JP2010235629A - 大腸ガンの化学的予防薬剤および化学的治療薬剤としての2−ヒドロキシ−5−フェニルアゾ安息香酸誘導体の使用 - Google Patents
大腸ガンの化学的予防薬剤および化学的治療薬剤としての2−ヒドロキシ−5−フェニルアゾ安息香酸誘導体の使用 Download PDFInfo
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Abstract
大腸ガンの化学的予防について理想的な薬物を提供することであって、その薬物は、以下のプロフィールを有する薬物である:1)大腸特異的;2)限定された吸収−親および代謝物の吸収が最小である;3)全身的な活性がないこと−一旦吸収されると、代謝性の不活性化により、薬物を不活性な形態に変換され、それにより腎臓およびGIシステムへの全身的な効果を制限する;4)抗酸化特性−大腸特異的抗酸化活性は、発ガン物質負荷を軽減するようにさらに働く;および5)NSAID様抗炎症機構−活性代謝物は、炎症誘導性エイコサノイド経路を阻害するべきであるが、基底の維持経路を損なわないエイコサノイド阻害が好ましい。
【解決手段】
以下の一般式
【化5】
の2-ヒドロキシ-5-フェニルアゾ安息香酸誘導体を含む薬学的組成物の使用。
【選択図】なし
Description
技術分野
本発明は、大腸ガンの化学的予防および化学的治療に関する。
大腸ガンは現在、アメリカ合衆国において悪性腫瘍に起因する年間の全死亡数の11%を占める。100,000人あたり62人の発症率、および100,000人あたり300人の有病率で、この疾患は現在、男性の死亡原因の第3位であり、そして女性の死亡原因の第4位である。大腸ガンは、5年生存率が50%未満と特に悪く、これは一般に、診断が後期になされることに起因する。現行の好ましい処置(化学療法と併用される外科手術)では、この生存率は増加していない。必要とされているのは、大腸ガンを発症する危険性が大きいことが知られている患者集団において、初期に開始され得る安全かつ効果的な予防的治療である。
1)大腸特異的−上部GI管において作成される活性を有しないプロドラッグであるが、大腸への到達時には活性な形態に変換されるべきである(スリンダク様);
2)限定された吸収−親および代謝物の吸収が(特にその活性形態に一旦変換されると)最小である;
3)全身的な活性がないこと−一旦吸収されると、代謝性の不活性化により、薬物を不活性な形態に変換すべきであり、それにより腎臓およびGIシステムに対する全身的な効果を制限する;
4)抗酸化特性−大腸特異的抗酸化活性は、発ガン物質負荷を軽減するようにさらに働く;および
5)NSAID様抗炎症機構−活性代謝物は、炎症誘導性エイコサノイド経路を阻害するべきであるが、基底の維持経路を損なわないエイコサノイド阻害が好ましい。
(項目1) 以下の一般式の2-ヒドロキシ-5-フェニルアゾ安息香酸誘導体を含む薬学的組成物の使用であって:
(項目2).前記薬剤が、固体または液体の薬学的希釈剤またはキャリアとの混合物中に、2-ヒドロキシ-5-フェニルアゾ安息香酸誘導体またはそれらのエステルまたは活性代謝物または活性代謝物の酸化生成物、あるいは2-ヒドロキシ-5-フェニルアゾ安息香酸誘導体またはそれらのエステルまたは活性代謝物または活性代謝物の酸化生成物の塩から本質的になる、項目1に記載の使用。
(項目3).前記2-ヒドロキシ-5-フェニルアゾ安息香酸誘導体が、バルサラジドである、項目1に記載の使用。
(項目4).前記活性代謝物が5-ASAである、項目1に記載の使用。
(項目5).前記活性代謝物の酸化生成物が5-ASAの酸化生成物である、項目1に記載の使用。
(項目6).前記5-ASAの酸化生成物がゲンチジン酸である、項目5に記載の使用。
(項目7).前記5-ASAの酸化生成物が5-ニトロ-サリチル酸である、項目5に記載の使用。
(項目8).前記薬学的組成物が、2-ヒドロキシ-5-フェニルアゾ安息香酸誘導体またはそれらのエステルまたは活性代謝物または活性代謝物の酸化生成物あるいは2-ヒドロキシ-5-フェニルアゾ安息香酸誘導体またはそれらのエステルまたは活性誘導体または活性代謝物の酸化生成物の塩の1〜14g/70kg体重/日の範囲の1日用量において、該組成物を必要とするヒトに経口投与される、項目1に記載の使用。
(項目9).前記薬学的組成物が、2-ヒドロキシ-5-フェニルアゾ安息香酸誘導体またはそれらのエステルまたは活性代謝物または活性代謝物の酸化生成物あるいは2-ヒドロキシ-5-フェニルアゾ安息香酸誘導体またはそれらのエステルまたは活性誘導体または活性代謝物の酸化生成物の塩の1〜14g/70kg体重/日の範囲の1日用量において、該組成物を必要とするヒトに直腸から投与される、項目1に記載の使用。
2-ヒドロキシ-5-フェニル安息香酸誘導体、特にバルサラジドおよびその活性な代謝産物は、大腸ガンの化学的予防に有効であることが見出されている。これらの2-ヒドロキシ-5-フェニル安息香酸誘導体は、以下の一般式を有する:
従って、本発明の2-ヒドロキシ-5-フェニル安息香酸誘導体、特にバルサラジドおよびその代謝産物は、大腸ガンの化学的治療に有用である。これらは好ましくは、大腸ガンを患っている、または大腸ガンを発症する危険性のあるヒト個体に、2-ヒドロキシ-5-フェニル安息香酸誘導体を含有する薬学的組成物の形態で投与される。薬学的組成物はまた、1またはそれ以上の非毒性の薬学的に受容可能なキャリア、賦形剤、および/または希釈剤を含み得る。経口投与が好ましい。標準的な薬学的処方技術が用いられる(例えば、Remington'sPharmaceutical Sciences,Mack Publishing Co.,Easton,PA,最新版に開示されている)。
バルサラジドおよびその代謝産物である5-ASAのヒト大腸ガン細胞の増殖に対する活性を、ヒト腺腫細胞HT-29およびLS174Tを使用してインビトロで実証した。細胞は、10%仔ウシ血清を添加したダルベッコの改変Eagle培地で、5%CO2雰囲気中で37℃にて増殖させた。増殖試験のために、細胞を24ウェル組織培養皿(2cm2/ウェル)に、20,000細胞/ウェルの密度で播き、そして12時間接着させた。次いで、増殖培地を交換し、そして試験薬物を含有する新鮮培地で置き換えた。
異常陰窩は、発ガン物質に誘導される大腸粘膜中の「大きさ、厚さの増大した上皮内層および増大した周陰窩帯」の陰窩として最初に記載された(Birdら (1989) Cancer Surv. 8:189-200)。NSAIDは、ラットにおいて発ガン物質のアゾキシメタン(AOM)により誘導される異常陰窩形成の最も強力なインヒビターのうちの一つである(Wargovichら(1992) J.Cell.Biochem. 16G : 51-54)。これらの薬剤のいくつかの抗腫瘍活性は、より長期なAOM動物研究で確証されている。従って、異常陰窩モデルは、バルサラジドおよび代謝産物の効力についての理想的なインビボアッセイである。
実施例3:インビトロでの大腸ガン細胞の増殖における5-ASAの酸化生成物の影響
上記の実施例でバルサラジドで見られた阻害は、両方の細胞タイプの間で同一であったが、LS174T細胞は、常にHT-29細胞よりも5-ASAの作用に対してより感受性であった。さらに、5-ASAに対する両方の細胞タイプでの阻害応答は、個々の実験間で最大70%から最低10%まで変化した。この可変性の原因を決定するための実験の設計において、細胞に添加する最小3日前に作製された5-ASA貯蔵溶液は、一貫してより大きな阻害効果を生じることが決定された。この差異を、図7に示す。
Claims (1)
- 以下の一般式の2-ヒドロキシ-5-フェニルアゾ安息香酸誘導体を含む薬学的組成物の使用であって:
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EP1565187A4 (en) * | 2002-11-13 | 2010-02-17 | Novartis Vaccines & Diagnostic | CANCER TREATMENT METHODS AND RELATED METHODS |
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DE602005022175D1 (de) * | 2004-05-28 | 2010-08-19 | Salix Pharmaceuticals Inc | Prävention, behandlung und linderung strahlungsinduzierter enteritis |
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CN101247812A (zh) * | 2005-08-24 | 2008-08-20 | 萨利克斯药品公司 | 巴柳氮制剂及其生产和应用 |
US7452872B2 (en) | 2005-08-24 | 2008-11-18 | Salix Pharmaceuticals, Inc. | Formulations and uses of 2-hydroxy-5-phenylazobenzoic acid derivatives |
RU2354384C1 (ru) * | 2007-12-28 | 2009-05-10 | Михаил Владимирович Кутушов | Применение органических красителей в качестве средства для лечения онкологических заболеваний |
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US5498608A (en) * | 1994-01-07 | 1996-03-12 | Salix Pharmaceuticals | Use of 2-hydroxy-5-phenylazobenzoic acid derivatives as colon cancer chemopreventative and chemotherapeutic agents |
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EP0738152A4 (en) | 2000-12-13 |
CA2180571C (en) | 2001-03-20 |
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FI962735A0 (fi) | 1996-07-03 |
NO962841D0 (no) | 1996-07-05 |
AU1557595A (en) | 1995-08-01 |
ES2248796T3 (es) | 2006-03-16 |
DE69534564T2 (de) | 2006-07-27 |
EP0738152A1 (en) | 1996-10-23 |
NO962841L (no) | 1996-08-29 |
CZ196796A3 (en) | 1996-12-11 |
ATE308327T1 (de) | 2005-11-15 |
US5498608A (en) | 1996-03-12 |
RU2161487C2 (ru) | 2001-01-10 |
JP4601466B2 (ja) | 2010-12-22 |
CN1140994A (zh) | 1997-01-22 |
DK0738152T3 (da) | 2006-01-30 |
NZ279062A (en) | 1999-11-29 |
FI962735A (fi) | 1996-08-26 |
CZ286460B6 (en) | 2000-04-12 |
HU9601846D0 (en) | 1996-09-30 |
DE69534564D1 (de) | 2005-12-08 |
RO116525B1 (ro) | 2001-03-30 |
JP2006096738A (ja) | 2006-04-13 |
EP0738152B1 (en) | 2005-11-02 |
WO1995018622A1 (en) | 1995-07-13 |
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