JPWO2013099939A1 - Squamous cell carcinoma preventive agent, squamous cell carcinoma model animal and method for producing the same - Google Patents
Squamous cell carcinoma preventive agent, squamous cell carcinoma model animal and method for producing the same Download PDFInfo
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- A23C9/1238—Fermented milk preparations; Treatment using microorganisms or enzymes using only microorganisms of the genus lactobacteriaceae; Yoghurt using specific L. bulgaricus or S. thermophilus microorganisms; using entrapped or encapsulated yoghurt bacteria; Physical or chemical treatment of L. bulgaricus or S. thermophilus cultures; Fermentation only with L. bulgaricus or only with S. thermophilus
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
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- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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Abstract
カンジダ感染に起因して進行する扁平上皮癌の予防に有効な発酵物の提供。従来のモデル動物よりもバラつきが少なく、より適切に薬効評価を行えるカンジダ感染に起因する扁平上皮癌モデル動物とその作製方法の提供。乳をＬ．ｂｕｌｇａｒｉｃｕｓ、Ｓ．ｔｈｅｒｍｏｐｈｉｌｕｓおよびＬ．ｇａｓｓｅｒｉを用いて発酵させた発酵物を有効成分とするカンジダ感染に起因する扁平上皮癌予防剤。Provision of an effective fermented product for the prevention of squamous cell carcinoma that progresses due to Candida infection. Providing a model animal for squamous cell carcinoma caused by Candida infection and its production method, which has less variation than conventional model animals and can be used to evaluate drug efficacy more appropriately. L. milk. bulgaricus, S .; thermophilus and L.M. A prophylactic agent for squamous cell carcinoma caused by Candida infection comprising a fermented product fermented with gasseri as an active ingredient.
Description
本発明は、カンジダ感染に起因する扁平上皮癌の予防剤、並びに扁平上皮癌モデル動物の作製方法、当該扁平上皮癌モデル動物及び当該モデル動物を利用したスクリーニング方法に関する。 The present invention relates to a prophylactic agent for squamous cell carcinoma caused by Candida infection, a method for producing a squamous cell carcinoma model animal, the squamous cell carcinoma model animal, and a screening method using the model animal.
口腔癌や食道癌は重層扁平上皮由来の癌であり、特に食道癌は難治性の癌であり死亡率が高い。一方、Ｃａｎｄｉｄａ ａｌｂｉｃａｎｓ（Ｃ．ａｌｂｉｃａｎｓ）は健康人の口腔内からも検出される常在菌であるが、臓器移植や大手術後の患者、肝硬変症や糖尿病の患者といったような、免疫機能が衰えた患者においては、しばしば重篤な口腔カンジダ症や食道カンジダ症を引き起こすことが知られている。また、寝たきりの高齢者が増加するに従い、低栄養状態に陥り免疫機能の低下と共に感染の機会が増加していることも問題となっている。このように、免疫機能が低下している患者や高齢者では、Ｃ．ａｌｂｉｃａｎｓに感染し易く、深在性真菌症、さらには悪性腫瘍へ進展し重篤な結果を招くため、重大な問題となっている。
よって、カンジダ症から扁平上皮癌への進行を抑制し、扁平上皮癌の発症を予防する医薬品や食品の提供が望まれている。Oral cancer and esophageal cancer are cancers derived from the stratified squamous epithelium. In particular, esophageal cancer is intractable and has a high mortality rate. On the other hand, Candida albicans (C. albicans) is a resident bacterium that is also detected in the oral cavity of healthy people, but its immune function declines, such as patients after organ transplantation and major surgery, cirrhosis and diabetes patients. In many patients, it is often known to cause severe oral candidiasis and esophageal candidiasis. In addition, as the number of bedridden elderly people increases, there is a problem that the chances of infection increase as the immune function declines due to undernutrition. Thus, in patients with reduced immune function and elderly people, C.I. It is a serious problem because it is susceptible to infection with albicans and develops into deep mycosis and further malignant tumors with serious consequences.
Therefore, it is desired to provide pharmaceuticals and foods that suppress the progression from candidiasis to squamous cell carcinoma and prevent the development of squamous cell carcinoma.
一方、Ｌａｃｔｏｂａｃｉｌｌｕｓ ｇａｓｓｅｒｉ（Ｌ．ｇａｓｓｅｒｉ）を含む発酵乳には、ピロリ菌に対する除菌効果があり、これに基づく胃炎や胃潰瘍の予防効果を有することが知られている（特許文献２及び３）。しかしながら、カンジダ感染に対する効果については全く知られていない。 On the other hand, fermented milk containing Lactobacillus gasseri (L. gasseri) has a sterilizing effect against H. pylori, and is known to have a preventive effect on gastritis and gastric ulcer based on this (Patent Documents 2 and 3). However, nothing is known about the effect on Candida infection.
また一般に、疾患に有効な医薬品や食品のスクリーニングには、疾患モデルを作成することが有効であり、扁平上皮癌のモデル動物については、Ａｌｄｈ２欠損哺乳類動物（ヒトを除く）の皮内又は皮下にエタノール及び／又はアセトアルデヒドを投与して作成される扁平上皮癌モデル動物が報告されている（特許文献１）。しかしながら、当該扁平上皮癌モデル動物は、アルコール代謝に関与しているＡＬＤＨ２遺伝子が不活性型のヒトに高頻度で発症する扁平上皮癌の発症メカニズムの解明や治療法の開発を目的としたものであり、カンジダ感染に伴う扁平上皮癌の発症とは異なるものである。 In general, it is effective to create a disease model for screening for drugs and foods effective for diseases. For a model animal of squamous cell carcinoma, intradermally or subcutaneously in an Aldh2-deficient mammalian animal (excluding humans). A squamous cell carcinoma model animal prepared by administering ethanol and / or acetaldehyde has been reported (Patent Document 1). However, the model animal for squamous cell carcinoma is intended to elucidate the pathogenesis of squamous cell carcinoma that develops frequently in humans who have an inactive human ALDH2 gene involved in alcohol metabolism and to develop a therapeutic method. Yes, it is different from the development of squamous cell carcinoma associated with Candida infection.
本発明者らは、アロキサン投与により糖尿病を誘発したＷＢＮ／Ｋｏｂラットの前胃において重度の感染性慢性炎症を伴った扁平上皮癌が発生することを見出している（非特許文献１）。しかしながらこのモデルでは、アロキサン誘発糖尿病ラットの前胃増殖性病変の程度や発症率には個体差が大きく、カンジダ症から扁平上皮癌への進行を抑制する医薬品や食品のスクリーニングを適切に行うためには、よりバラツキの少ない病態モデルを確立する必要があった。 The present inventors have found that squamous cell carcinoma accompanied by severe infectious chronic inflammation develops in the forebrain of WBN / Kob rats in which diabetes is induced by administration of alloxan (Non-patent Document 1). However, in this model, there are large individual differences in the degree and incidence of progastric proliferative lesions in alloxan-induced diabetic rats, and in order to appropriately screen for drugs and foods that suppress the progression from candidiasis to squamous cell carcinoma It was necessary to establish a disease state model with less variation.
本発明は、カンジダ感染に起因して進行する扁平上皮癌の予防に有効な発酵物を提供することを課題とする。さらに本発明は、従来のモデル動物よりもバラつきが少なく、より適切に薬効評価を行えるカンジダ感染に起因する扁平上皮癌モデル動物とその作製方法を提供することを課題とする。 An object of the present invention is to provide a fermented product effective in preventing squamous cell carcinoma that progresses due to Candida infection. Furthermore, an object of the present invention is to provide a model animal for squamous cell carcinoma caused by Candida infection that has less variation than conventional model animals and can be more appropriately evaluated for drug efficacy, and a method for producing the same.
本発明者らは、上記課題を解決するため鋭意検討を重ねた結果、ラットにアロキサンを投与して糖尿病を誘発した直後から、Ｃ．ａｌｂｉｃａｎｓを強制的に経口投与することで、ラットの前胃において、カンジダ感染による慢性炎症を伴う増殖性病変を早期に誘発でき、その病変の個体差が少ない扁平上皮癌モデル動物を作成できることを見出した。また、乳をＬａｃｔｏｂａｃｉｌｌｕｓ ｂｕｌｇａｒｉｃｕｓ（Ｌ．ｂｕｌｇａｒｉｃｕｓ）、ＳｔｒｅｐｔｏｃｏｃｃｕＳ．ｔｈｅｒｍｏｐｈｉｌｕｓ（Ｓ．ｔｈｅｒｍｏｐｈｉｌｕｓ）およびＬ．ｇａｓｓｅｒｉを用いて発酵させた発酵物が、Ｃ．ａｌｂｉｃａｎｓ感染による炎症を抑制すると共に増殖性の病変の進行を抑制し、カンジダ感染に起因する扁平上皮癌の予防に有用であることを見出した。 As a result of intensive studies to solve the above-mentioned problems, the present inventors found that C.I. It has been found that, by forcibly administering albicans orally, proliferative lesions associated with chronic inflammation due to Candida infection can be induced in the early stomach of rats at an early stage, and a squamous cell carcinoma model animal with little individual difference can be created. It was. In addition, milk was obtained from Lactobacillus bulgaricus (L. bulgaricus), Streptococcus S. thermophilus (S. thermophilus) and L. thermophilus. A fermented product fermented with gasseri is C.I. The present invention has been found to be useful for the prevention of squamous cell carcinoma caused by Candida infection by suppressing inflammation caused by albicans infection and suppressing the progression of proliferative lesions.
すなわち、本発明は以下を包含する。
［１］乳をＬ．ｂｕｌｇａｒｉｃｕｓ、Ｓ．ｔｈｅｒｍｏｐｈｉｌｕｓおよびＬ．ｇａｓｓｅｒｉを用いて発酵させた発酵物を有効成分とするカンジダ感染に起因する扁平上皮癌予防剤。
［２］発酵物が、Ｌ．ｂｕｌｇａｒｉｃｕｓおよびＳ．ｔｈｅｒｍｏｐｈｉｌｕｓを乳に配合して発酵させた後に、Ｌ．ｇａｓｓｅｒｉを配合した発酵乳である前記［１］に記載のカンジダ感染に起因する扁平上皮癌予防剤。
［３］Ｌ．ｇａｓｓｅｒｉがＬ．ｇａｓｓｅｒｉ ＯＬＬ２７１６株（ＦＥＲＭ ＢＰ−６９９９）である、前記[１]又は[２]に記載のカンジダ感染に起因する扁平上皮癌予防剤。
［４］扁平上皮が口腔および／または食道の扁平上皮である前記［１］〜［３］に記載のカンジダ感染に起因する扁平上皮癌予防剤。
［５］カンジダ感染に起因する扁平上皮癌予防剤を製造するための、乳をＬ．ｂｕｌｇａｒｉｃｕｓ、Ｓ．ｔｈｅｒｍｏｐｈｉｌｕｓおよびＬ．ｇａｓｓｅｒｉを用いて発酵させた発酵物の使用。
［６］カンジダ感染に起因する扁平上皮癌予防のために使用する、乳をＬ．ｂｕｌｇａｒｉｃｕｓ、Ｓ．ｔｈｅｒｍｏｐｈｉｌｕｓおよびＬ．ｇａｓｓｅｒｉを用いて発酵させた発酵物。
［７］乳をＬ．ｂｕｌｇａｒｉｃｕｓ、Ｓ．ｔｈｅｒｍｏｐｈｉｌｕｓおよびＬ．ｇａｓｓｅｒｉを用いて発酵させた発酵物を投与又は摂取するカンジダ感染に起因する扁平上皮癌の予防方法。
［８］糖尿病誘発物質を投与して糖尿病を誘発させた糖尿病発症モデル動物にＣ．ａｌｂｉｃａｎｓを強制経口投与する工程を含む扁平上皮癌モデル動物の作製方法。
［９］動物がラットである前記[８]に記載の作製方法。
［１０］前記［８］又は［９］に記載の方法により作製された扁平上皮癌モデル動物。
［１１］前記［１０］に記載の扁平上皮癌モデル動物に被検物質を投与して扁平上皮癌病変部の変化を観察する工程を含む扁平上皮癌の予防剤および／または治療剤のスクリーニング方法。That is, the present invention includes the following.
[1] bulgaricus, S .; thermophilus and L.M. A prophylactic agent for squamous cell carcinoma caused by Candida infection comprising a fermented product fermented with gasseri as an active ingredient.
[2] The fermented product is L. bulgaricus and S. After thermophilus is mixed with milk and fermented, L. The agent for preventing squamous cell carcinoma resulting from Candida infection according to the above [1], which is fermented milk containing gasseri.
[3] L. gasseri is L. The agent for preventing squamous cell carcinoma caused by Candida infection according to [1] or [2] above, which is gasseri OLL2716 strain (FERM BP-6999).
[4] The agent for preventing squamous cell carcinoma caused by Candida infection according to the above [1] to [3], wherein the squamous epithelium is a squamous epithelium of the oral cavity and / or esophagus.
[5] Milk for producing a prophylactic agent for squamous cell carcinoma resulting from Candida infection bulgaricus, S .; thermophilus and L.M. Use of fermented material fermented with gasseri.
[6] The milk used for the prevention of squamous cell carcinoma caused by Candida infection is L. bulgaricus, S .; thermophilus and L.M. Fermented material fermented with gasseri.
[7] bulgaricus, S .; thermophilus and L.M. A method for preventing squamous cell carcinoma caused by Candida infection by administering or ingesting a fermented product fermented with gasseri.
[8] Diabetes onset model animals in which diabetes is induced by administering a diabetes-inducing substance are introduced into C.I. A method for producing an animal model of squamous cell carcinoma, comprising a step of gavage oral administration of albicans.
[9] The production method according to the above [8], wherein the animal is a rat.
[10] A squamous cell carcinoma model animal produced by the method according to [8] or [9].
[11] A screening method for a prophylactic and / or therapeutic agent for squamous cell carcinoma, comprising the step of observing changes in the lesion of the squamous cell carcinoma by administering a test substance to the squamous cell carcinoma model animal according to [10] above .
本発明のカンジダ感染に起因する扁平上皮癌予防剤によれば、カンジダ症及びカンジダ症から扁平上皮癌への進行を有効に抑制することができる。また、本発明によれば、カンジダ感染に起因する扁平上皮癌への進行を、病変の程度や発生率に個体差が少なく再現できる扁平上皮癌モデル動物が作成でき、これを用いることにより、扁平上皮癌の治療に有用な物質やカンジダ感染に起因する扁平上皮癌予防剤のスクリーニングが可能となり、また、Ｃ．ａｌｂｉｃａｎｓの感染による扁平上皮癌発症のメカニズムの解明や新たな扁平上皮癌の治療及び予防方法の研究が可能となる。 According to the agent for preventing squamous cell carcinoma resulting from Candida infection of the present invention, candidiasis and progression from candidiasis to squamous cell carcinoma can be effectively suppressed. Further, according to the present invention, it is possible to create a squamous cell carcinoma model animal that can reproduce progression to squamous cell carcinoma caused by Candida infection with little individual difference in the degree and incidence of lesions, and by using this, a squamous cell carcinoma model animal can be produced. It is possible to screen for substances useful for the treatment of epithelial cancer and preventive agents for squamous cell carcinoma caused by Candida infection. It becomes possible to elucidate the mechanism of the onset of squamous cell carcinoma caused by albicans infection and to study a new treatment and prevention method for squamous cell carcinoma.
以下、本発明を詳細に説明するが、本発明は以下に述べる個々の形態には限定されない。
（カンジダ感染に起因する扁平上皮癌予防剤）
本発明のカンジダ感染に起因する扁平上皮癌予防剤の有効成分である発酵物は、乳を、Ｌ．ｂｕｌｇａｒｉｃｕｓ、Ｓ．ｔｈｅｒｍｏｐｈｉｌｕｓおよびＬ．ｇａｓｓｅｒｉを用いて発酵させた発酵物である。
当該発酵物は、Ｌ．ｂｕｌｇａｒｉｃｕｓ、Ｓ．ｔｈｅｒｍｏｐｈｉｌｕｓおよびＬ．ｇａｓｓｅｒｉを、乳に配合（添加）して発酵させる他、Ｌ．ｂｕｌｇａｒｉｃｕｓおよびＳ．ｔｈｅｒｍｏｐｈｉｌｕｓを乳に配合（添加）して発酵させた後に、Ｌ．ｇａｓｓｅｒｉを配合（添加）してさらに発酵させるものでもよい。
ここで、発酵原料である乳としては、特に制限されず、獣乳（牛乳、羊乳、山羊乳、水牛乳などの哺乳類由来の乳）などを一般的に使用することが可能である。なお、この乳は、生乳や殺菌乳のみから構成されるわけではなく、発酵を阻害しない範囲で、還元乳原料（バター、クリーム、脱脂乳、全脂濃縮乳、脱脂濃縮乳、全脂粉乳、脱脂粉乳、練乳など）や、必要に応じて、その他の食品や食品添加物も配合（添加）することが可能である。Hereinafter, the present invention will be described in detail, but the present invention is not limited to the individual forms described below.
(Preventive agent for squamous cell carcinoma caused by Candida infection)
The fermented product, which is an active ingredient of the agent for preventing squamous cell carcinoma resulting from Candida infection of the present invention, contains milk, L. bulgaricus, S .; thermophilus and L.M. It is a fermented product fermented with gasseri.
The fermented product is L.P. bulgaricus, S .; thermophilus and L.M. In addition to fermenting (adding) gasseri into milk, bulgaricus and S. After adding (adding) thermophilus to milk and fermenting it, L. Gasseri may be blended (added) and further fermented.
Here, the milk that is a fermentation raw material is not particularly limited, and animal milk (milk derived from mammals such as milk, sheep milk, goat milk, buffalo milk) and the like can be generally used. This milk is not composed only of raw milk or pasteurized milk, and it is a reduced milk raw material (butter, cream, nonfat milk, full fat concentrated milk, nonfat concentrated milk, full fat powdered milk, Nonfat dry milk, condensed milk, etc.) and other foods and food additives can be blended (added) as necessary.
Ｌ．ｂｕｌｇａｒｉｃｕｓ及びＳ．ｔｈｅｒｍｏｐｈｉｌｕｓとしては、発酵乳の製造に一般的に用いられ、コーデックス規格でヨーグルトスターターとして規格化されているＬ．ｂｕｌｇａｒｉｃｕｓとＳ．ｔｈｅｒｍｏｐｈｉｌｕｓの混合スターターをベースとするスターターを好適に用いることができる。例えば、Ｌ．ｄｅｌｂｒｕｅｃｋｉｉ ｓｕｂｓｐ． ｂｕｌｇａｒｉｃｕｓ ＪＣＭ１００２Ｔと、Ｓ．ｔｈｅｒｍｏｐｈｉｌｕｓ ＡＴＣＣ１９２５８等が挙げられる。このほか、Ｓｔｒｅｐｔｏｃｏｃｃｕｓ属、Ｌｅｕｃｏｎｏｓｔｏｃ属、Ｐｅｄｉｏｃｏｃｃｕｓ属等の乳酸菌や、ビフィズス菌、酵母等を添加しても良い。L. bulgaricus and S. As thermophilus, L. is commonly used in the production of fermented milk and is standardized as a yogurt starter in the Codex standard. bulgaricus and S. A starter based on a thermophilus mixed starter can be preferably used. For example, L.M. delbrueckii subsp. bulgaricus JCM1002 T ; thermophilus ATCC 19258 and the like. In addition, lactic acid bacteria such as Streptococcus genus, Leuconostoc genus, and Pediococcus genus, bifidobacteria, and yeast may be added.
また、Ｌ．ｇａｓｓｅｒｉとしては、特に限定されるものではないが、例えば、Ｌ．ｇａｓｓｅｒｉ ＯＬＬ２７１６株が挙げられる。なお、Ｌ．ｇａｓｓｅｒｉ ＯＬＬ２７１６株は、前記特許文献３に記載されているとおり、１９９９年５月２４日付（原寄託日）で独立行政法人産業技術総合研究所特許生物寄託センター（茨城県つくば市東１−１−１ つくばセンター 中央第６）に、受託番号ＦＥＲＭ ＢＰ−６９９９の下でブタペスト条約に基づき国際寄託されている。本寄託株は１９９９年５月２４日付の微工研菌寄第Ｐ−１７３９９号の国内寄託（原寄託）から、２０００年１月１４日にブダペスト条約に基づく国際寄託に移管された。 L. The gasseri is not particularly limited. gasseri OLL2716 strain. In addition, L. As described in Patent Document 3, gasseri OLL2716 strain was incorporated on April 24, 1999 (original deposit date), National Institute of Advanced Industrial Science and Technology, Patent Biological Deposit Center (1-1-1 Tsukuba City, Ibaraki Prefecture). It is deposited internationally under the Budapest Treaty under the accession number FERM BP-6999. The deposited strain was transferred from the domestic deposit (original deposit) of MAKkenken No. P-17399 dated May 24, 1999 to an international deposit based on the Budapest Treaty on January 14, 2000.
本発明の発酵物は、後記実施例に示すように、Ｃ．ａｌｂｉｃａｎｓ感染による炎症を抑制し、扁平上皮細胞の癌化を有意に抑制する。従って、本発明の発酵物は、カンジダ感染に起因する扁平上皮癌予防剤として使用することができる。
尚、当該使用は、ヒト若しくは非ヒト動物における使用であり得、また治療的使用であっても非治療的使用であってもよい。ここで、「非治療的」とは、医療行為を含まない概念、すなわち人間を手術、治療又は診断する方法を含まない概念、より具体的には医師又は医師の指示を受けた者が人間に対して手術、治療又は診断を実施する方法を含まない概念である。As shown in the examples below, the fermented product of the present invention has a C.I. It suppresses inflammation caused by albicans infection and significantly suppresses squamous cell transformation. Therefore, the fermented product of the present invention can be used as a preventive agent for squamous cell carcinoma caused by Candida infection.
In addition, the said use may be use in a human or a non-human animal, and may be therapeutic use or non-therapeutic use. Here, “non-therapeutic” means a concept that does not include medical practice, that is, a concept that does not include a method for operating, treating, or diagnosing a person, more specifically, a doctor or a person who has received instructions from a doctor It is a concept that does not include a method for performing surgery, treatment, or diagnosis on the subject.
本発明において、「カンジダ感染に起因する扁平上皮癌の予防」とは、カンジダ、好ましくはＣ．ａｌｂｉｃａｎｓに感染した扁平上皮細胞で構成される組織の癌化を抑制して扁平上皮癌の発症を予防すること、すなわちカンジダ症から扁平上皮癌への進行を抑制するとを意味すると共に、扁平上皮細胞が癌化する前の前癌病変、すなわちカンジダ感染による炎症（カンジダ症）を抑制（予防）又は治療することを意味する。ここで、扁平上皮細胞で構成される組織は、口腔、食道、咽頭、喉頭、肛門、皮膚などが挙げられるが、本発明では、上部消化管である口腔、食道、咽頭、喉頭が好適に挙げられる。
尚、本発明において「扁平上皮癌」とは、形態学的に識別可能な典型的な扁平上皮癌のほか、扁平上皮の過形成病変が含まれる。
したがって、本発明のカンジダ感染に起因する扁平上皮癌の予防には、例えば、口腔癌、咽頭癌、喉頭癌、食道癌の予防の他、急性口腔カンジダ症、急性偽膜性カンジダ症、鵞口瘡、急性萎縮性カンジダ症、慢性口腔カンジダ症、慢性萎縮性口内炎、慢性肥厚性カンジダ症、慢性粘膜皮膚カンジダ症、正中菱形舌炎などの口腔内真菌症、食道カンジダ症などの抑制（予防）又は治療が包含される。In the present invention, “prevention of squamous cell carcinoma caused by Candida infection” means Candida, preferably C.I. Suppressing the onset of squamous cell carcinoma by inhibiting the canceration of tissues composed of albicans-infected squamous cells, ie, inhibiting the progression from candidiasis to squamous cell carcinoma, and squamous cell Means suppression (prevention) or treatment of precancerous lesions before canceration, that is, inflammation (candidiasis) caused by Candida infection. Here, examples of tissues composed of squamous epithelial cells include the oral cavity, esophagus, pharynx, larynx, anus, and skin. In the present invention, the oral digestive tract that is the oral cavity, esophagus, pharynx, and larynx are preferably exemplified. It is done.
In the present invention, “squamous cell carcinoma” includes not only typical squamous cell carcinoma morphologically distinguishable but also hyperplastic lesions of squamous epithelium.
Therefore, for prevention of squamous cell carcinoma caused by Candida infection of the present invention, for example, prevention of oral cancer, pharyngeal cancer, laryngeal cancer, esophageal cancer, acute oral candidiasis, acute pseudomembranous candidiasis, phlegm, acute Suppression (prevention) or treatment of oral mycosis such as atrophic candidiasis, chronic oral candidiasis, chronic atrophic stomatitis, chronic hypertrophic candidiasis, chronic mucocutaneous candidiasis, median rhomboid glossitis, and esophageal candidiasis Is included.
本発明のカンジダ感染に起因する扁平上皮癌予防剤は、それ自体、ヒトを含む動物に摂取又は投与した場合に、カンジダに感染した扁平上皮細胞の癌化を抑制し、カンジダ症から扁平上皮癌への進行を抑制する効果を発揮する、ヒト若しくは動物用の医薬品、食品であってもよく、或いは当該医薬品又は食品に配合して使用される素材又は製剤であってもよい。ここで、当該食品には、カンジダ感染に起因する扁平上皮癌の予防や、カンジダ症の予防又は治療をコンセプトとし、必要に応じてその旨を表示した、機能性食品、病者用食品、特定保健用食品が包含される。 The agent for preventing squamous cell carcinoma resulting from Candida infection of the present invention itself suppresses canceration of Candida-infected squamous cells when ingested or administered to animals including humans. It may be a human or veterinary drug or food that exhibits the effect of suppressing the progression to the drug, or may be a material or preparation used by blending with the drug or food. Here, the food includes functional foods, foods for the sick, specific foods with the concept of prevention of squamous cell carcinoma caused by Candida infection and prevention or treatment of candidiasis, as necessary. Health foods are included.
本発明の発酵物を含有した上記医薬品の投与形態としては、予防目的や改善目的、投与経路等に応じて剤型を選択することができ、例えば錠剤、被覆錠剤、丸剤、カプセル剤、顆粒剤、散剤、液剤、懸濁剤、乳剤、シロップ剤、注射剤、坐剤、浸剤、煎剤、チンキ剤等が挙げられる。これらの各種製剤は、常法に従って主薬に対して必要に応じて充填剤、増量剤、賦形剤、結合剤、保湿剤、崩壊剤、界面活性剤、滑沢剤、着色剤、矯味矯臭剤、溶解補助剤、懸濁剤、コーティング剤などの医薬の製剤技術分野において通常使用しうる既知の補助剤を用いて製剤化することができる。また、この医薬製剤中に着色剤、保存剤、香料、風味剤、甘味剤等や他の医薬品を含有させてもよい。 As the dosage form of the above pharmaceutical product containing the fermented product of the present invention, the dosage form can be selected according to the purpose of prevention, the purpose of improvement, the route of administration, etc. For example, tablets, coated tablets, pills, capsules, granules Agents, powders, solutions, suspensions, emulsions, syrups, injections, suppositories, dip agents, decoction, tinctures and the like. These various preparations are prepared according to conventional methods as necessary with respect to the active ingredient, such as fillers, extenders, excipients, binders, humectants, disintegrants, surfactants, lubricants, coloring agents, flavoring agents. The pharmaceutical composition can be formulated using known adjuvants that can be usually used in the pharmaceutical preparation technical field, such as solubilizing agents, suspension agents, and coating agents. Moreover, you may contain a coloring agent, a preservative, a fragrance | flavor, a flavoring agent, a sweetening agent, etc. and other pharmaceuticals in this pharmaceutical formulation.
本発明の発酵物を含有した上記食品の形態としては、牛乳、清涼飲料、発酵乳、ヨーグルト、チーズ、パン、ビスケット、クラッカー、ピッツァクラスト、調製粉乳、流動食、病者用食品、幼児用粉乳等食品、授乳婦用粉乳等食品、栄養食品等、いずれの形態であってもよく、その性状についても、通常用いられる飲食品の状態、例えば、固体状（粉末、顆粒状その他）、ペースト状、液状ないし懸濁状のいずれでもよい。 Examples of the form of the food containing the fermented product of the present invention include milk, soft drinks, fermented milk, yogurt, cheese, bread, biscuits, crackers, pizza crust, prepared milk powder, liquid food, food for the sick, infant milk powder Etc., any form of food such as milk powder for breastfeeding women, nutritional food, etc., and the state of the food or drink normally used, such as solid (powder, granular and others), paste Any of liquid or suspension may be used.
斯かる食品は、本発明の発酵物をそのまま使用し、あるいは他の食品ないし食品成分と混合するなど、通常の飲食品組成物における常法に従って製造できる。
他の食品成分としては、特に限定されないが、例えば水、タンパク質、糖質、脂質、ビタミン類、ミネラル類、有機酸、有機塩基、果汁、フレーバー類等が挙げられる。ここで、タンパク質としては、例えば全脂粉乳、脱脂粉乳、部分脱脂粉乳、カゼイン、ホエイ粉、ホエイタンパク質、ホエイタンパク質濃縮物、ホエイタンパク質分離物、α―カゼイン、β―カゼイン、κ−カゼイン、β―ラクトグロブリン、α―ラクトアルブミン、ラクトフェリン、大豆タンパク質、鶏卵タンパク質、肉タンパク質等の動植物性タンパク質、これら加水分解物；バター、乳清ミネラル、クリーム、ホエイ、非タンパク態窒素、シアル酸、リン脂質、乳糖等の各種乳由来成分などが挙げられる。糖質としては糖類、加工澱粉（テキストリンのほか、可溶性澱粉、ブリティッシュスターチ、酸化澱粉、澱粉エステル、澱粉エーテル等）、食物繊維などが挙げられる。脂質としては、例えば、ラード、魚油等、これらの分別油、水素添加油、エステル交換油等の動物性油脂；パーム油、サフラワー油、コーン油、ナタネ油、ヤシ油、これらの分別油、水素添加油、エステル交換油等の植物性油脂などが挙げられる。ビタミン類としては、例えば、ビタミンＡ、カロチン類、ビタミンＢ群、ビタミンＣ、ビタミンＤ群、ビタミンＥ、ビタミンＫ群、ビタミンＰ、ビタミンＱ、ナイアシン、ニコチン酸、パントテン酸、ビオチン、イノシトール、コリン、葉酸などが挙げられ、ミネラル類としては、例えば、カルシウム、カリウム、マグネシウム、ナトリウム、銅、鉄、マンガン、亜鉛、セレン、乳清ミネラルなどが挙げられる。有機酸としては、例えば、リンゴ酸、クエン酸、乳酸、酒石酸などが挙げられる。これらの成分は、２種以上を組み合わせて使用することができ、合成品及び／又はこれらを多く含む食品を用いてもよい。Such a food can be produced according to a conventional method in a normal food or beverage composition, such as using the fermented product of the present invention as it is or mixing it with other foods or food ingredients.
Examples of other food ingredients include, but are not limited to, water, proteins, carbohydrates, lipids, vitamins, minerals, organic acids, organic bases, fruit juices, and flavors. Here, examples of the protein include whole milk powder, skim milk powder, partially skim milk powder, casein, whey powder, whey protein, whey protein concentrate, whey protein isolate, α-casein, β-casein, κ-casein, β -Lactoglobulin, α-lactalbumin, lactoferrin, soy protein, chicken egg protein, meat protein and other animal and vegetable proteins, hydrolysates thereof; butter, whey minerals, cream, whey, non-protein nitrogen, sialic acid, phospholipids And various milk-derived components such as lactose. Examples of the saccharide include saccharides, processed starch (in addition to text phosphorus, soluble starch, British starch, oxidized starch, starch ester, starch ether, etc.), dietary fiber, and the like. Examples of the lipid include animal oils such as lard, fish oil, etc., fractionated oils, hydrogenated oil, transesterified oil, etc .; palm oil, safflower oil, corn oil, rapeseed oil, coconut oil, fractionated oils thereof, Examples include vegetable oils such as hydrogenated oils and transesterified oils. Examples of vitamins include vitamin A, carotene, vitamin B group, vitamin C, vitamin D group, vitamin E, vitamin K group, vitamin P, vitamin Q, niacin, nicotinic acid, pantothenic acid, biotin, inositol, choline. And minerals include, for example, calcium, potassium, magnesium, sodium, copper, iron, manganese, zinc, selenium, and whey minerals. Examples of the organic acid include malic acid, citric acid, lactic acid, and tartaric acid. These components can be used in combination of two or more, and synthetic products and / or foods containing a large amount thereof may be used.
上記医薬品又は食品中の本発明の発酵物の含有量は、その目的、用途に応じて任意に定めることができる。例えば、乾燥物換算で、全体量に対して通常、０．００１〜１００重量％の含量で配合することができ、好ましくは０．０１〜１００重量％、さらに好ましくは０．１〜１００重量％の含量で配合することができる。また、発酵物中のＬ．ｂｕｌｇａｒｉｃｕｓ及びＳ．ｔｈｅｒｍｏｐｈｉｌｕｓの菌数としては、両者の乳酸菌数が合計で１ｍＬあたり１０００万（１×１０７個）以上であることが好ましい。また、Ｌ．ｇａｓｓｅｒｉが１ｍＬあたり１００万（１×１０６個）以上であることが好ましく、Ｌ．ｇａｓｓｅｒｉが１ｍＬあたり１０００万（１×１０７個）以上であることがより好ましい。The content of the fermented product of the present invention in the pharmaceutical product or food can be arbitrarily determined according to its purpose and use. For example, it can be blended in a content of 0.001 to 100% by weight, preferably 0.01 to 100% by weight, more preferably 0.1 to 100% by weight, based on the total amount in terms of dry matter. It can mix | blend with the content of. In addition, L. bulgaricus and S. As the number of thermophilus bacteria, the total number of both lactic acid bacteria is preferably 10 million (1 × 10 7 ) or more per mL. L. The gasseri is preferably 1 million (1 × 10 6 ) or more per mL. More preferably, the gasseri is 10 million (1 × 10 7 ) or more per mL.
上記医薬品又は食品の投与又は摂取量は、被験体の生物種、齢数、体重、投与又は摂取回数等により異なり、当業者の裁量によって広範囲に変更することができる。例えば本発明の発酵物（乾燥物換算）として、０．０１〜１００００ｍｇ／ｋｇ体重／ｄａｙ、好ましくは０．０５〜６０００ｍｇ／ｋｇ体重／ｄａｙ、さらに好ましくは０．３〜５０００ｍｇ／ｋｇ体重／ｄａｙでありうる。また、投与又は摂取回数は、単回でも反復でもよいが、好ましくは反復投与又は摂取である。
また、投与又は摂取対象としては、それを必要としているヒトであれば特に限定されないが、例えば口腔カンジダ症、食道カンジダ症等の患者、又はその予備軍等が挙げられる。The administration or intake of the above-mentioned pharmaceutical or food varies depending on the species of the subject, age, body weight, number of administration or intake, etc., and can be widely changed at the discretion of those skilled in the art. For example, as the fermented product of the present invention (in terms of dry matter), 0.01 to 10000 mg / kg body weight / day, preferably 0.05 to 6000 mg / kg body weight / day, more preferably 0.3 to 5000 mg / kg body weight / day. It can be. The number of administrations or intakes may be single or repeated, but is preferably repeated administration or intake.
In addition, the administration or ingestion target is not particularly limited as long as it is a human in need thereof, and examples thereof include patients with oral candidiasis and esophageal candidiasis, or reserves thereof.
（扁平上皮癌モデル動物）
本発明の扁平上皮癌モデル動物の作製で用いる「動物」とは、例えば、マウス、ラットを意味し、動物の性別、週齢、体重等については、目的とするスクリーニングに適用可能である限り特に制限はない。ヒトの口腔や舌、食道は、重層扁平上皮に覆われており、ヒト・サル・イヌでは一部分のみで角化しているが、マウス・ラットでは前胃に至る全域で完全角化していることが知られている（日薬理誌、１３１，３７３−３７７，２００８）。本発明では、マウスやラットの前胃に病変を形成させることを特徴とするものである。当該「動物」としては、例えばＷＢＮ／ＫｏｂラットやＦ３４４ラットなどが挙げられる。(Squamous cell carcinoma model animal)
The “animal” used in the production of the squamous cell carcinoma model animal of the present invention means, for example, a mouse or a rat, and the sex, age, weight, etc. of the animal are particularly limited as long as they are applicable to the intended screening. There is no limit. The oral cavity, tongue, and esophagus of humans are covered with stratified squamous epithelium. In humans, monkeys, and dogs, only a part is keratinized. It is known (Japanese Pharmacology Journal, 131, 373-377, 2008). The present invention is characterized in that lesions are formed in the anterior stomach of mice or rats. Examples of the “animal” include WBN / Kob rat and F344 rat.
本発明の扁平上皮癌モデル動物の作製では、糖尿病動物にＣ．ａｌｂｉｃａｎｓを強制経口投与することを特徴とする。糖尿病動物はとしては、例えばラット（正常ラット）やマウス（正常マウス）にアロキサンやストレプトゾトシン等の薬物を投与して糖尿病を惹起した動物以外にも、遺伝性糖尿病動物を使用することもできるが、糖尿病誘発物質を投与して発病させるのが発症時期や重症度を均一化できるため好ましく、糖尿病誘発物質であるアロキサンにより発症させた糖尿病ラットを用いるのが遺伝毒性発癌物質でないため好ましい。糖尿病が発症しているかどうかの確認は、動物の血糖や尿糖を測定する等、通常の方法で確認できる。 In the production of a squamous cell carcinoma model animal of the present invention, C.I. albicans is orally administered by gavage. As a diabetic animal, for example, a genetically diabetic animal can be used in addition to an animal that causes diabetes by administering a drug such as alloxan or streptozotocin to a rat (normal rat) or a mouse (normal mouse). It is preferable to cause diabetes by administering a diabetes-inducing substance because the onset time and severity can be made uniform, and it is preferable to use a diabetic rat caused by alloxan, which is a diabetes-inducing substance, because it is not a genotoxic carcinogen. Whether or not diabetes has developed can be confirmed by a normal method such as measuring blood sugar or urine sugar in animals.
本発明では、糖尿病を誘発後、Ｃ．ａｌｂｉｃａｎｓを強制経口投与することを特徴とする。Ｃ．ａｌｂｉｃａｎｓの検体は、生理食塩水に懸濁して経口投与するのが好ましい。本発明では、強制経口投与するＣ．ａｌｂｉｃａｎｓ の菌数や投与頻度、投与期間は、Ｃ．ａｌｂｉｃａｎｓ が動物の扁平上皮細胞に定着すれば良く、使用する動物の生物種、齢数、体重、投与経路、投与回数等により異なり、当業者の裁量によって広範囲に変更することができる。例えば、１０週齢のＷＢＮ／Ｋｏｂラットに投与する場合には、１×１０6個／ｍＬ以上、好ましくは、１×１０7個／ｍＬ以上の菌数を週１回〜週４回の頻度で強制経口投与することなどが挙げられる。In the present invention, after induction of diabetes, C.I. albicans is orally administered by gavage. C. Preferably, the albicans specimen is suspended in physiological saline and administered orally. In the present invention, C.I. The number, administration frequency, and administration period of C. albicans are C.I. The albicans only needs to settle in the squamous cells of the animal, and varies depending on the species, age, body weight, route of administration, number of times of administration, etc. of the animal to be used, and can be changed widely within the discretion of those skilled in the art. For example, when administered to a 10-week-old WBN / Kob rat, the frequency is 1 × 10 6 cells / mL or more, preferably 1 × 10 7 cells / mL or more once a week to 4 times a week. And oral gavage.
本発明の扁平上皮癌モデル動物の作製では、通常は、投与開始から３ヶ月、好ましくは６ヶ月程度でラット前胃の扁平上皮過形成が形成される。本発明において「扁平上皮癌」の用語は、形態学的に識別可能な典型的な扁平上皮癌のほか、扁平上皮の過形成病変を含むものである。
本発明のモデル動物が病変を生じた後、その病変部の一部を採取して病理組織学的に前癌病変を判定することができる。例えば、組織をヘマトキシリン-エオジン染色（ＨＥ染色）して扁平上皮の乳頭状増殖の所見が認められれば、病変部に過形成が形成されたことを証明できる。さらに、過形成から連続性に浸潤増殖する病変をみいだし、構造異型または核異型を証明することによっても癌細胞の存在を確認できる。In the production of a squamous cell carcinoma model animal of the present invention, the squamous cell hyperplasia of the rat stomach is usually formed in about 3 months, preferably about 6 months from the start of administration. In the present invention, the term “squamous cell carcinoma” includes not only typical squamous cell carcinoma morphologically distinguishable but also hyperplastic lesions of the squamous epithelium.
After the model animal of the present invention has developed a lesion, a part of the lesion can be collected to determine the precancerous lesion from histopathology. For example, if the tissue is stained with hematoxylin-eosin (HE staining) and a papillary growth of the squamous epithelium is observed, it can be proved that hyperplasia has formed in the lesion. Furthermore, the presence of cancer cells can also be confirmed by finding lesions that continuously infiltrate and proliferate from hyperplasia and prove structural or nuclear variants.
本発明の方法により作製された扁平上皮癌を担持するモデル動物は、扁平上皮癌の治療薬のスクリーニングに用いることができる。モデル動物に対して被検物質を経口投与又は非経口投与し、例えば癌病変部の縮小や癌の進行抑制などの治療効果を観察することにより、扁平上皮癌の治療に有用な物質をスクリーニングできる。モデル動物の作製に際しては、予め被検物質を投与しておき、その後にＣ．ａｌｂｉｃａｎｓを強制的に経口投与することによって、扁平上皮癌の予防薬のスクリーニングも可能である。
また、本発明のモデル動物は、Ｃ．ａｌｂｉｃａｎｓの感染による扁平上皮癌発症のメカニズムの解明や扁平上皮癌の治療方法及び予防方法の研究にも有用である。The model animal carrying squamous cell carcinoma produced by the method of the present invention can be used for screening for therapeutic agents for squamous cell carcinoma. A test substance is orally or parenterally administered to a model animal and, for example, a substance useful for the treatment of squamous cell carcinoma can be screened by observing therapeutic effects such as reduction of cancerous lesions and suppression of cancer progression . When preparing a model animal, a test substance is administered in advance, and then C.I. By forcibly administering albicans orally, screening for a prophylactic agent for squamous cell carcinoma is also possible.
The model animal of the present invention is C.I. It is also useful for elucidating the mechanism of the development of squamous cell carcinoma due to infection with albicans and for researching methods for treating and preventing squamous cell carcinoma.
以下、実施例を挙げて本発明をさらに詳細に説明するが、本発明はこれにより限定されるものではない。なお、実施例において「％」表示は特に明記する場合を除き重量％を示すものとする。 EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated further in detail, this invention is not limited by this. In the examples, “%” indicates weight% unless otherwise specified.
［実施例１］病態モデルの確立
アロキサンで糖尿病を誘発した直後からＣ．ａｌｂｉｃａｎｓを実験的に投与し、早期の炎症および増殖性病変の誘発を試みた。[Example 1] Establishment of pathological model C.V. albicans was administered experimentally to attempt to induce early inflammation and proliferative lesions.
１０週齢の雌ＷＢＮ／Ｋｏｂラットにアロキサン（シグマ社）を４０ｍｇ／ｋｇの投与量で尾静脈より単回投与し、２週間にわたって糖尿病の状態を確認した。糖尿病が発症しなかった動物には、再度、アロキサンを投与し、糖尿病を発症させた。群構成は表１の通りであり、糖尿病を誘発後、Ｃ．ａｌｂｉｃａｎｓ（６×１０7個／ｍＬ）を強制経口投与した群(ＡＣ群、１５匹)、糖尿病を誘発後、Ｃ．ａｌｂｉｃａｎｓを強制経口投与しない群（Ａ群、１４匹）、さらに、アロキサンを投与せずＣ．ａｌｂｉｃａｎｓの強制経口投与のみ行った群(Ｃ群、１０匹)を用いた。ＡＣ群には、アロキサン投与後２週より、Ｃ．ａｌｂｉｃａｎｓを６×１０7個／ｍＬとなるように生理食塩水にて稀釈した被験物質を１匹あたり１ｍＬ、週に３回、強制経口投与した。その後は、週１回の頻度で８週間投与し、合計１０週間、１４回、強制経口投与した。いずれの群もＣ．ａｌｂｉｃａｎｓ投与後２５週にて剖検を実施し、上部消化管について病理組織学的観察を行った。尚、Ｃ．ａｌｂｉｃａｎｓは２００８年２月に解剖したＦ３４４アロキサン雄１８９６の増殖性病変を有する胃から採取し、摂南大学薬学部病理学研究室にて培養・保管されている生菌を用いた。Alloxan (Sigma) was administered once to a 10-week-old female WBN / Kob rat at a dose of 40 mg / kg from the tail vein, and the diabetic state was confirmed over 2 weeks. To animals that did not develop diabetes, alloxan was administered again to develop diabetes. The group composition is as shown in Table 1. After inducing diabetes, C.I. C. albicans (6 × 10 7 cells / mL) orally administered by gavage (AC group, 15 animals); C. albicans was not administered by oral gavage (group A, 14 animals), and alloxan was not administered. A group (group C, 10 animals) in which only oral gavage of albicans was performed was used. In the AC group, C.I. The test substance diluted with physiological saline so as to be 6 × 10 7 cells / mL of albicans was orally administered by gavage 3 times a week at 1 mL per mouse. Thereafter, administration was carried out once a week for 8 weeks, for a total of 10 weeks, 14 times by gavage. Both groups are C.I. Necropsy was performed 25 weeks after administration of albicans, and histopathological observation was performed on the upper gastrointestinal tract. In addition, C.I. albicans was collected from the stomach having a proliferative lesion of F344 alloxan male 1896 dissected in February 2008, and live bacteria cultured and stored in the Department of Pathology, Faculty of Pharmaceutical Sciences, Setan University were used.
ＡＣ群、Ａ群およびＣ群の病理所見の結果を表２に示した。Ｃ群（図１）では、前胃扁平上皮の過形成、Ｃ．ａｌｂｉｃａｎｓの感染および炎症は認めなかった。Ａ群では、１４例中４例（２８．６％）で前胃扁平上皮細胞が軽度から中等度の過形成（Ｓｑｕａｍｏｕｓ ｃｅｌｌ ｈｙｐｅｒｐｌａｓｉａ）を認め、１４例中７例（５０％）で好中球の集族（Ａｃｃｕｍｕｌａｔｉｏｎ ｏｆ ｎｅｕｔｒｏｐｈｉｌｓ）および、１４例中９例（６４．３％）で粘膜固有層から粘膜下織におけるリンパ球形質細胞浸潤（Ｌｙｍｐｈｏｃｙｔｉｃ ａｎｄ ｐｌａｓｍａｃｙｔｉｃ ｉｎｆｉｌｔｒａｉｏｎ ｉｎ ｓｕｂｍｕｃｏｓａ）からなる慢性炎症を伴っていたが、病変の程度は軽度〜中等度であり、発生率も低いものであった。一方、ＡＣ群では、１５匹中１４例で前胃扁平上皮が中等度から高度の過形成となり、粘膜表層部にはＣ．ａｌｂｉｃａｎｓの感染と化膿性炎症、粘膜固有層から粘膜下織にはリンパ球形質細胞浸潤からなる慢性炎症が認められた（図１）。このうち、1例でごく初期の扁平上皮癌に進展していた（図２）。
以上の結果から、Ｃ．ａｌｂｉｃａｎｓ感染がアロキサン誘発糖尿病ラットの前胃において慢性炎症を伴う増殖性病変を早期に誘発することが明らかとなった。さらにこの病態モデルはバラつきが非常に少なく、薬効評価に有用なモデルであることがわかった。
The results of pathological findings of AC group, A group and C group are shown in Table 2. In group C (FIG. 1), hypergastric squamous epithelial hyperplasia, C.I. Neither albicans infection nor inflammation was observed. In group A, 4 of 14 cases (28.6%) had mild to moderate hyperplasia of squamous epithelial cells, and 7 out of 14 cases (50%) had neutrophils. In 9 of 14 cases (64.3%) with chronic inflammation consisting of lamina propria to submucosal lymphocyte plasma cell infiltration (Lymphocytic and plasma infiltration in submucosa) However, the extent of the lesion was mild to moderate and the incidence was low. In the AC group, on the other hand, 14 out of 15 animals had moderate to severe hyperplasia of the anterior stomach squamous epithelium. albicans infection and purulent inflammation, chronic inflammation consisting of lymphocyte plasma cell infiltration was observed in the lamina propria to submucosa (FIG. 1). Of these, one had progressed to very early squamous cell carcinoma (FIG. 2).
From the above results, C.I. It has been shown that albicans infection induces proliferative lesions with chronic inflammation in the early stomach of alloxan-induced diabetic rats early. Furthermore, this pathological model has very little variation, and was found to be a useful model for drug efficacy evaluation.
［実施例２］
実施例１の結果より、Ｃ．ａｌｂｉｃａｎｓをアロキサン誘発糖尿病ラットに投与することにより、前胃に増殖性および炎症性病変を誘発し癌化させることが明らかとなった。
コーデックス規格でヨーグルトスターターとして規格化されているＬ．ｂｕｌｇａｒｉｃｕｓとＳ．ｔｈｅｒｍｏｐｈｉｌｕｓの混合スターターをベースとするスターターで発酵させた後にＬ．ｇａｓｓｅｒｉ ＯＬＬ２７１６を添加し発酵してなる本発明の発酵物により、Ｃ．ａｌｂｉｃａｎｓ感染誘発前胃増殖性および炎症病変が抑制されるかを検討した。
本発明の発酵物は次のように調製した。まず、Ｌ．ｇａｓｓｅｒｉ ＯＬＬ２７１６株、Ｌ．ｄｅｌｂｒｕｅｃｋｉｉ ｓｕｂｓｐ． ｂｕｌｇａｒｉｃｕｓ ＪＣＭ１００２Ｔ、Ｓ．ｔｈｅｒｍｏｐｈｉｌｕｓ ＡＴＣＣ１９２５８をそれぞれ１０％脱脂粉乳培地に１％で接種し、３７℃で１５時間培養してバルクスターターを調製した。その後、９５℃で５分間加熱処理したヨーグルトミックス（ＳＮＦ:９．５％、ＦＡＴ:３．０％）に、Ｌ．ｄｅｌｂｒｕｅｃｋｉｉ ｓｕｂｓｐ． ｂｕｌｇａｒｉｃｕｓ ＪＣＭ１００２Ｔ、Ｓ．ｔｈｅｒｍｏｐｈｉｌｕｓ ＡＴＣＣ１９２５８のスターターを各１％、Ｌ．ｇａｓｓｅｒｉ ＯＬＬ２７１６株のスターターを５％接種して、４３℃で４時間発酵させた。発酵・冷却直後のＬ．ｇａｓｓｅｒｉ ＯＬＬ２７１６株、Ｌ．ｄｅｌｂｒｕｅｃｋｉｉ ｓｕｂｓｐ． ｂｕｌｇａｒｉｃｕｓ ＪＣＭ１００２Ｔ、Ｓ．ｔｈｅｒｍｏｐｈｉｌｕｓ ＡＴＣＣ１９２５８それぞれの生菌数は９．０×１０7ＣＦＵ／ｍＬ、６．４×１０７ＣＦＵ／ｍＬ、１１．０×１０８ＣＦＵ／ｍＬであった。以下、本発明の発酵物をＬＧ２１と称する。[Example 2]
From the results of Example 1, C.I. It has been shown that administration of albicans to alloxan-induced diabetic rats induces proliferative and inflammatory lesions in the foregut and causes cancer.
L. standardized as a yogurt starter in the Codex standard. bulgaricus and S. after fermentation in a starter based on a thermophilus mixed starter. gasseri OLL2716 was added and fermented, and the fermented product of the present invention produced C.I. It was examined whether pregastric proliferative and inflammatory lesions induced by albicans infection were suppressed.
The fermented product of the present invention was prepared as follows. First, L.M. gasseri OLL2716 strain, L. delbrueckii subsp. bulgaricus JCM1002 T , S. Thermophilus ATCC 19258 was inoculated at 1% in 10% non-fat dry milk medium and cultured at 37 ° C. for 15 hours to prepare a bulk starter. Thereafter, the yogurt mix (SNF: 9.5%, FAT: 3.0%) heat-treated at 95 ° C. for 5 minutes was added to L.P. delbrueckii subsp. bulgaricus JCM1002 T , S. thermophilus ATCC 19258 starter 1% each, L.P. Gasseri OLL2716 strain starter was inoculated 5% and fermented at 43 ° C. for 4 hours. L. just after fermentation and cooling. gasseri OLL2716 strain, L. delbrueckii subsp. bulgaricus JCM1002 T , S. The number of viable bacteria of thermophilus ATCC 19258 was 9.0 × 10 7 CFU / mL, 6.4 × 10 7 CFU / mL, and 11.0 × 10 8 CFU / mL. Hereinafter, the fermented product of the present invention is referred to as LG21.
ＷＢＮ／Ｋｏｂラットにアロキサン（シグマ社製）を投与し糖尿病を誘発後、表３に示すような群構成で試験を行った。具体的には、Ｃ．ａｌｂｉｃａｎｓおよび本発明の発酵物（ＬＧ２１）を経口投与したＤＣ＋ＬＧ２１群、Ｃ．ａｌｂｉｃａｎｓのみを経口投与したＤＣ群を設けた。ＤＣ群には、アロキサン投与後３週より、最初の２週間にわたって、Ｃ．ａｌｂｉｃａｎｓ ６×１０7個／ｍＬとなるように生理食塩水にて稀釈した被験物質を１匹あたり１ｍＬの投与量で、週に３回、強制経口投与した。その後は、週１回の頻度で、アロキサン投与後２７週まで、Ｃ．ａｌｂｉｃａｎｓを強制経口投与したＤＣ＋ＬＧ２１群では、アロキサン投与後２週からアロキサン投与後２７週までの期間、本発明の発酵物であるＬＧ２１を５ｍＬ／ｋｇ体重の投与量で、１日１回の頻度で強制経口投与を開始し、アロキサン投与後３週より、最初の２週間にわたって、Ｃ．ａｌｂｉｃａｎｓ ６×１０7個／ｍＬとなるように生理食塩水にて稀釈した被験物質を１匹あたり１ｍＬの投与量で、週に３回、強制経口投与した。その後は、週１回の頻度で、アロキサン投与後２７週まで、Ｃ．ａｌｂｉｃａｎｓを強制経口投与した。ＤＣ＋ＬＧ２１群、ＤＣ群の両群は、アロキサン投与２７週（３５週齢）にて剖検し、前胃の増殖性病変、Ｃ．ａｌｂｉｃａｎｓ感染ならびに炎症性病変を比較した。Alloxan (manufactured by Sigma) was administered to WBN / Kob rats to induce diabetes, and then the test was conducted in a group configuration as shown in Table 3. Specifically, C.I. DC + LG21 group to which C. albicans and the fermented product of the present invention (LG21) were orally administered, C.I. A DC group in which only albicans was orally administered was provided. The DC group received C.I. over 3 weeks after alloxan administration over the first 2 weeks. The test substance diluted with physiological saline so as to be 6 × 10 7 albicans was administered orally by gavage 3 times a week at a dose of 1 mL per mouse. Thereafter, C.I. was administered once a week until 27 weeks after alloxan administration. In the DC + LG21 group in which albicans was orally administered by gavage, LG21, which is a fermented product of the present invention, was administered once a day at a dose of 5 mL / kg body weight for a period from 2 weeks after alloxan administration to 27 weeks after alloxan administration. Forcible oral administration was started, and C.I. The test substance diluted with physiological saline so as to be 6 × 10 7 albicans was administered orally by gavage 3 times a week at a dose of 1 mL per mouse. Thereafter, C.I. was administered once a week until 27 weeks after alloxan administration. albicans was orally administered by gavage. Both the DC + LG21 group and the DC group were necropsied at 27 weeks (35 weeks of age) after alloxan administration, and proliferative lesions in the foregut, C.I. albicans infection as well as inflammatory lesions were compared.
ＤＣ＋ＬＧ２１群およびＤＣ群の病理所見の結果を表４に示した。前胃扁平上皮過形成および炎症は、両群とも小弯側で強く、大弯側で弱かった。大弯側では、ＤＣ＋ＬＧ２１群の過形成はＤＣ群に比較して有意に弱く（図３）、細胞の増殖マーカーであるＫｉ−６７陽性率もＤＣ＋ＬＧ２１群において有意な低値を示した（図４）。また、Ｃ．ａｌｂｉｃａｎｓ感染および粘膜の化膿性炎症も、大弯側でＤＣ＋ＬＧ２１群おいてやや軽度であった。以上の結果から、本発明の発酵物は扁平上皮細胞の癌化を有意に抑制することが明らかとなった。 The results of pathological findings of DC + LG21 group and DC group are shown in Table 4. Pregastric squamous hyperplasia and inflammation were strong on the small heel side and weak on the large heel side in both groups. On the vaginal side, the hyperplasia of the DC + LG21 group was significantly weaker than that of the DC group (FIG. 3), and the Ki-67 positive rate, which is a cell proliferation marker, also showed a significantly lower value in the DC + LG21 group (FIG. 4). ). In addition, C.I. albicans infection and purulent inflammation of the mucosa were also slightly milder in the DC + LG21 group on the greater heel side. From the above results, it has been clarified that the fermented product of the present invention significantly suppresses canceration of squamous epithelial cells.
本発明によれば、カンジダ感染に起因して進行する扁平上皮癌の予防剤を提供できる。また、従来のモデル動物よりもバラつきが少なく、より適切に薬効評価を行えるカンジダ感染に起因する扁平上皮癌モデル動物とその作製方法、当該モデル動物を利用したスクリーニング方法を提供できる。 ADVANTAGE OF THE INVENTION According to this invention, the preventive agent of the squamous cell carcinoma which progresses resulting from Candida infection can be provided. In addition, it is possible to provide a squamous cell carcinoma model animal caused by Candida infection and its production method, and a screening method using the model animal, which have less variation than conventional model animals and can be more appropriately evaluated for drug efficacy.
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| "Ｃ型肝炎ウイルス研究の進歩と展望 Progress and perspective in HCV research", 日本臨床（別冊・増刊） ５月号, JPN6017005252, 2011, pages vol.69, suppl 4 * |
| "Ｈ．ｐｙｌｏｒｉ感染スナネズミモデル H. pylori-infected Mongolian gerbil model", 日本臨床（増刊）Ｈ．ＰＹＬＯＲＩ時代の消化性潰瘍学, JPN6017005256, 2002, pages 729 - 734 * |
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| 日本癌学会学術総会記事, JPN6013010366, 2009, pages 01 - 1 * |
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