salt, and may be in various forms such as a solvate. In the antihematological malignant tumor drug of the present invention, for example, it is preferable to use the free form of tofogliflozin and tofogliflozin hydrate.
トホグリフロジンは、ナトリウム-グルコース共輸送体-２（sodium-glucose cotransporter 2：SGLT2）における、ナトリウムとグルコースの交換を阻害して、血中の過剰なグルコースを尿中に***することで血糖値を低下させ、血液中のグルコース濃度の増大を抑制する薬剤（SGLT2阻害剤）である。SGLT2阻害剤としてグリフロジン系化合物が知られており、トホグリフロジンをはじめとして、イプラグリフロジン、ダパグリフロジン、カナグリフロジン、エンパグリフロジンなどが知られている。本発明の抗血液悪性腫瘍薬には、トホグリフロジン以外のSGLT2阻害剤を含有せしめることができる。 Tofogliflozin lowers blood sugar levels by inhibiting the exchange of sodium and glucose in sodium-glucose cotransporter 2 (SGLT2) and excreting excess glucose in the blood into the urine. It is a drug (SGLT2 inhibitor) that suppresses the increase in glucose concentration in the blood. Gliflozin compounds are known as SGLT2 inhibitors, including tofogliflozin, ipragliflozin, dapagliflozin, canagliflozin, empagliflozin, and the like. The antihematologic malignant tumor drug of the present invention can contain an SGLT2 inhibitor other than tofogliflozin.
本発明の抗血液悪性腫瘍薬は、トホグリフロジンがSGLT2を阻害し、血液悪性腫瘍細胞の増殖抑制をはじめとする抗血液悪性腫瘍作用を発揮することにより、血液悪性腫瘍の予防ないし治療の効果を示すものと推測される。
また、本発明の抗血液悪性腫瘍薬は、任意の血液悪性腫瘍に用いることができるが、成人Ｔ細胞白血病（ATL）または急性リンパ性白血病（ALL）における血液悪性腫瘍細胞においてより好ましい効果を発揮するものであり、その中でも特に成人Ｔ細胞白血病における血液悪性腫瘍細胞において好ましい効果を発揮するものである。
加えて、本発明の抗血液悪性腫瘍薬は、血液悪性腫瘍細胞の増殖抑制剤としても機能し得るものである。
The anti-hematological malignant tumor drug of the present invention exhibits the effect of preventing or treating hematological malignant tumors, as tofogliflozin inhibits SGLT2 and exerts anti-hematological malignant tumor effects, including suppressing the proliferation of hematological malignant tumor cells. It is assumed that
Furthermore, the anti-hematologic malignant tumor drug of the present invention can be used for any hematologic malignancy, but exhibits a more favorable effect on hematologic malignant tumor cells in adult T-cell leukemia (ATL) or acute lymphoblastic leukemia (ALL). Among these, it exhibits particularly favorable effects on hematological malignant tumor cells in adult T-cell leukemia.
In addition, the anti-hematological malignant tumor drug of the present invention can also function as a growth inhibitor of hematological malignant tumor cells.
本発明の抗血液悪性腫瘍薬は、トホグリフロジンに加えて、他の抗がん剤を組み合わせてもよい。トホグリフロジンと、他の1種又は複数種の抗がん剤を組み合わせることにより、血液悪性腫瘍の予防ないし治療効果を、より向上させる効果を期待することができる。
本発明においてトホグリフロジンと抗がん剤とを組み合わせる場合、期待する治療効果に従って、投与の時期や投与経路は適宜検討して決定することができる。投与のタイミングとしては、同時または異時に投与することが挙げられ、投与の経路としては、いずれも経口投与であったり、いずれか一方を経口投与して、他方を静脈内投与するといった種々の手法で行うことができる。このような手法として、例えば、トホグリフロジンと抗がん剤を組み合わせた単一の製剤（配合剤）にすることや、別々に製剤化したものを同時又は異時に投与することや、投与時にトホグリフロジンと抗がん剤を配合（用時調製）して投与することなどが挙げられる。また、トホグリフロジンと抗がん剤を連続的に投与したり、トホグリフロジンを経口による継続的投与を行いながら抗がん剤を単回投与することもできる。
トホグリフロジン及び抗がん剤は、通常行われる手段に従って、錠剤、顆粒剤、散剤、カプセル剤、乳剤、懸濁剤、シロップ剤などの経口投与製剤に、あるいは無菌性溶液、懸濁液剤などの注射剤といった静脈内投与製剤に、テープ剤、パップ剤などの経皮投与製剤などに製剤化することができる。これら有効成分を別々に製剤化して得られる２種の製剤とした場合には、それぞれの製剤を同時に投与してもよいし、異時に投与してもよい。
本発明において２種以上の製剤とする場合は、従来の使用方法とは異なるなどの理由から、例えば、市販されている医薬の添付文書や販売パンフレット等の文書に、それぞれを併用する旨を記載することが好ましい。
The anti-hematologic malignant tumor drug of the present invention may be combined with other anti-cancer agents in addition to tofogliflozin. By combining tofogliflozin with one or more other anticancer drugs, it can be expected that the effects of preventing or treating hematological malignancies will be further improved.
When tofogliflozin and an anticancer drug are used in combination in the present invention, the timing and route of administration can be appropriately determined according to the expected therapeutic effect. The timing of administration includes simultaneous or different administration, and the routes of administration include various methods such as oral administration for both, or oral administration of one and intravenous administration of the other. It can be done with Such methods include, for example, combining tofogliflozin and anticancer drugs into a single formulation (compound formulation), administering separately formulated formulations at the same time or at different times, and administering tofogliflozin and anticancer drugs at the same time. Examples include combining anticancer drugs (prepared at the time of use) and administering the drug. Furthermore, tofogliflozin and the anticancer drug can be administered continuously, or the anticancer drug can be administered once while tofogliflozin is continuously administered orally.
Tofogliflozin and anticancer drugs can be prepared in oral preparations such as tablets, granules, powders, capsules, emulsions, suspensions, and syrups, or by injection as sterile solutions and suspensions, according to customary procedures. It can be formulated into intravenous preparations such as a drug, and transdermal preparations such as tapes and poultices. When two types of formulations are obtained by separately formulating these active ingredients, each formulation may be administered at the same time or at different times.
In the case of using two or more types of formulations in the present invention, for reasons such as differences from conventional usage methods, for example, the fact that they are used together is stated in documents such as package inserts and sales pamphlets of commercially available pharmaceuticals. It is preferable to do so.
本発明において抗がん剤は、トホグリフロジンとの組み合わせにより血液悪性腫瘍の予防及び／又は治療効果等を向上させるものであれば特に限定する必要はなく、あらゆる抗がん剤を用いることができる。このような抗がん剤として、化学療法剤、分子標的治療剤、ホルモン療法剤、免疫療法剤などが挙げられる。
また、血液悪性腫瘍に特に好適に用いられる抗がん剤として化学療法剤が挙げられ、例えば、アルキル化薬、白金化合物、代謝拮抗薬、トポイソメラーゼ阻害剤、微小管阻害剤、抗生物質などが挙げられる。このような抗がん剤として、例えば、シクロホスファミド、シタラビン、メルカプトプリン、メトトレキサート、塩酸エピルビシン、エトポシド、ビンクリスチン、インターフェロンα、イマチニブ、ダサチニブ、ニロチニブ、オファツムマブ、レチノイン、レブラミド、モガリズマブ等が挙げられる。これらのうち、悪性腫瘍細胞の増殖スピードの早い白血病や悪性リンパ腫を対象とした観点から、DNA合成阻害作用をもつ殺細胞性抗がん剤であるシクロホスファミド、シタラビン、塩酸エピルビシン、エトポシド、ビンクリスチンが好ましく、併用頻度が高く、単剤でもある程度の抗腫瘍効果を認めるという観点で最も優れているという理由からエトポシドが好ましい。
In the present invention, the anticancer agent does not need to be particularly limited as long as it improves the preventive and/or therapeutic effect of hematological malignancies when combined with tofogliflozin, and any anticancer agent can be used. Examples of such anticancer drugs include chemotherapeutic agents, molecular target therapeutic agents, hormonal therapeutic agents, immunotherapeutic agents, and the like.
In addition, chemotherapeutic agents are listed as anticancer drugs particularly suitable for use in hematological malignancies, such as alkylating drugs, platinum compounds, antimetabolites, topoisomerase inhibitors, microtubule inhibitors, and antibiotics. It will be done. Examples of such anticancer drugs include cyclophosphamide, cytarabine, mercaptopurine, methotrexate, epirubicin hydrochloride, etoposide, vincristine, interferon alpha, imatinib, dasatinib, nilotinib, ofatumumab, retinoin, Revlimid, mogalizumab, etc. . Among these, from the viewpoint of targeting leukemia and malignant lymphoma where malignant tumor cells proliferate rapidly, cyclophosphamide, cytarabine, epirubicin hydrochloride, etoposide, which are cell-killing anticancer drugs that inhibit DNA synthesis, Vincristine is preferred, and etoposide is preferred because it is frequently used in combination and is the most superior in that it exhibits some degree of antitumor effect even as a single agent.
本発明における血液悪性腫瘍とは、トホグリフロジンが抗血液悪性腫瘍作用を発揮しうる限り特に限定する必要はなく、種々の血液悪性腫瘍を対象とすることができる。このような血液悪性腫瘍として、例えば、白血病、悪性リンパ腫、多発性骨髄腫などが挙げられ、白血病としては、その経過や血液悪性腫瘍細胞の由来から、急性骨髄性白血病（AML）、急性リンパ性白血病（ALL）、慢性骨髄性白血病（CML）、慢性リンパ性白血病（CLL）などが挙げられる。
本発明における血液悪性腫瘍において、難治性が高く新たな治療戦略が望まれるという観点から、リンパ性の悪性腫瘍を対象とすることが好ましく、より好ましくは成人Ｔ細胞白血病または急性リンパ性白血病であり、さらに好ましくは成人Ｔ細胞白血病である。
成人Ｔ細胞白血病（ATL）は、ウイルスの一種であるHTLV-1（human T-lymphotropic virus type-I）が、白血球であるT細胞に感染し、悪性腫瘍化した細胞（ATL細胞）が無制限に増殖することで発症する。ATLは、血液悪性腫瘍のうち、リンパ性の白血病または非ホジキンリンパ腫の悪性リンパ腫に分類される。ATL細胞は血液中だけではなくリンパ節でも増殖するため、多くはリンパ節の腫れが認められるが、病変の広がりは全身性である。病型は、急性型、リンパ腫型、慢性型、くすぶり型に分類されるが、本発明において、特に限定はされない。
The hematological malignant tumor in the present invention is not particularly limited as long as tofogliflozin can exhibit an anti-hematological malignant tumor effect, and various hematological malignant tumors can be targeted. Examples of such hematological malignant tumors include leukemia, malignant lymphoma, and multiple myeloma. Leukemia is classified into acute myeloid leukemia (AML), acute lymphoid leukemia, and acute lymphoid leukemia, depending on its course and the origin of hematological malignant tumor cells. These include leukemia (ALL), chronic myeloid leukemia (CML), and chronic lymphocytic leukemia (CLL).
Regarding the hematological malignant tumor in the present invention, it is preferable to target a lymphoid malignant tumor, more preferably adult T-cell leukemia or acute lymphocytic leukemia, from the viewpoint that it is highly refractory and a new therapeutic strategy is desired. , more preferably adult T cell leukemia.
Adult T-cell leukemia (ATL) is a type of virus, HTLV-1 (human T-lymphotropic virus type-I), that infects T cells, which are white blood cells, and the cells that have turned into malignant tumors (ATL cells) become unrestricted. It develops due to proliferation. Among hematological malignancies, ATL is classified as lymphocytic leukemia or malignant lymphoma of non-Hodgkin's lymphoma. ATL cells proliferate not only in the blood but also in the lymph nodes, so swollen lymph nodes are often observed, but the lesions are systemic. The disease type is classified into acute type, lymphoma type, chronic type, and smoldering type, but is not particularly limited in the present invention.
本発明において血液悪性腫瘍の予防及び／又は治療とは、典型的には、悪性腫瘍細胞の消滅、増殖抑制、活動性低下、機能停止などが挙げられるがこれらに限定されるものではない。すなわち、血液悪性腫瘍細胞に直接的又は間接的に発揮される様々な効果を含むものであり、例えば、治療剤や治療補助剤の用量低減、投与期間の短縮、投与回数の低減、悪性腫瘍に起因する種々の症状の抑制及び安定化、発症・再発・進行の抑制、副作用の低減、患者の生存延長、患者の生活の質の向上などが挙げられる。
発症の抑制とは、ウイルス感染等の外部因子により発症する場合に事前に発症を抑制すること、再発の抑制とは、治療又は切除により悪性腫瘍細胞あるいは病変が消失した患者における再発を事前に抑制すること、進行の抑制とは、進行を遅延、後退させることを意味する。
In the present invention, prevention and/or treatment of hematological malignant tumors typically includes, but is not limited to, eradication of malignant tumor cells, suppression of proliferation, reduction in activity, and cessation of function. In other words, it includes various effects that are directly or indirectly exerted on blood malignant tumor cells, such as reducing the dose of therapeutic agents or therapeutic adjuvants, shortening the administration period, reducing the number of administrations, and reducing the number of doses administered to malignant tumors. Examples include suppression and stabilization of various symptoms caused by the disease, suppression of onset, recurrence, and progression, reduction of side effects, prolongation of patient survival, and improvement of patient quality of life.
Suppression of onset refers to the prevention of onset when it occurs due to external factors such as viral infection, and suppression of recurrence refers to the prevention of recurrence in patients whose malignant tumor cells or lesions have disappeared through treatment or resection. To do something or to suppress progress means to delay or retard progress.
本発明の抗血液悪性腫瘍薬は、血液悪性腫瘍における予防ないし治療効果を発揮しうる限り特に限定する必要はなく、様々な方法により投与を行うことができる。本発明の抗血液悪性腫瘍薬の投与量については、年齢、体重、症状、治療効果、投与方法、処理時間等を勘案して、適切な投与量とすればよい。 The anti-hematologic malignant tumor drug of the present invention does not need to be particularly limited as long as it can exert a preventive or therapeutic effect on hematological malignant tumors, and can be administered by various methods. The dosage of the antihematological malignant tumor drug of the present invention may be determined appropriately by taking into consideration age, body weight, symptoms, therapeutic effects, administration method, treatment time, and the like.
本発明の抗血液悪性腫瘍薬の有効成分であるトホグリフロジンの投与量は、投与対象、投与方法などを勘案して設定することができ、例えば経口投与の場合は、患者（60kg）に対して、１日にトホグリフロジンとして0.1～60mg、好ましくは0.5～40mg、さらに好ましくは0.5～20mgとなるように投与することができる。投与するに際して、１日１回でもよく、また複数回に分けて投与してもよい。
これに対し、トホグリフロジンと組み合わせる抗がん剤の１日の投与量は、例をあげて説明すると、エトポシド(経口剤)の場合は、患者（60kg）に対して、１日に１～200mg投与することができるが、骨髄抑制など副作用の理由から好ましくは10～100mg投与し、さらに悪性リンパ腫では1クールで３週間連日内服することが多い理由から好ましくは25～50mg投与することが好ましい。また、エトポシド（注射剤）の場合は、患者の体表面積（１m2）に対して、1日量1～150mg投与することができるが、骨髄抑制など副作用の理由から好ましくは10～100mg、さらに他の抗がん剤と併用することが多い理由から好ましくは10～60mg投与すればよい。
この量は、医師用添付文書で指示される量若しくは当該用量より少ない量であるが、少ない量でも効果を期待できる理由は多剤併用が可能であることと、用量依存性ではなく、時間依存性に効果を発揮することが推測できるからである。
そのため、エトポシド以外の抗がん剤に関しても、前記エトポシドと同様に、医師用添付文書で指示される量若しくは当該用量より少ない量でも効果を期待できる。
これより、本発明は、抗がん剤の量として通常使用される用量よりも少ない量で効果を発揮でき、医師用添付文書で指示される量より少ない、例えばエトポシド25～50mgでも効果を期待できる。ひいては、抗がん剤に由来する副作用の軽減にもつながり得る。
The dose of tofogliflozin, which is the active ingredient of the antihematologic malignant tumor drug of the present invention, can be determined by taking into consideration the subject to be administered, the administration method, etc. For example, in the case of oral administration, Tofogliflozin can be administered in an amount of 0.1 to 60 mg, preferably 0.5 to 40 mg, and more preferably 0.5 to 20 mg per day. When administering, the drug may be administered once a day, or may be administered in multiple doses.
On the other hand, the daily dosage of anticancer drugs combined with tofogliflozin is, for example, in the case of etoposide (oral formulation), 1 to 200 mg is administered per day to a patient (60 kg). However, it is preferable to administer 10 to 100 mg due to side effects such as bone marrow suppression, and more preferably 25 to 50 mg because one course of malignant lymphoma is often taken orally for three weeks. In the case of etoposide (injection), the daily dose can be 1 to 150 mg per patient's body surface area (1 m 2 ), but for reasons of side effects such as bone marrow suppression, it is preferably 10 to 100 mg. Since it is often used in combination with other anticancer drugs, it is preferable to administer 10 to 60 mg.
This amount is the amount instructed by the doctor's package insert or a lower amount than the relevant dose, but the reason why the effect can be expected even with a small amount is that multiple drugs can be used together, and the effect is not dose-dependent but time-dependent. This is because it can be inferred that it has an effect on sex.
Therefore, with respect to anticancer drugs other than etoposide, similar effects can be expected even with the amount instructed in the physician's package insert or a dose smaller than the dose.
From this, the present invention can be effective with a dose lower than that normally used as an anticancer drug, and is expected to be effective even with a lower dose than prescribed in the doctor's package insert, for example, 25 to 50 mg of etoposide. can. In turn, this may lead to a reduction in side effects caused by anticancer drugs.
本発明において、トホグリフロジンと抗がん剤の配合比は、薬剤の種類、投与対象、投与方法等により適宜検討して設定すればよく、例えば、本発明の抗血液悪性腫瘍薬をヒトに投与する場合には、トホグリフロジン１質量部に対して抗がん剤を3.0×10-5～8.0×10-3質量部の割合で組み合わせた場合に、個々の薬剤を投与する場合よりも優れた抗血液悪性腫瘍作用を得ることが可能である。
特に抗がん剤がエトポシドの場合、トホグリフロジン１質量部に対してエトポシドが3.3×10-3～4.0×10-3質量部の割合で組み合わせることが好ましい。これにより、それぞれの薬剤を単独で投与した場合よりも少量で、充分な効果を得ることが期待できる。また、副作用の少ない医薬とすることが可能である。
In the present invention, the compounding ratio of tofogliflozin and the anticancer drug may be set by appropriately considering the type of drug, administration target, administration method, etc. For example, when administering the antihematologic malignant tumor drug of the present invention to humans. In some cases, a combination of anticancer drugs at a ratio of 3.0 × 10 -5 to 8.0 × 10 -3 parts by mass to 1 part by mass of tofogliflozin provides better anti-hematologic effects than when administering each drug individually. It is possible to obtain a malignant tumor effect.
In particular, when the anticancer drug is etoposide, it is preferable to combine etoposide in a proportion of 3.3×10 −3 to 4.0×10 −3 parts by mass per 1 part by mass of tofogliflozin. As a result, it can be expected that a sufficient effect can be obtained with a smaller amount than when each drug is administered alone. Furthermore, it is possible to produce a medicine with fewer side effects.
本発明の抗血液悪性腫瘍薬は、血液悪性腫瘍の予防及び／又は治療のために、さらに他の薬剤（トホグリフロジン以外のイプラグリフロジン、ダパグリフロジン、カナグリフロジン、エンパグリフロジン等の他のSGLT阻害剤または抗がん剤を含む。）とともに組み合わせて使用してもよいし、他の治療（放射線治療等）とともに組み合わせて使用してもよい。 The anti-hematologic malignant tumor drug of the present invention may be used to prevent and/or treat hematologic malignant tumors by using other drugs (other SGLT inhibitors other than tofogliflozin, such as ipragliflozin, dapagliflozin, canagliflozin, and empagliflozin). or anti-cancer drugs), or in combination with other treatments (radiotherapy, etc.).
以下に、実施例等を挙げ、本発明を更に詳細に説明するが、本発明はこれらの実施例等に何ら限定されるものではない。 The present invention will be described in more detail below with reference to Examples, but the present invention is not limited to these Examples.
＜＜試験例１．ATL細胞株での培地グルコース濃度の差異による細胞増殖能の評価＞＞
ATL細胞株を用いて、培地におけるグルコース濃度を変化させ、細胞増殖能に変化がみられるかを調べることを目的に検討を行った。
<<Test Example 1. Evaluation of cell proliferation ability based on differences in medium glucose concentration in ATL cell lines >>
Using the ATL cell line, we conducted a study with the purpose of changing the glucose concentration in the medium and examining whether there was a change in cell proliferation ability.
＜実験方法＞
１．ATL細胞株MT-2（琉球大学医学部保健学科血液免疫検査学分野 福島卓也先生より分譲）について、グルコース濃度の異なる２種類の培地で培養を行った（培地：RPMI1640、RPMI1640 Hybri-Max、培養条件：37℃、5％CO2 T25-フラスコを用いた、細胞数：3.9×102）。それぞれのグルコース濃度については、通常濃度が11mM、高濃度が25mMのグルコース濃度に調整して、72時間、培養を行った。
２．培養後24時間、48時間、72時間において細胞数の計測（WST-8法、Cell counting kit-8、同仁化学研究所、CK04）を行った。細胞数の計測については、マイクロプレートリーダー（TEKAN、Spark（登録商標））を用いて、450nmの吸光度を測定することにより行った。
<Experimental method>
1. The ATL cell line MT-2 (provided by Dr. Takuya Fukushima, Department of Hematology and Immunology, Faculty of Health Sciences, University of the Ryukyus) was cultured in two types of media with different glucose concentrations (medium: RPMI1640, RPMI1640 Hybri-Max, culture conditions : 37°C, 5% CO 2 using a T25-flask, cell number: 3.9 × 10 2 ). The respective glucose concentrations were adjusted to a normal concentration of 11 mM and a high concentration of 25 mM, and culture was performed for 72 hours.
2. Cell numbers were counted (WST-8 method, Cell counting kit-8, Dojindo Laboratories, CK04) 24 hours, 48 hours, and 72 hours after culture. The number of cells was measured by measuring absorbance at 450 nm using a microplate reader (TEKAN, Spark (registered trademark)).
＜実験結果＞
１．結果を図１に示す。
(1) グルコースの通常濃度（normal）、高濃度（high）、いずれにおいても細胞数は経時的に増加していた。
(2) また、いずれの時間点においても、高濃度の方が、通常濃度と比較して、細胞数が大きく増加しており、その差は有意であった。
２．これらの結果から、グルコース高濃度下で、ATL細胞の増殖が促進されることが示された。
<Experiment results>
1. The results are shown in Figure 1.
(1) The number of cells increased over time at both normal and high glucose concentrations.
(2) Furthermore, at all time points, the number of cells increased significantly at higher concentrations than at normal concentrations, and the difference was significant.
2. These results showed that ATL cell proliferation was promoted under high glucose concentrations.
＜＜試験例２．ATL細胞株等における、SGLT2mRNA発現の評価＞＞
ATL細胞株ならびにATL患者の末梢血等を試料として、RT-PCRを用いて、SGLT2mRNAの発現を調べることを目的として検討を行った。
<<Test Example 2. Evaluation of SGLT2 mRNA expression in ATL cell lines etc. >>
The purpose of this study was to examine the expression of SGLT2 mRNA using RT-PCR using ATL cell lines and peripheral blood samples from ATL patients.
＜実験方法＞
１．各細胞（MT-2、ATL急性型及びB-ALLの細胞数:1～6×106、PBMLは末梢血40mlからFicollを用いて分離した。ヒト大腸癌RNAはOriGene Technologiesより購入し、使用した。）からRNA抽出を行い、RT-PCR（Applied Biosystems StepOne Plusを用いて、95℃10分→40サイクル（95℃・15秒→60℃,1分））により、核酸増幅を行った。
２．なお、SGLT2mRNAは、それぞれの細胞における内在性コントロールとしてβ-actinの核酸増幅を併せて行い、これで割ることにより算出した。
<Experimental method>
1. Each cell (MT-2, ATL acute type, and B-ALL cell number: 1 to 6 × 10 6 PBML was isolated from 40 ml of peripheral blood using Ficoll. Human colorectal cancer RNA was purchased from OriGene Technologies and used. ), and nucleic acid amplification was performed by RT-PCR (95°C, 10 minutes → 40 cycles (95°C, 15 seconds → 60°C, 1 minute) using Applied Biosystems StepOne Plus).
2. In addition, SGLT2 mRNA was calculated by simultaneously performing nucleic acid amplification of β-actin as an endogenous control in each cell and dividing by this.
＜実験結果＞
１．結果を図２（陽性コントロールを１とした図、RQ＝relative quantification）に示す。
図２において、MT-2がATL細胞株、PBMLが末梢血由来健常人単核球細胞（陰性コントロール）、human colon cancerがヒト大腸がん細胞（陽性コントロール）、ATL急性型が末梢血ATL細胞、B-ALLが急性リンパ性白血病細胞（末梢血）を示す。
(1) 陰性コントロールであるPBMLでは、SGLT2mRNAの発現増加は認められなかった。陽性コントロールであるhuman colon cancerでは、SGLT2mRNA発現量の明らかな増加が認められた（positive controlとしてヒト大腸癌で発現を認め、negative controlであるPBMLでは発現が低い。）。
(2) 一方、MT-2、ATL急性型、B-ALLでは、SGLT2mRNAの明らかな増加が認められた（Negative controlに対してATL急性型、B-ALL、MT-２での発現を認めた。）。
２．これらの結果から、下記のことが考えられた。
(1) ATL検体等では、SGLT2により細胞内へのグルコースの取り込みが促進されることが推測される。
(2) 試験例１の結果と合わると、ATLでは、細胞内へのグルコースの取り込み促進により、細胞増殖がより盛んになると考察できる。
<Experiment results>
1. The results are shown in Figure 2 (diagram with positive control as 1, RQ = relative quantification).
In Figure 2, MT-2 is an ATL cell line, PBML is a peripheral blood-derived healthy human mononuclear cell (negative control), human colon cancer is a human colon cancer cell (positive control), and ATL acute type is a peripheral blood ATL cell. , B-ALL indicates acute lymphocytic leukemia cells (peripheral blood).
(1) No increase in SGLT2 mRNA expression was observed in PBML, a negative control. A clear increase in SGLT2 mRNA expression was observed in human colon cancer, a positive control (expression was observed in human colon cancer as a positive control, and low expression was observed in PBML, a negative control).
(2) On the other hand, a clear increase in SGLT2 mRNA was observed in MT-2, ATL acute type, and B-ALL (expression was observed in ATL acute type, B-ALL, and MT-2 compared to negative control). ).
2. From these results, the following was considered.
(1) In ATL samples, it is assumed that SGLT2 promotes glucose uptake into cells.
(2) When combined with the results of Test Example 1, it can be considered that cell proliferation becomes more active in ATL due to promotion of glucose uptake into cells.
＜＜試験例３．SGLT2阻害剤による細胞増殖抑制効果＞＞
ATL細胞株において、トホグリフロジンの存在下、細胞増殖にどのような影響を及ぼすかを調べることを目的に検討を行った。
<<Test Example 3. Cell proliferation inhibitory effect of SGLT2 inhibitor >>
The purpose of this study was to investigate the effect of tofogliflozin on cell proliferation in ATL cell lines.
＜実験方法＞
１．各濃度のトホグリフロジン存在下、試験例１と同じ条件の11mMのグルコース濃度に調整した培地のみを使って、その他は試験例１と同じ条件でATL細胞株MT-2の培養を行った。
２．各時間点（24時間、48時間、72時間）における細胞数の計測（WST-8法、Cell counting kit-8、同仁化学研究所、CK04）を、試験例１と同様に行った。
<Experimental method>
1. ATL cell line MT-2 was cultured in the presence of tofogliflozin at various concentrations using only a medium adjusted to a glucose concentration of 11 mM under the same conditions as in Test Example 1, except for the same conditions as in Test Example 1.
2. Cell number measurement (WST-8 method, Cell counting kit-8, Dojindo Laboratories, CK04) at each time point (24 hours, 48 hours, 72 hours) was performed in the same manner as in Test Example 1.
＜実験結果＞
１．結果を、図３に示す。図３は、トホグリフロジンの濃度が50μM、100μMにおいて、各時間点における細胞生存率を、トホグリフロジン非存在下のものと比較して表した図である。
(1) トホグリフロジン非存在下においては、検討を行ったいずれにおいても細胞生存率は、ほぼ100%であった。
(2) これに対し、トホグリフロジン存在下においては、いずれの時間点においても、トホグリフロジン非存在下のものと比較して、細胞生存率は有意に低下しており、その低下は濃度依存的であった。
(3) 加えて、トホグリフロジン存在下においては、時間の経過とともに、細胞生存率が低下していた。
<Experiment results>
1. The results are shown in FIG. FIG. 3 is a diagram showing the cell survival rate at each time point at tofogliflozin concentrations of 50 μM and 100 μM, compared with that in the absence of tofogliflozin.
(1) In the absence of tofogliflozin, the cell survival rate was almost 100% in all cases tested.
(2) On the other hand, in the presence of tofogliflozin, the cell survival rate was significantly lower than that in the absence of tofogliflozin at all time points, and the decrease was concentration dependent. Ta.
(3) In addition, cell viability decreased over time in the presence of tofogliflozin.
２．これらの結果から、SGLT2阻害剤添加によるATL細胞の増殖抑制が認められた。
この増殖抑制については、次のメカニズムが考えられる。
(1) ATL細胞におけるSGLT2ｍRNA発現上昇。
(2) SGLT2阻害剤によるグルコース取り込み抑制。
(3) SGLT2阻害剤による細胞内ATP産生低下。
(4) SGLT2阻害剤によるATL細胞増殖抑制。
2. These results showed that addition of the SGLT2 inhibitor suppressed the growth of ATL cells.
The following mechanism may be considered for this growth inhibition.
(1) Increased SGLT2 mRNA expression in ATL cells.
(2) Suppression of glucose uptake by SGLT2 inhibitors.
(3) Decreased intracellular ATP production by SGLT2 inhibitors.
(4) Suppression of ATL cell proliferation by SGLT2 inhibitor.
本発明により、新たな抗血液悪性腫瘍薬を提供でき、適切な治療、生存期間の延長、生活の質の向上等に有用な薬剤として利用可能である。
INDUSTRIAL APPLICABILITY The present invention can provide a new anti-hematologic malignant tumor drug, which can be used as a drug useful for appropriate treatment, prolonging survival time, improving quality of life, etc.
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| US20110015141A1 (en) | 2008-03-18 | 2011-01-20 | Bristol-Myers Squibb Company | Method for treating cancers having high glucose requirements employing an sglt2 inhibitor and compositions thereof |
| JP2015514756A (en) | 2012-04-19 | 2015-05-21 | エライゾン ファーマシューティカルズ， エルエルシー | Glufosfamide combination therapy for cancer |
| WO2018026673A1 (en) | 2016-08-01 | 2018-02-08 | IC-MedTech Corp. | Ascorbic acid, quinone compound, and sodium glucose cotransporter inhibitor for treating cancer |
| WO2018073154A1 (en) | 2016-10-19 | 2018-04-26 | Boehringer Ingelheim International Gmbh | Combinations comprising an ssao/vap-1 inhibitor and a sglt2 inhibitor, uses thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US20110015141A1 (en) | 2008-03-18 | 2011-01-20 | Bristol-Myers Squibb Company | Method for treating cancers having high glucose requirements employing an sglt2 inhibitor and compositions thereof |
| JP2015514756A (en) | 2012-04-19 | 2015-05-21 | エライゾン ファーマシューティカルズ， エルエルシー | Glufosfamide combination therapy for cancer |
| WO2018026673A1 (en) | 2016-08-01 | 2018-02-08 | IC-MedTech Corp. | Ascorbic acid, quinone compound, and sodium glucose cotransporter inhibitor for treating cancer |
| WO2018073154A1 (en) | 2016-10-19 | 2018-04-26 | Boehringer Ingelheim International Gmbh | Combinations comprising an ssao/vap-1 inhibitor and a sglt2 inhibitor, uses thereof |
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