JP5882889B2 - Antitumor agent - Google Patents
Antitumor agent Download PDFInfo
- Publication number
- JP5882889B2 JP5882889B2 JP2012505674A JP2012505674A JP5882889B2 JP 5882889 B2 JP5882889 B2 JP 5882889B2 JP 2012505674 A JP2012505674 A JP 2012505674A JP 2012505674 A JP2012505674 A JP 2012505674A JP 5882889 B2 JP5882889 B2 JP 5882889B2
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- Prior art keywords
- iron
- adjuvant
- tumor
- cancer
- cell
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Description
本発明は、抗腫瘍作用補助剤に関する。詳しくは、癌治療剤の作用を増強しうる抗腫瘍作用補助剤に関し、より詳しくは体内の鉄分を低減することで、抗腫瘍作用を増強しうる抗腫瘍作用補助剤に関する。 The present invention relates to an antitumor action auxiliary agent. More specifically, the present invention relates to an antitumor action adjuvant that can enhance the action of a cancer therapeutic agent, and more particularly to an antitumor action adjuvant that can enhance the antitumor action by reducing the iron content in the body.
本出願は、参照によりここに援用されるところの日本出願、特願２０１０−０５７２８４号優先権を請求する。 This application claims the Japanese application and Japanese Patent Application No. 2010-057284 priority which are used here by reference.
近年、ウイルス性肝炎、非アルコール性脂肪肝炎、アルコール性肝障害などの患者において、肝臓に過剰な鉄が蓄積し、肝機能を障害するという報告があり、また鉄分の多い食品を控えることで肝機能が改善するということが報告されている。肝炎では肝臓の細胞に鉄分が蓄積され、この肝臓細胞内の鉄分により活性酸素が細胞内取り込まれ、アポトーシスが引き起こされる。肝臓では、アポトーシスにより傷付いた肝細胞を排除しようとする免疫機能の働きがあるが、肝炎ではこれらアポトーシスが過剰に機能し、肝硬変に至る場合がある。鉄分が肝臓細胞に過剰に蓄積されている場合には、早急に鉄分を消費させる必要が出てくる。この際、瀉血によって人為的に貧血状態を引き起こさせ、ヘモグロビン合成に鉄分を消費させるという除鉄療法と呼ばれる治療法がある。特にインターフェロンの効き難いＣ型肝炎では、同治療法の効果が期待されている。 In recent years, in patients with viral hepatitis, non-alcoholic steatohepatitis, alcoholic liver disorder, etc., it has been reported that excessive iron accumulates in the liver, impairing liver function, and hepatitis by refraining from foods rich in iron It has been reported that functionality improves. In hepatitis, iron is accumulated in liver cells, and the active oxygen is taken up by the iron in the liver cells to cause apoptosis. In the liver, there is a function of an immune function that tries to eliminate hepatocytes damaged by apoptosis, but in hepatitis these apoptosis functions excessively and may lead to cirrhosis. When iron is excessively accumulated in liver cells, it is necessary to consume iron immediately. At this time, there is a treatment called iron removal therapy in which anemia is artificially caused by hemoptysis and iron is consumed for hemoglobin synthesis. In particular, for hepatitis C, where interferon is less effective, the effect of this treatment is expected.
Ｃ型肝炎から肝癌の発生は、肝細胞中の余剰鉄分による活性酸素の生成が原因とされ、潟血や鉄の少ない食餌が発癌を抑制するといわれている。一方、青石綿による中皮腫の発生も、石綿中の鉄が細胞内で水酸化ラジカルを生成し、ＤＮＡを損傷するからではないかといわれている。一般的に鉄分は過剰になり難いミネラルである。大部分の食品の鉄分は植物に多い非ヘム鉄であるから吸収されにくく、90％近くが排泄されるといわれている。また肉類、魚類の鉄分はヘム鉄で、植物含有非ヘム鉄に比べ10倍以上吸収されやすいが、ふすまのフィチン酸、植物のポリフェノールにより吸収阻害されるといわれている。 The occurrence of hepatic cancer from hepatitis C is caused by the production of active oxygen by excess iron in hepatocytes, and it is said that diets with little gata blood or iron suppress carcinogenesis. On the other hand, the occurrence of mesothelioma due to asbestos is said to be because iron in asbestos generates hydroxyl radicals in cells and damages DNA. Generally, iron is a mineral that does not easily become excessive. The iron content of most foods is non-heme iron abundant in plants, so it is said that it is difficult to absorb and nearly 90% is excreted. In addition, the iron content of meat and fish is heme iron, which is more than 10 times easier to absorb than plant-containing non-heme iron, but is said to be inhibited by bran phytic acid and plant polyphenols.
血清鉄を減らす事で、動物に移植した腫瘍の増殖抑制効果が認められるという報告はあったが（非特許文献１）、その機構については解明されていない。そのため、血清鉄を低下させることにより抗腫瘍効果を得る治療法は一般的にはなっていない。また、血清鉄を減らす事で、既存の癌治療剤の効果を増強した報告はない。 There has been a report that the growth inhibition effect of tumors transplanted to animals is recognized by reducing serum iron (Non-patent Document 1), but the mechanism has not been elucidated. Therefore, a treatment method that obtains an antitumor effect by lowering serum iron has not become common. Moreover, there is no report which increased the effect of the existing cancer therapeutic agent by reducing serum iron.
血清鉄を低下させうる薬剤として、輸血による慢性鉄過剰症に対する治療薬であるデフェラシロクス懸濁用錠（商品名：エクジェイド(R)懸濁用錠）が上市されている（非特許文献２）。しかしながら、血清鉄を低下させることによる、腫瘍をターゲットにした癌治療剤（抗腫瘍剤）及び食品は開発されていない。As a drug that can lower serum iron, deferasirox suspension tablets (trade name: Exjade (R) suspension tablets), which is a therapeutic drug for chronic iron overload caused by blood transfusion, are marketed (Non-patent Document 2). ). However, cancer therapeutic agents (antitumor agents) and foods targeting tumors by lowering serum iron have not been developed.
本発明者らは、上記課題を解決するために鋭意検討を重ねた結果、癌治療剤とは別に、鉄のキレート剤や、鉄分を含まない臨床栄養剤及び／又は栄養調整食品の提供により血清鉄を低減させる事で、腫瘍の増殖自体を抑制し、同時に血管新生が亢進しうることを見出し、本発明を完成した。 As a result of intensive studies to solve the above problems, the present inventors have found that, apart from cancer therapeutic agents, serum is provided by providing iron chelating agents, clinical nutrients and / or nutritionally adjusted foods not containing iron. The inventors have found that by reducing iron, tumor growth itself can be suppressed, and at the same time, angiogenesis can be enhanced, and the present invention has been completed.
即ち、本発明は以下よりなる。
１．癌治療剤と共に使用する抗腫瘍作用補助剤であって、生体内の鉄分を低減化しうる物質からなることを特徴とする抗腫瘍作用補助剤。
２．生体内の鉄分を低減化しうる物質が、鉄キレート剤、又は鉄分を含まない臨床栄養剤若しくは栄養調整食品である、前項１に記載の抗腫瘍作用補助剤。
３．臨床栄養剤若しくは栄養調整食品が、ミネラル成分として、少なくともナトリウム、カルシウム、マグネシウムを含み、鉄分を含まないことを特徴とする前項１又は２に記載の抗腫瘍作用補助剤。
４．さらに、ビタミンを含むことを特徴とする、前項３に記載の抗腫瘍作用補助剤。
５．臨床栄養剤が、経口栄養剤、末梢非経口栄養剤、完全静脈栄養剤又は経腸栄養剤である前項２〜４のいずれか１に記載の抗腫瘍作用補助剤。
６．癌治療剤が、血管新生阻害剤である、前項１〜５のいずれか１に記載の抗腫瘍作用補助剤。That is, this invention consists of the following.
1. An antitumor action auxiliary agent used together with a cancer therapeutic agent, comprising an agent capable of reducing iron in a living body.
2. 2. The antitumor action adjuvant according to item 1 above, wherein the substance capable of reducing the iron content in the living body is an iron chelating agent, or a clinical nutrition or a nutritionally adjusted food containing no iron.
3. 3. The antitumor action adjuvant according to item 1 or 2, wherein the clinical nutrient or the nutritionally adjusted food contains at least sodium, calcium and magnesium as mineral components and does not contain iron.
4). Furthermore, the antitumor action adjuvant of the preceding clause 3 characterized by including a vitamin.
5). 5. The antitumor action adjuvant according to any one of items 2 to 4 above, wherein the clinical nutrition is an oral nutrition, a peripheral parenteral nutrition, a complete parenteral nutrition, or an enteral nutrition.
6). 6. The antitumor action adjuvant according to any one of 1 to 5 above, wherein the cancer therapeutic agent is an angiogenesis inhibitor.
本発明は、書面の走査位置またはその直前（直後）を常に目視可能とするため、書面に垂直な方向に対して傾斜した光路で受光することを最も主要な特徴とする。 The main feature of the present invention is that light is received by an optical path inclined with respect to a direction perpendicular to the document so that the scanning position of the document or immediately before (immediately after) can be visually confirmed.
本発明の抗腫瘍作用補助剤により血清鉄を減らす事で、癌細胞や腫瘍の増殖自体を抑制し、同時に血管新生が亢進する事が突き止められた。そこで、血管新生を標的とする癌治療剤（血管新生阻害剤）と組み合わせて使用することで、非常に高い抗腫瘍効果が得られた。 By reducing serum iron with the antitumor action adjuvant of the present invention, it has been found that cancer cells and tumor growth itself are suppressed, and at the same time, angiogenesis is enhanced. Therefore, when used in combination with a cancer therapeutic agent (angiogenesis inhibitor) that targets angiogenesis, a very high antitumor effect was obtained.
本発明は、癌治療剤と共に使用する抗腫瘍作用補助剤であって、生体内の鉄分を低減化しうる物質からなることを特徴とする抗腫瘍作用補助剤に関する。本発明は、鉄分を含まない、及び／又は鉄キレート作用を有することを特徴とする抗腫瘍作用補助剤に関する。本発明において、抗腫瘍作用補助剤とは、癌治療剤に対する抗腫瘍作用を補助しうる組成物であればよく特に限定されないが、例えば、鉄キレート剤、又は鉄分を含まない臨床栄養剤若しくは栄養調整食品などが挙げられる。従来の鉄代謝に関する治療方法は、鉄過剰症に対するものがほとんどである。一方、腫瘍に関しては、鉄代謝が癌細胞の増殖に影響を与えることは知られているが、それ以外の鉄の影響については、ほとんど解明されていない。 The present invention relates to an antitumor action auxiliary agent used together with a cancer therapeutic agent, which is composed of a substance capable of reducing iron content in a living body. The present invention relates to an antitumor action adjuvant characterized by not containing iron and / or having an iron chelating action. In the present invention, the anti-tumor action adjuvant is not particularly limited as long as it is a composition capable of assisting the anti-tumor action against a cancer therapeutic agent. For example, an iron chelator, or a clinical nutrition or nutrition that does not contain iron. Examples include adjusted foods. Most conventional treatments related to iron metabolism are for iron overload. On the other hand, regarding tumors, it is known that iron metabolism affects the growth of cancer cells, but the effects of other irons have not been elucidated.
本発明の鉄キレート剤としては、特に限定されないが、例えばデフェラシロクス(4-[(3,5‐Bis-(2‐hydroxy-phenyl)-1,2,4)triazol-1-yl]-benzoic acid)、デフェリプロン（1,2 dimethyl-3-hidroxypyridin-4-one)やデフェロキサミン(desferoxamine: DFO)等が挙げられる。補助剤として使用するためには、生体内から鉄をキレートするのが好適であり、例えばデフェラシロクスやデフェリプロンが好適であり、最も好適にはデフェラシロクスが挙げられる。こられより選択されるいずれかの鉄キレート剤は、それぞれ購入により、入手が可能である。 The iron chelating agent of the present invention is not particularly limited. For example, deferasirox (4-[(3,5-Bis- (2-hydroxy-phenyl) -1,2,4) triazol-1-yl]- benzoic acid), deferiprone (1,2 dimethyl-3-hidroxypyridin-4-one), and deferoxamine (desferoxamine: DFO). For use as an adjuvant, it is preferable to chelate iron from the living body, for example, deferasirox and deferiprone are preferred, and most preferably deferasirox. Any iron chelating agent selected from these can be obtained by purchase.
本発明において臨床栄養剤とは、臨床の現場において通常用いられる意味で定義されるが、例えば患者に対して細胞に十分な栄養素と酸素を与えて、細胞の代謝を正常にする栄養剤をいう。 In the present invention, the term “clinical nutrient” is defined in the meaning normally used in the clinical field, and refers to a nutrient that normalizes cell metabolism by giving sufficient nutrients and oxygen to cells, for example. .
栄養調整食品とは、特に厳密な定義はないが、不足しがちなビタミン・ミネラル・食物繊維などを添加したり、あるいはそれらを多く含む食品を原料に用いて日々の食事を補う食品が挙げられる。一般的には、サプリメントともいい、例えば厚生労働省から認可を得ることで特定の保健用途における効能を表示することが可能な特定保健用食品や、ビタミンとミネラルのいずれかが一定量含まれ、その栄養素の機能を厚生労働省に届出や申請なしに表示できる食品である栄養機能食品などが挙げられる。 Nutrition-adjusted foods are not particularly strict definitions, but include foods supplemented with daily diets by adding vitamins, minerals, dietary fiber, etc., which tend to be deficient, or using foods rich in them as raw materials. . In general, it is also called a supplement.For example, a specific health food that can be used to display its efficacy in a specific health use with approval from the Ministry of Health, Labor and Welfare, or a certain amount of either vitamins or minerals are included. Examples include nutritional functional foods that can display the functions of nutrients without submitting to the Ministry of Health, Labor and Welfare.
2005年現在の栄養機能食品の規格基準では、例えば、1日当たりの摂取目安量に含まれる栄養成分量の上限値・下限値が定められており、ミネラル成分としては、例えば亜鉛（3〜15mg）、カルシウム（250〜600mg）、鉄（4〜10mg）、銅（0.5〜5mg）、マグネシウム（80〜300mg）などを含むことが基準として示されている。従来の臨床栄養剤や栄養調整食品には、上記規格基準に示すように、鉄分を含むことが求められる。鉄は、赤血球を作るのに必要な栄養素であるからである。 In 2005, the standards for functional nutritional foods, for example, set the upper and lower limits of the amount of nutritional components contained in the daily intake standard amount. As a mineral component, for example, zinc (3-15mg) , Calcium (250-600 mg), iron (4-10 mg), copper (0.5-5 mg), magnesium (80-300 mg), etc. are indicated as standards. Conventional clinical nutrients and nutritionally adjusted foods are required to contain iron as shown in the above standard. This is because iron is a nutrient necessary to make red blood cells.
本発明の抗腫瘍作用補助剤は、例えば、上述の臨床栄養剤及び／又は栄養調整食品を構成する組成物から鉄分を除去してなる組成物である。本発明の抗腫瘍作用補助剤には、ミネラルとして少なくともナトリウム、カルシウム、マグネシウムを含み、鉄分を含まないことを特徴とする。さらには、ビタミン類を含んでいても良い。ビタミンの種類としては、水溶性ビタミンであっても脂溶性ビタミンであってもよく、特に限定されないが、本発明の抗腫瘍作用補助剤の剤型や用途に応じて適宜決定される。水溶性ビタミンの例としては、ビタミンC、ビタミンB1、ビタミンB2、ビタミンB6、ビタミンB12、ナイアシン、ビオチン、パントテン酸や葉酸が挙げられ、脂溶性ビタミンの例としては、ビタミンA、ビタミンDやビタミンEが挙げられる。 The anti-tumor action adjuvant of the present invention is, for example, a composition obtained by removing iron from the composition constituting the above-described clinical nutrient and / or nutritionally adjusted food. The anti-tumor action adjuvant of the present invention is characterized in that it contains at least sodium, calcium, and magnesium as minerals and does not contain iron. Furthermore, vitamins may be included. The type of vitamin may be a water-soluble vitamin or a fat-soluble vitamin, and is not particularly limited, but is appropriately determined according to the dosage form and use of the antitumor action adjuvant of the present invention. Examples of water-soluble vitamins include vitamin C, vitamin B1, vitamin B2, vitamin B6, vitamin B12, niacin, biotin, pantothenic acid and folic acid. Examples of fat-soluble vitamins include vitamin A, vitamin D and vitamins. E.
本発明の抗腫瘍作用補助剤は、例えば、蛋白質、脂質、糖質、食物繊維、灰分、水分、ビタミン類（ビタミンA，RE，D，E，K，B1，B2，B6，B12，C、ナイアシン、葉酸、ビオチン、パントテン酸）、ミネラル（ナトリウム，カリウム，カルシウム，マグネシウム，リン，亜鉛，銅，マンガン，クロム，モリブデン，セレン，ヨウ素，塩素）等から選択される必要な成分を適宜含むことができる。 The antitumor action adjuvant of the present invention includes, for example, protein, lipid, carbohydrate, dietary fiber, ash, moisture, vitamins (vitamin A, RE, D, E, K, B1, B2, B6, B12, C, Necessary components selected from niacin, folic acid, biotin, pantothenic acid), minerals (sodium, potassium, calcium, magnesium, phosphorus, zinc, copper, manganese, chromium, molybdenum, selenium, iodine, chlorine) etc. are included as appropriate. Can do.
本発明の抗腫瘍作用補助剤は、さらには炭水化物を含んでいても良い。炭水化物としては、グリセリン、グルコース、スクロース、フルクトース、マルトース、アラビノース、キシロース、ガラクトースから選択される必要な成分を適宜含むことができる。上記の糖類は単独または任意の比率で混合してグリセリンと併用して用いることができる。これらの成分は速く吸収され、低血糖時に血中グルコース濃度を早急に高める作用がある。特にグリセリンは、食物中の糖類と異なり、腸管より腸壁に吸収され、直接門脈を経て肝臓に運ばれるため、生体内でより速く利用される。また、グリセリンは3炭糖であるため、6炭糖のグルコースなどよりも代謝されるのが速く、エネルギー産生もより速やかである。 The antitumor action adjuvant of the present invention may further contain a carbohydrate. As the carbohydrate, necessary components selected from glycerin, glucose, sucrose, fructose, maltose, arabinose, xylose and galactose can be appropriately included. The above saccharides can be used alone or mixed at an arbitrary ratio and used in combination with glycerin. These components are absorbed quickly and have the effect of rapidly increasing the blood glucose concentration during hypoglycemia. In particular, glycerin, unlike sugars in food, is absorbed into the intestinal wall from the intestinal tract and is directly transported to the liver via the portal vein, so that it is used faster in vivo. In addition, since glycerin is a tricarbon sugar, it is metabolized faster than hexose glucose and the like, and energy production is faster.
また、中程度の速度で吸収される成分として、例えばマンノース、マルトデキストリン、フラクトオリゴ糖、ガラクトオリゴ糖、乳果オリゴ糖、大豆オリゴ糖、乳糖、果糖等の炭水化物から選択される必要な成分を適宜含むことができる。これらものは、単独で用いてもよいし混合して使用してもよい。 Moreover, as a component absorbed at a moderate rate, for example, a necessary component selected from carbohydrates such as mannose, maltodextrin, fructooligosaccharide, galactooligosaccharide, dairy oligosaccharide, soybean oligosaccharide, lactose, and fructose is appropriately included. be able to. These may be used alone or in combination.
本発明の抗腫瘍作用補助剤に用いる脂質としては、脂肪すなわち、乳脂肪、サフラワー油、カノーラ(canola)油、卵黄油、オリーブ油、コーン油、綿実油、ココナッツ油、パーム油、パーム核(kemel)油、大豆油、ヒマワリ油、魚油及びそれらから得られた油の画分、例えば、パーム・オレイン、中鎖トリグリセリド(MCT)、並びに脂肪酸のエステル等が挙げられる。これらの油脂類は、単独で用いてもよいし併用して用いてもよい。より好ましくは、吸収速度が速いMCT油が挙げられる。また、分画あるいは精製した脂肪酸とグリセリンから合成した生成油を用いてもよい。脂質は高カロリー食品であり、カロリー源として有用である。脂質の配合量は、45重量％未満であり、好ましくは、3〜35重量％である。なお、食品形態が水分を多量に含むドリンク剤やゼリー飲料については、外観や作業性の面で脂質を含まないほうが好ましい場合がある。 Lipids used in the antitumor action adjuvant of the present invention include fat, that is, milk fat, safflower oil, canola oil, egg yolk oil, olive oil, corn oil, cottonseed oil, coconut oil, palm oil, palm kernel (kemel) ) Oil, soybean oil, sunflower oil, fish oil and oil oil fractions such as palm olein, medium chain triglycerides (MCT), and esters of fatty acids. These fats and oils may be used alone or in combination. More preferably, MCT oil with a high absorption rate is mentioned. Further, a product oil synthesized from a fractionated or purified fatty acid and glycerin may be used. Lipids are high calorie foods and are useful as calorie sources. The amount of lipid blended is less than 45% by weight, preferably 3 to 35% by weight. In addition, about the drink agent and jelly drink which a food form contains a lot of water | moisture contents, it is preferable that the lipid is not included from the surface and the workability | operativity.
本発明の抗腫瘍作用補助剤は、上述の成分の他にさらに食物繊維を配合することができる。本発明に用いる食物繊維としては、可溶性、不溶性、発酵性、非発酵性の繊維、例えば、大豆繊維、ペクチン、特定の耐性デンプン、オリゴフルクトース、イヌリン、オート（ｏａｔ）繊維、ユンドウマメ（ｐｅａ）繊維、グアー・ガム、アラビアガム、修飾セルロース等を挙げることができる。これらの食物繊維は、単独で用いてもよいし併用してもよい。 The antitumor action adjuvant of the present invention may further contain dietary fiber in addition to the above-mentioned components. The dietary fiber used in the present invention includes soluble, insoluble, fermentable, and non-fermentable fibers such as soybean fiber, pectin, specific resistant starch, oligofructose, inulin, oat fiber, and pea fiber. , Guar gum, gum arabic, and modified cellulose. These dietary fibers may be used alone or in combination.
本発明の抗腫瘍作用補助剤には、乳化剤、安定剤、ゲル化剤として、例えば、レシチン（例えば、卵又は大豆）、修飾レシチン（例えば、酵素又はアセチル化されたもの）、カラギーナン、キサンタン・ガム、モノ−及びジグリセリド、グアー・ガム、力ルボキシメチル・セルロース、ステアロイル・ラクチレートコハク酸モノグリセリド、ショ糖脂肪酸エステル、モノグリセリドのジアシル酒石酸エステル、脂肪酸のポリグリセロール・エステル等を用いることができる。 The antitumor action adjuvant of the present invention includes, for example, lecithin (eg, egg or soybean), modified lecithin (eg, enzyme or acetylated), carrageenan, xanthan Gum, mono- and diglycerides, guar gum, strong ruxymethyl cellulose, stearoyl lactylate succinic acid monoglyceride, sucrose fatty acid ester, diacyl tartaric acid ester of monoglyceride, polyglycerol ester of fatty acid and the like can be used.
本発明の抗腫瘍作用補助剤には、場合により、嗜好性を高めるために他の食品や天然又は人工香料等を１種以上添加することができる。ただし、この場合においても、鉄分を含まない物質であることが必要である。 In some cases, one or more kinds of other foods, natural or artificial fragrances and the like can be added to the antitumor action adjuvant of the present invention in order to enhance palatability. However, even in this case, it is necessary that the substance does not contain iron.
本発明の本発明の抗腫瘍作用補助剤は、種々の形態にして提供することが可能である。臨床栄養剤としては、例えば経口栄養剤、末梢非経口栄養剤、完全静脈栄養剤や経腸栄養剤として提供することができる。栄養調整食品としては、例えば、飲料、半固体形態とすることができ、例えば、プディング、あるいは固体形態、例えば、栄養バー又はクッキーなどの形態で提供することができる。 The antitumor action adjuvant of the present invention can be provided in various forms. As clinical nutrients, for example, oral nutritional agents, peripheral parenteral nutritional agents, complete parenteral nutritional agents, and enteral nutritional agents can be provided. The nutritionally adjusted food can be, for example, a beverage, a semi-solid form, and can be provided, for example, in the form of a pudding or a solid form, such as a nutrition bar or cookie.
本発明の抗腫瘍作用補助剤は、鉄分を含まないので、例えば継続的に摂取することで、血清中の鉄分を低減化させることができる。例えば、癌細胞を移植したマウスに本発明の抗腫瘍作用補助剤を与えることで、血清成分の鉄分を低減化させることができ、そこで癌細胞の増殖自体を抑制し、同時に血管新生を亢進させることができる。この作用は、ヒトにおいても期待することができる。 Since the antitumor action adjuvant of the present invention does not contain iron, for example, by continuously taking it, the iron content in serum can be reduced. For example, by providing the anti-tumor action adjuvant of the present invention to a mouse transplanted with cancer cells, it is possible to reduce the iron content of serum components, thereby suppressing the proliferation of cancer cells per se and simultaneously enhancing angiogenesis. be able to. This effect can also be expected in humans.
本発明の抗腫瘍作用補助剤は、癌治療剤に対して補助的に作用しうる組成物であり、具体的には癌治療剤に対する抗腫瘍作用増強剤として機能しうる。癌治療剤としては、血管新生阻害剤が挙げられ、例えば抗VEGFヒト化モノクローナル抗体であるベバシズマブに対して、優れた補助剤となり、抗腫瘍作用増強剤となりうる。本発明の抗腫瘍作用補助剤は、血管新生作用を増強させうることから、増強した分子標的（新生血管）に対して特異的に作用する薬剤に対して優れた補助剤となり得、具体的にはベバシズマブに対して、優れた補助剤となりうる。 The anti-tumor action adjuvant of the present invention is a composition that can act as an auxiliary to a cancer therapeutic agent, and specifically can function as an anti-tumor action enhancer for a cancer therapeutic agent. Examples of the therapeutic agent for cancer include angiogenesis inhibitors. For example, it can be an excellent adjuvant and an antitumor action enhancer for bevacizumab which is an anti-VEGF humanized monoclonal antibody. Since the antitumor action adjuvant of the present invention can enhance the angiogenesis action, it can be an excellent adjuvant for a drug that specifically acts on the enhanced molecular target (neovascularization). Can be an excellent adjunct to bevacizumab.
本発明は、抗腫瘍作用補助剤の作製方法にも及ぶ。臨床栄養剤及び／又は栄養調整食品から鉄分を除去することによる。 The present invention also extends to a method for producing an antitumor action adjuvant. By removing iron from clinical nutrients and / or dietary supplements.
以下、実施例及び実験例に基づいて本発明を詳細に説明するが、本発明はこれらの実施例に限定されるものではない。 EXAMPLES Hereinafter, although this invention is demonstrated in detail based on an Example and an experiment example, this invention is not limited to these Examples.
（実施例１）抗腫瘍作用補助剤（鉄分欠乏食）
本発明の抗腫瘍作用補助剤の一例として、マウス餌（日本クレア製）の組成物から、鉄分を除去したものを作製した（表１参照）。なお、以下の実験例では、マウスに対する抗腫瘍作用を確認したので、本実施例ではマウスの餌から鉄分を除去したもの（鉄分欠乏食）を抗腫瘍作用補助剤としたが、例えばヒトに対する抗腫瘍作用補助剤として適用する場合は、表１に示される組成物に限定されるものではない。(Example 1) Antitumor action adjuvant (iron-deficient diet)
As an example of the antitumor action adjuvant of the present invention, a composition obtained by removing iron from a composition of mouse food (manufactured by CLEA Japan) was prepared (see Table 1). In the following experimental examples, the antitumor effect on mice was confirmed. In this example, the anti-tumor action supplement was obtained by removing iron from the mouse food (iron-deficient diet). When applied as a tumor action adjuvant, the composition is not limited to those shown in Table 1.
（実験例１−１）抗腫瘍作用補助剤投与後の血液組成
ヌードマウスを8匹用意し、実施例１の鉄分含有食（対照）投与群と鉄分欠乏食（抗腫瘍作用補助剤）投与群の2群に分け、4匹あたり100g×2/週で3週間投与した。各群について、全血組成及び血清鉄の値を測定した結果、ヘモグロビン(Hb)及び血清鉄について有意な低下が認められた（表２）。一方、赤血球、白血球及びヘマトクリットについては、若干の減少を認めたものの、有意な減少とはいえなかった。(Experimental example 1-1) Blood composition after administration of an anti-tumor action auxiliary agent Eight nude mice were prepared, and an iron-containing diet (control) administration group and an iron-deficient diet (anti-tumor action auxiliary agent) administration group of Example 1 The animals were divided into two groups of 100 g × 2 / week for 4 weeks and administered for 3 weeks. As a result of measuring the values of whole blood composition and serum iron for each group, significant reduction was observed for hemoglobin (Hb) and serum iron (Table 2). On the other hand, red blood cells, white blood cells, and hematocrit were slightly decreased but not significantly decreased.
（実験例１−２）抗腫瘍作用補助剤投与後の腫瘍増殖抑制効果の確認
ヌードマウスを16匹用意し、鉄分含有食（対照）投与群（8匹）と鉄分欠乏食（抗腫瘍作用補助剤）投与群（8匹）の2群に分け、4匹あたり100g×2/週で3週間投与した。その後、ヒト肺腺癌A549細胞（300万個/マウス）を移植し、皮下腫瘍を作製した。その後、鉄分含有食（対照）と鉄分欠乏食（抗腫瘍作用補助剤）をさらに、42日間投与した。その結果、鉄分欠乏食を投与した場合に、癌細胞増殖の抑制が有意に認められた（図１）。(Experimental Example 1-2) Confirmation of Tumor Growth Inhibitory Effect After Administration of Antitumor Action Adjuvant 16 nude mice were prepared, iron-containing diet (control) administration group (8 mice) and iron-deficient diet (antitumor activity assistance) The drug was divided into 2 groups, 8 administration groups, and 4 animals were administered at 100 g × 2 / week for 3 weeks. Thereafter, human lung adenocarcinoma A549 cells (3 million cells / mouse) were transplanted to prepare subcutaneous tumors. Thereafter, an iron-containing diet (control) and an iron-deficient diet (anti-tumor action adjuvant) were further administered for 42 days. As a result, when an iron-deficient diet was administered, suppression of cancer cell proliferation was significantly observed (FIG. 1).
（実験例１−３）抗腫瘍作用補助剤投与後の癌細胞における免疫組織染色
上記実験例の実験終了時に皮下腫瘍を回収し、間質の違いを解明するために、鉄分及び血管新生のマーカーとなるCD31について確認した。鉄成分検出のために、ベルリンブルー染色を行なった。またCD31検出のために、標識した抗CD31抗体（Santa Cruz Biotechnology社）を用いて免疫組織染色を行った。その結果、鉄分含有食（対照）投与群では癌細胞の間質に鉄の成分が認められたが（図２Ａ）、鉄分欠乏食（抗腫瘍作用補助剤）投与群では鉄成分は全く認められなかった（図２Ｂ）。CD31免疫染色では、鉄分含有食（対照）投与群（図２Ｃ）に比較して鉄分欠乏食投与群の癌細胞間質の血管周囲が強く染色され、血管新生の増強が示唆された（図２Ｄ）。(Experimental Example 1-3) Immunohistochemical staining of cancer cells after administration of antitumor action adjuvant In order to collect subcutaneous tumors at the end of the experiment of the above experimental examples and elucidate the difference in stroma, markers of iron and angiogenesis It confirmed about CD31 which becomes. Berlin blue staining was performed to detect iron components. For detection of CD31, immunohistochemical staining was performed using a labeled anti-CD31 antibody (Santa Cruz Biotechnology). As a result, in the iron-containing diet (control) administration group, an iron component was observed in the stroma of cancer cells (FIG. 2A), but in the iron-deficient diet (anti-tumor action adjuvant) administration group, no iron component was observed. There was no (Figure 2B). In the CD31 immunostaining, the blood vessel periphery of the cancer cell stroma in the iron-deficient diet administration group was strongly stained as compared with the iron-containing diet (control) administration group (FIG. 2C), suggesting enhanced angiogenesis (FIG. 2D). ).
（実験例１−４）抗腫瘍作用補助剤投与後の腫瘍内血管新生の確認
上記実験例の実験終了時に皮下腫瘍を回収し、微小血管密度(Micro vessel density)を調べた。その結果、有意に鉄分欠乏食（抗腫瘍作用補助剤）投与群で血管新生の増強が確認された（図３）。(Experimental Example 1-4) Confirmation of Intratumoral Angiogenesis after Administration of Antitumor Action Auxiliary Agent Subcutaneous tumors were collected at the end of the experiment of the above experimental example and examined for micro vessel density. As a result, it was confirmed that angiogenesis was enhanced significantly in the iron-deficient diet (anti-tumor action adjuvant) administration group (FIG. 3).
更に回収した皮下腫瘍から核蛋白を抽出し(n=3)、鉄の取り込み機構に係るトランスフェリン受容体１（TFR-1）及び低酸素で誘導されるマーカーであるHIF-1αをウエスタンブロッティング(Western blotting)法にて調べた。抗体は抗HIF-1α抗体（Cell Signaling社）及び抗TFR-1α抗体（Invitrogen社）を用いた。その結果、HIF-1α及びTFR-1は、鉄分欠乏食（抗腫瘍作用補助剤）投与群で強く検出され、組織低酸素が起こる事により、血管新生が増強されている事が示唆された（図４）。 Furthermore, nuclear proteins were extracted from the collected subcutaneous tumors (n = 3), and transferrin receptor 1 (TFR-1) related to iron uptake mechanism and HIF-1α, a marker induced by hypoxia, were Western blotted (Western (blotting) method. Anti-HIF-1α antibody (Cell Signaling) and anti-TFR-1α antibody (Invitrogen) were used as antibodies. As a result, HIF-1α and TFR-1 were strongly detected in the iron-deficient diet (antitumor action adjuvant) administration group, suggesting that angiogenesis was enhanced by the occurrence of tissue hypoxia ( FIG. 4).
（実験例１−５）既存の癌治療剤と抗腫瘍作用補助剤の併用効果の確認
ヌードマウス20匹を用意し、実験例２と同様に、鉄分含有食（対照）投与群と鉄分欠乏食（抗腫瘍作用補助剤）投与群の2群に分け、各々投与した後、ヒト肺腺癌A549細胞（300万個/マウス）を移植し、皮下腫瘍を作製した。その後、それらの2群についてさらに血管新生阻害剤（Bevacizumab：ベバシズマブ）投与群と生理食塩液投与群の2群に分けた。腫瘍体積が約50mm3となった時点（移植後2日目）から、血管新生阻害剤投与群にはベバシズマブを5mg/kg、週2回、腹腔内投与を行った。その結果、鉄分欠乏食（抗腫瘍作用補助剤）投与群では、鉄分含有食（対照）投与群と比較して、有意に癌細胞増殖が抑制され、かつ血管新生阻害剤を併用する事で相加的に高い増殖抑制効果が認められた（図5）。移植後39日目の各群における腫瘍の大きさを図2に示した。上記において、ベバシズマブは、血管内皮細胞増殖因子 (VEGF) に対するモノクローナル抗体である。VEGFの働きを阻害することにより、血管新生を抑えたり癌細胞の増殖や転移を抑制する作用を有することが確認された。(Experimental example 1-5) Confirmation of combined effect of existing cancer therapeutic agent and antitumor action adjuvant 20 nude mice were prepared, and in the same manner as in Experimental example 2, an iron-containing diet (control) administration group and an iron-deficient diet (Anti-tumor effect adjuvant) The administration group was divided into two groups, and after administration, human lung adenocarcinoma A549 cells (3 million cells / mouse) were transplanted to prepare subcutaneous tumors. Thereafter, these two groups were further divided into two groups, an angiogenesis inhibitor (Bevacizumab) administration group and a physiological saline administration group. From the time when the tumor volume reached about 50 mm 3 (2 days after transplantation), the angiogenesis inhibitor administration group was administered bevacizumab 5 mg / kg twice a week intraperitoneally. As a result, in the iron-deficient diet (anti-tumor action adjuvant) administration group, cancer cell growth was significantly suppressed and the angiogenesis inhibitor was used in combination with the iron-containing diet (control) administration group. In addition, a high growth inhibitory effect was observed (FIG. 5). The tumor size in each group on the 39th day after transplantation is shown in FIG. In the above, bevacizumab is a monoclonal antibody against vascular endothelial growth factor (VEGF). It was confirmed that by inhibiting the function of VEGF, it has an action of suppressing angiogenesis and suppressing the growth and metastasis of cancer cells.
（実験例１−６）抗腫瘍作用補助剤投与後の腫瘍における組織染色
実験例１−３と同手法により皮下腫瘍を回収し、癌細胞について、各種マーカーについて組織染色又は免疫組織染色を行った。
１）鉄分検出
フェロシアン化カリウムと塩酸で3価の鉄イオンをフェロシアン化鉄（ベルリン青）として検出した。
その結果、鉄分含有食（対照）投与群では癌細胞の間質に鉄の成分が認められたが、鉄分欠乏食（抗腫瘍作用補助剤）投与群では鉄成分は全く認められなかった（図７）。(Experimental Example 1-6) Tissue staining in tumor after administration of anti-tumor action adjuvant The subcutaneous tumor was collected by the same method as in Experimental Example 1-3, and cancer cells were subjected to tissue staining or immunohistochemical staining for various markers. .
1) Iron content detection Trivalent iron ions were detected as ferric ferrocyanide (Berlin blue) with potassium ferrocyanide and hydrochloric acid.
As a result, an iron component was observed in the stroma of cancer cells in the iron-containing diet (control) administration group, but no iron component was observed in the iron-deficient diet (antitumor action adjuvant) administration group (Fig. 7).
２）細胞増殖マーカーKi-67の検出
Ki-67は細胞の核で発現している蛋白で、細胞周期制御因子のサイクリン(cyclin)やCDK (Cyclin-dependent kinase)とは別に、いわゆる細胞増殖マーカーと称される細胞増殖関連蛋白である。Ki-67検出のために、標識した抗Ki-67抗体（Dako社）を用いて免疫組織化学染色を行った。
その結果、鉄分含有食（対照）投与群では鉄分欠乏食（抗腫瘍作用補助剤）投与群に比較してKi-67陽性細胞が多く認められ、Ki-67陽性率(labeling index)でも有意差が認められた（図７）。
(鉄分含有食 vs 鉄分欠乏食 = 0.211±0.035 vs 0.133±0.032; p=0.0459).
この事は鉄を欠乏させることで、細胞増殖が抑制されている事を示している。2) Detection of cell proliferation marker Ki-67
Ki-67 is a protein expressed in the cell nucleus and is a cell growth-related protein called a cell growth marker, apart from the cell cycle regulators cyclin and CDK (Cyclin-dependent kinase). . For detection of Ki-67, immunohistochemical staining was performed using a labeled anti-Ki-67 antibody (Dako).
As a result, there were more Ki-67 positive cells in the iron-containing diet (control) administration group compared to the iron-deficient diet (anti-tumor action adjuvant) administration group, and the Ki-67 positive rate (labeling index) was also significantly different Was observed (FIG. 7).
(Feed vs iron deficient diet = 0.211 ± 0.035 vs 0.133 ± 0.032; p = 0.0459).
This indicates that cell growth is suppressed by iron deficiency.
３）低酸素状態の検出
癌細胞内の低酸素状況を、ニトロイミダゾール化合物ピモニダゾール(pimonidazole )を用いて染色を行い、確認した。ピモニダゾールは、低酸素状態の細胞に結合する低酸素マーカーである。
その結果、鉄分含有食（対照）投与群ではピモニダゾールでほとんど染色されないのに対して、鉄分欠乏食（抗腫瘍作用補助剤）投与群では多くの部位で強く染色されており、鉄分欠乏食（抗腫瘍作用補助剤）投与群では組織が低酸素状態になっていると考えられた（図８）。3) Detection of hypoxia The hypoxia in cancer cells was confirmed by staining with the nitroimidazole compound pimonidazole. Pimonidazole is a hypoxic marker that binds to hypoxic cells.
As a result, the iron-containing diet (control) administration group was hardly stained with pimonidazole, whereas the iron-deficient diet (anti-tumor action adjuvant) administration group was strongly stained at many sites. It was considered that the tissue was in a hypoxic state in the (tumor effect adjuvant) administration group (FIG. 8).
４）血管新生状況の検出
血管新生のマーカーとなるCD31について確認した。CD31検出のために、標識した抗CD31抗体（Santa Cruz Biotechnology社）を用いて免疫組織染色を行った。
その結果、CD31免疫組織染色では、鉄分含有食（対照）投与群（図２Ｃ）に比較して鉄分欠乏食（抗腫瘍作用補助剤）投与群の癌細胞間質の血管周囲が強く染色され、血管新生の増強が示唆された（図８）。4) Detection of angiogenesis status CD31, which is a marker of angiogenesis, was confirmed. For detection of CD31, immunohistochemical staining was performed using a labeled anti-CD31 antibody (Santa Cruz Biotechnology).
As a result, in the CD31 immunohistochemical staining, the blood vessel periphery of the cancer cell stroma in the iron-deficient diet (antitumor action adjuvant) administration group was strongly stained as compared to the iron-containing diet (control) administration group (FIG. 2C). Enhanced angiogenesis was suggested (Figure 8).
（実施例２）抗腫瘍作用補助剤（鉄キレート剤）
本発明の抗腫瘍作用補助剤の一例として、鉄キレート剤の効果について確認した。鉄キレート剤としてデフェラシロクス(Deferasirox)を用いた。(Example 2) Antitumor action adjuvant (iron chelating agent)
As an example of the antitumor action adjuvant of the present invention, the effect of an iron chelator was confirmed. Deferasirox was used as the iron chelator.
（実験例２−１）鉄キレート剤の効果（in vitro）
ヒト肺腺癌由来細胞（A549）及びヒト非小細胞性肺癌由来細胞（H1299）を培養し、鉄キレート剤の抗腫瘍効果をin vitroにて確認した。各細胞を、24時間10%FCSを含む培養液で培養し、各濃度のデフェラシロクス（NOVARTIS社）を添加し、さらに24時間培養した。その後、細胞生存率、細胞周期における各細胞比率を確認し、さらに核蛋白及び培養上清について、HIF-1α及びVEGFの発現を確認した。(Experimental example 2-1) Effect of iron chelator (in vitro)
Human lung adenocarcinoma-derived cells (A549) and human non-small cell lung cancer-derived cells (H1299) were cultured, and the antitumor effect of the iron chelator was confirmed in vitro. Each cell was cultured for 24 hours in a culture solution containing 10% FCS, each concentration of deferasirox (NOVARTIS) was added, and further cultured for 24 hours. Thereafter, the cell viability and the cell ratio in the cell cycle were confirmed, and the expression of HIF-1α and VEGF was confirmed for the nuclear protein and the culture supernatant.
上記の結果を図９〜１２に示した。鉄キレート剤投与により細胞増殖抑制効果が確認された（図９）。鉄キレート剤投与により各細胞においてG1停止(G1 arrest)を起こして細胞周期を止め、細胞増殖が抑制されていることが確認された（図１０）。これにより、鉄キレート剤による細胞増殖抑制のメカニズムが確認された。次に、低酸素で誘導される細胞マーカーとして、HIF-1αの発現をウエスタンブロッティング法により確認した。抗体は、抗HIF-1α抗体（Cell signaling社)を用いた。HIF-1αは実験例１−４と同様に鉄キレート剤の濃度依存的に増加していることが確認された（図１１）。また、VEGFをELISA kit（R&D Systems社）を用いて検出し、HIF-1αによりVEGFが誘導されていることが確認された（図１２）。 The above results are shown in FIGS. Cell growth inhibitory effect was confirmed by administration of the iron chelator (FIG. 9). It was confirmed that administration of an iron chelator caused G1 arrest in each cell to stop the cell cycle and suppress cell growth (FIG. 10). Thereby, the mechanism of the cell growth suppression by an iron chelating agent was confirmed. Next, as a cell marker induced by hypoxia, expression of HIF-1α was confirmed by Western blotting. An anti-HIF-1α antibody (Cell signaling) was used as the antibody. It was confirmed that HIF-1α increased in an iron chelating agent concentration-dependent manner as in Experimental Example 1-4 (FIG. 11). Moreover, VEGF was detected using ELISA kit (R & D Systems), and it was confirmed that VEGF was induced by HIF-1α (FIG. 12).
（実験例２−２）鉄キレート剤の効果（in vivo）
ヌードマウス20匹を用意し、ヒト肺腺癌由来細胞（A549）300万個/マウスを移植し、皮下腫瘍を作製した。移植後7日目より、対照群(生理食塩水投与群)とデフェラシロクス投与群（50mg/kg）の2群に分け、それぞれを週5回連続で投与した。それらの2群についてさらに血管新生阻害剤（Bevacizumab：ベバシズマブ）投与群と生理食塩液投与群の2群に分けた。腫瘍体積が約50mm3となった時点（移植後7日目）から、血管新生阻害剤投与群にはベバシズマブを5mg/kg、週2回、腹腔内投与を行った。その結果、鉄キレート剤は、癌細胞の増殖抑制作用を有し、更にベバシズマブと併用することで高い増殖抑制効果が認められた。この事は、鉄制限食のみならず鉄キレート剤を用いて体内鉄を減らしても同様にベバシズマブの効果を増強出来ることを示している（図１３）。(Experimental example 2-2) Effect of iron chelator (in vivo)
Twenty nude mice were prepared, and 3 million human lung adenocarcinoma-derived cells (A549) / mouse were transplanted to prepare subcutaneous tumors. From the 7th day after transplantation, it was divided into two groups, a control group (saline-administered group) and a deferasirox-administered group (50 mg / kg), and each was administered 5 times a week. These two groups were further divided into two groups, an angiogenesis inhibitor (Bevacizumab) administration group and a physiological saline administration group. From the time when the tumor volume reached about 50 mm 3 (7 days after transplantation), the angiogenesis inhibitor administration group was administered bevacizumab 5 mg / kg twice a week intraperitoneally. As a result, the iron chelator has a cancer cell growth inhibitory effect, and a high growth inhibitory effect was observed when used in combination with bevacizumab. This indicates that the effects of bevacizumab can be similarly enhanced by reducing not only the iron-restricted diet but also iron iron using an iron chelator (FIG. 13).
以上詳述したように、癌治療剤とは別に、本発明の抗腫瘍作用補助剤の提供により血清鉄を低減させる事で、癌細胞の増殖自体を抑制し、同時に血管新生が亢進する事が突き止められた。そこで、本発明の抗腫瘍作用補助剤と血管新生を標的とする癌治療剤（血管新生阻害剤）との組み合わせで非常に高い抗腫瘍効果が得られることが確認できた。血清鉄は臨床栄養剤及び／又は栄養調整食品として投与することによっても減らす事も可能である。薬による副作用を回避する事と、非常に高価な癌治療剤の複数使用を抑制する事で医療経済的にも優れている。また、現在、血管新生阻害薬が認可されている癌腫（大腸癌、非小細胞肺癌、海外では乳癌）に対して、その抗腫瘍効果を増強する可能性が高く、これらの患者数（毎年の死亡推計数は肺癌134万人、大腸癌50万人、乳癌40万人）から考えると、市場性も有望であると見込まれる。 As described in detail above, by reducing the serum iron by providing the antitumor action auxiliary agent of the present invention separately from the cancer therapeutic agent, the proliferation of cancer cells itself can be suppressed and at the same time angiogenesis can be enhanced. I was ascertained. Thus, it was confirmed that a very high antitumor effect can be obtained by combining the antitumor action adjuvant of the present invention with a cancer therapeutic agent (angiogenesis inhibitor) targeting angiogenesis. Serum iron can also be reduced by administration as a clinical nutrient and / or nutritional supplement. It is also medically economical because it avoids side effects caused by drugs and suppresses the use of multiple expensive cancer therapeutic agents. In addition, it is highly likely that the anti-tumor effect will be enhanced against carcinomas for which angiogenesis inhibitors are currently approved (colon cancer, non-small cell lung cancer, and breast cancer overseas). The estimated death rate is 1.34 million lung cancer, 500,000 colorectal cancer, and 400,000 breast cancer).
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