JP6218084B2 - 悪性腫瘍転移抑制用医薬 - Google Patents
悪性腫瘍転移抑制用医薬 Download PDFInfo
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- JP6218084B2 JP6218084B2 JP2014539853A JP2014539853A JP6218084B2 JP 6218084 B2 JP6218084 B2 JP 6218084B2 JP 2014539853 A JP2014539853 A JP 2014539853A JP 2014539853 A JP2014539853 A JP 2014539853A JP 6218084 B2 JP6218084 B2 JP 6218084B2
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- metastasis
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- malignant tumor
- adrenomedullin
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Description
また、上皮系以外の悪性腫瘍(肉腫など)においても、悪性化して、運動能・浸潤能を獲得した腫瘍細胞が、血管等へ侵入し、遠隔組織の血管内皮への定着、及び組織内への浸潤を経て、転移巣が形成されることとなる。
また、非特許文献29には、HMG−CoA還元酵素阻害薬であるロバスタチンがEセレクチンの発現を阻害し、大腸癌細胞のHUVEC(ヒト臍帯静脈内皮細胞)に対する接着を阻害することが記載されている。
本発明において、悪性腫瘍(細胞)の転移には、悪性腫瘍(細胞)の遠隔転移(転移)及び悪性腫瘍の再発(原発巣(原発性腫瘍)部位における再発)が含まれる。悪性腫瘍の転移の抑制又は予防とは、悪性腫瘍の遠隔転移を抑制又は予防すること、及び/又は悪性腫瘍の再発(原発巣部位における再発)を抑制又は予防することを意味する。
(1)以下の(i)〜(iv)から選択される少なくとも一種類の血管保護剤又はその薬理的に許容される塩を有効成分として含有する、悪性腫瘍の転移を抑制又は予防するための医薬組成物、および
(i)アンジオテンシンII受容体拮抗薬
(ii)HMG−CoA還元酵素阻害薬
(iii)グレリン又はその誘導体
(iv)アドレノメデュリン又はその誘導体
(i)アンジオテンシンII受容体拮抗薬
(ii)HMG−CoA還元酵素阻害薬
(iii)グレリン又はその誘導体
(iv)アドレノメデュリン又はその誘導体
本発明はまた、上記(i)〜(iv)から選択される少なくとも一種類の血管保護剤又はその薬理的に許容される塩の有効量を患者に投与することを含む、抗癌剤及び/又は抗腫瘍剤による悪性腫瘍の転移の増悪及び/又は増大を抑制又は予防するための治療又は予防方法に関する。
本発明はまた、抗癌剤及び/又は抗腫瘍剤による悪性腫瘍の転移の増悪及び/又は増大の抑制又は予防に使用するための、上記(i)〜(iv)から選択される少なくとも一種類の血管保護剤又はその薬理的に許容される塩に関する。
本発明は、上記(i)〜(iv)から選択される少なくとも一種類の血管保護剤又はその薬理的に許容される塩の有効量を患者に投与することを含む、血管内皮への悪性腫瘍細胞の定着又は浸潤を抑制又は予防する方法も包含する。
本発明は、血管内皮への悪性腫瘍細胞の定着又は浸潤の抑制又は予防に使用するための、上記(i)〜(iv)から選択される少なくとも一種類の血管保護剤又はその薬理的に許容される塩も包含する。
また、抗癌剤/抗腫瘍剤(例えば、シスプラチン(CDDP)等の白金系抗腫瘍剤)の投与により、血管内皮の障害が引き起こされ、これにより、悪性腫瘍の血管内皮細胞への接着および浸潤が促進されることによって、悪性腫瘍の転移が生じやすくなることを本発明の発明者らは見出しているが、本発明の医薬組成物は、その血管保護的な作用により、抗癌剤/抗腫瘍剤の投与によって促進される悪性腫瘍の血管内皮への接着を抑制することにより、優れた腫瘍転移抑制効果(腫瘍の転移(遠隔転移)抑制効果、及び/又は腫瘍の再発抑制効果)を発揮する。よって本発明の医薬組成物を用いると、抗癌剤及び/又は抗腫瘍剤による悪性腫瘍の転移の増悪及び/又は増大を効果的に抑制又は予防することができる。
更に、本発明の医薬組成物は、その血管保護的な作用により、外科的手術或いはこれにより促進される全身的及び局所的な腫瘍細胞の血管内皮細胞への接着も抑制することができ、優れた腫瘍転移抑制効果を有する。
グレリン(Ghrelin)は、成長ホルモン分泌促進因子レセプター1a(Growth Hormone Secretagogue- Receptor 1a:GHS-R1a)に作用し、下垂体からの成長ホルモン(Growth Hormone:GH)の分泌を亢進させる作用を有する。
: GSS(n-octanoyl)FLSPEHQRVQQRKESKKPPAKLQPR (配列番号1)
: GSS(n-octanoyl)FLSPEHQRVQRKESKKPPAKLQPR (配列番号2)
ラット(Rat)
: GSS(n-octanoyl)FLSPEHQKAQQRKESKKPPAKLQPR (配列番号3)
: GSS(n-octanoyl)FLSPEHQKAQRKESKKPPAKLQPR (配列番号4)
マウス(Mouse)
: GSS(n-octanoyl)FLSPEHQKAQQRKESKKPPAKLQPR (配列番号5)
ブタ(Porcine)
: GSS(n-octanoyl)FLSPEHQKVQQRKESKKPAAKLKPR (配列番号6)
ウシ(Bovine):
: GSS(n-octanoyl)FLSPEHQKLQRKEAKKPSGRLKPR (配列番号7)
ヒツジ(Ovine):
: GSS(n-octanoyl)FLSPEHQKLQRKEPKKPSGRLKPR (配列番号8)
イヌ(Canine)
: GSS(n-octanoyl)FLSPEHQKLQQRKESKKPPAKLQPR (配列番号9)
ウマ(Equine)
: GSS(n-butanoyl)FLSPEHHKVQHRKESKKPPAKLKPR (配列番号10)
(上記表記において、アミノ酸残基は一文字標記により表している。)
例えば、ヒトのグレリンは、配列番号1又は2に示されるアミノ酸配列を有するペプチドであって、アミノ末端から3番目のアミノ酸残基(セリン残基)はその側鎖(水酸基)が脂肪酸(n-オクタン酸)によりアシル化された修飾アミノ酸残基である。
(2)配列番号1〜10のいずれか1つに示されるアミノ酸配列において1〜数個のアミノ酸が欠失、置換及び/又は付加されたアミノ酸配列を有するペプチドであって、アミノ末端から3番目のアミノ酸残基はその側鎖が脂肪酸によりアシル化された修飾アミノ酸残基であるペプチド;及び
(3)配列番号1〜10のいずれか1つに示されるアミノ酸配列において、アミノ末端から少なくとも4番目までの配列が保存されており、かつ、当該保存配列以外の部分において1〜数個のアミノ酸が欠失、置換及び/又は付加されたアミノ酸配列を有するペプチドであり、さらに、アミノ末端から3番目のアミノ酸残基はその側鎖が脂肪酸によりアシル化された修飾アミノ酸残基であるペプチド。
その他のグレリンの誘導体は、例えば、Matsumoto らの文献(Structural similarity of ghrelin derivatives to peptidyl growth hormone secretagogues. Matsumoto M, Kitajima Y, Iwanami T, Hayashi Y, Tanaka S, Minamitake Y, Hosoda H, Kojima M, Matsuo H, Kangawa K. Biochem Biophys Res Commun. 2001 Jun 15;284(3):655-9.)等を適宜参照して設計することが出来る。
より詳細には、例えば、グレリン又はその誘導体を成長ホルモン分泌促進因子レセプター1aに接触せしめ、それが当該レセプターに結合することにより細胞内カルシウムイオン濃度を上昇させるかどうか、を試験し、細胞内カルシウムイオン濃度を上昇があればアゴニスト作用があると判断できる。
グレリン及びその誘導体は、天然の原料から単離することもできる。
アドレノメデュリンは、血管拡張作用及び降圧作用(血圧降下作用)を有するポリペプチドである。生体内で、アドレノメデュリンの前駆体より、生理活性を持つアドレノメデュリン(活性型アドレノメデュリン)及びPAMP(proadrenomedullin N-terminal 20 peptide)が生合成される(以下、PAMPはアドレノメデュリンの誘導体に含めることとする)。アドレノメデュリンは、血小板、血管内皮細胞及び平滑筋細胞の細胞内cAMPを増加させる作用、並びに血小板凝集抑制作用、強力な血管拡張作用及び降圧作用を発揮する。
配列番号11には、アドレノメデュリン前駆体のcDNAの塩基配列を示した。配列番号12には、アドレノメデュリン前駆体のアミノ酸配列を示した。配列番号12のアミノ酸配列は、配列番号11の塩基配列にコードされるアミノ酸配列である。また、配列番号13には、アドレノメデュリン(活性型)のアミノ酸配列を示した。また、配列番号14には、PAMPのアミノ酸配列を示した。
アドレノメデュリン誘導体の中には、アドレノメデュリンの前駆体も含まれる。また、アドレノメデュリン誘導体の中には、PAMPも含まれる。
(1)配列番号12、13又は14に示されるアミノ酸配列を有するポリペプチド;
(2)配列番号12、13又は14に示されるアミノ酸配列において1〜数個のアミノ酸が欠失、置換及び/又は付加されたアミノ酸配列を有するポリペプチド;及び
(3)配列番号11に示される塩基配列からなる核酸とストリンジェントな条件下においてハイブリダイズし得る核酸によりコードされるポリペプチド。
上記(3)において、核酸は、RNA、DNAのいずれでもよいが、DNAが好ましい。
アンジオテンシンII受容体拮抗薬は、アンジオテンシンII受容体(AT1受容体)にアンジオテンシンIIが結合するのを妨げる作用を有する。本発明の有効成分として用いるアンジオテンシンII受容体拮抗薬は、前記の作用を有するものであればよい。
HMG−CoA還元酵素阻害薬は、HMG−CoA還元酵素を特異的に阻害する作用を有する。本発明の有効成分として用いるHMG−CoA還元酵素阻害薬は、前記の作用を有するものであればよい。
このように宿主側へ作用することから、本発明は、悪性腫瘍(例えば癌)の種類によらず、全ての悪性腫瘍に対して優れた転移抑制効果を発揮することができる。
本発明の悪性腫瘍の転移を抑制又は予防する方法、及び治療若しくは予防方法は、血管内皮への悪性腫瘍細胞の定着又は浸潤を抑制又は予防するための方法としても好適である。
他の転移抑制薬を非経口投与、例えば静脈内投与する場合には、好ましくはインフュージョンポンプ、カテーテル等を利用して持続的に投与され、数時間〜数日間(例えば、3〜14日間、好ましくは3〜7日間程度)投与されるような形態において使用される。
本発明の医薬組成物および他の転移抑制薬を組み合わせて用いる場合、それぞれ投与方法に応じた上述の投与期間を適用して、本発明の医薬組成物および他の転移抑制薬を使用することができる。
また、有効成分がペプチド性物質をコードする核酸の形態である場合、かかる核酸(ペプチド性物質をコードする遺伝子等)を、レトロウイルス、アデノウイルス、アデノ随伴ウイルス等のウイルスベクターをベクターとして用いて、又はプラスミド等の形態として、静脈注射、筋肉注射、局所注射等により患者に導入することもできる。
アンジオテンシンII受容体拮抗薬又はHMG−CoA還元酵素阻害薬を経口投与する場合には、例えば、1日1回〜3回程度投与する形が好ましい。例えば、アンジオテンシンII受容体拮抗薬又はHMG−CoA還元酵素阻害薬を使用する場合には、体重あたり有効成分として、1日あたり約1〜100mg/kgを経口投与することが好ましく、それぞれ高血圧症又は高コレステロール血症に用いられる用量以下で投与することができる。
本発明は、血管保護剤又はその薬理的に許容される塩の有効量を患者に投与することを含む、抗癌剤及び/又は抗腫瘍剤による悪性腫瘍の転移の増悪及び/又は増大を抑制又は予防する方法も包含する。
抗癌剤/抗腫瘍剤(例えば、シスプラチン等の白金系抗腫瘍剤)を投与する場合、本発明の医薬組成物および他の転移抑制薬の組み合わせを同時または別々に投与することができる。
かかる組み合わせにおける本発明の医薬組成物は、通常、抗癌剤/抗腫瘍剤投与開始の約1週間以上前、好ましくは約10日以上前から、本発明の医薬組成物の投与を開始し、抗癌剤/抗腫瘍剤投与の終了後、約1週間以上後、好ましくは約10日以上後迄、投与を継続するのが好ましい。
本発明の医薬組成物の剤形及び投与経路は特に限定されず、患者の状況に合わせて、1種または2種以上の経口剤または非経口剤を選択することができ、経口剤および非経口剤の2種以上を組み合わせて使用することもできる。
ホルモンとしては、例えば、ヒドロコルチゾン、デキサメタゾン、メチルプレドニゾロン、プレドニゾロン、プラステロン、ベタメタゾン、トリアムシノロン、オキシメトロン、ナンドロロン、メテノロン、ホスフェストロール、エチニルエストラジオール、クロルマジノン又はメドロキシプロゲステロン等が挙げられる。
抗腫瘍性抗体、分子標的薬としては、トラスツズマブ、リツキシマブ、セツキシマブ、ニモツズマブ、デノスマブ、ベバシズマブ、インフリキシマブ、メシル酸イマチニブ、ゲフィチニブ、エルロチニブ、スニチニブ、ラパチニブ、ソラフェニブ等が挙げられる。
シスプラチン(CDDP)はシスプラチン注「マルコ」(日医工ファーマ)を使用した。Osmotic pumpはALZET(Cupertino, CA)のMODEL2002(14日間投与用)を使用した。また、グレリン(配列番号1のアミノ酸配列からなり、アミノ末端から3番目のセリンの側鎖水酸基がオクタノイル化されているペプチド)及びアドレノメデュリン(配列番号13)は、アスビオファーマ(株)より、それぞれ入手した凍結乾燥品を、生理的食塩水で溶解し、これを適宜濃度で調節して、以下の実験に用いた。実施例において、有意差は、χ2検定により求めた(*:P<0.05)。
マウスは6週齢の雄のC56BL/6Nマウス(日本SLC株式会社より購入)を用いた。マウスメラノーマB16-F10はATCCより購入し、10% FCSを含む DMEM (Life Technologies Corporation)にて37℃、5%CO2の条件下で培養し、サブコンフルエントの状態でEDTA-trypsin処理後、遠心し、5×106 cells/mLになるようserum free DMEMに懸濁した。100μL/mouseの用量で、5×105 個のメラノーマ細胞懸濁液をマウスの尾静脈より注入した。
マウスは8週齢の雄のC57BL6マウス(日本SLC株式会社より購入)を用いた。マウスメラノーマB16-F10はATCCより購入し、10% FCSを含む DMEM (Life Technologies Corporation)にて37℃、5%CO2の条件下で培養し、サブコンフルエントの状態でEDTA-trypsin処理後、遠心し、5×106 cells/mLになるようserum free DMEMに懸濁した。100μL/mouseの用量で、3×105 個のメラノーマ細胞懸濁液をマウスの尾静脈より注入した。
アンジオテンシンII受容体拮抗薬群には、バルサルタン(40mg/kg)、ロサルタン(30mg/kg)、オルメサルタン メドキソミル(5mg/kg)、アジルサルタン(10mg/kg)、カンデサルタン シレキセチル(8mg/kg)およびイルベサルタン(100mg/kg)を、それぞれの用量となるように調整された0.5%メチルセルロース水溶液を用い、それぞれ実験開始前(マウスに腫瘍細胞を注入する前)4日間経口摂取させ、実験を行った。アンジオテンシンII受容体拮抗薬群およびピタバスタチン群の各メチルセルロース水溶液は、腫瘍細胞注入後、実験終了まで前記用量で経口摂取させた。一方、コントロール群では各薬剤が入っていない同水溶液のみを経口摂取させ、実験を行った。各群の例数は、n=5。
ヒト微細肺動脈血管内皮細胞(ロンザジャパン株式会社製)をconfluentになるまで培養後、ロサルタン(終濃度5×10-6M)を添加し、その2時間後にPBS(リン酸緩衝生理食塩水)又はシスプラチン(CDDP)(終濃度5μM)を加え、さらにその1時間後に培養液を、新鮮培養液(Medium199, 1%BSA入り(Medium199はGibco (Invitrogen)製、BSA(bovine serum albumin)はSigma製)に入れ替えた後、蛍光ラベルしたA549-GFPヒト肺癌細胞株(AntiCancer Japan製)(1×105個ずつ)懸濁液を添加し、血管内皮細胞と肺癌細胞との共培養(3時間)を行った。その結果、CDDP 5μM前処置1時間にて血管内皮細胞への癌接着細胞数は増加したが、その2時間前にロサルタン(5×10-6M)で前処置を行うと、癌細胞の血管内皮細胞への接着は有意に抑制された。その結果を図9のA及び図9のBに示す。
Claims (10)
- (iii)グレリン又はその誘導体及び(iv)アドレノメデュリン又はその誘導体から選択される少なくとも一種類の血管保護剤又はその薬理的に許容される塩を有効成分として含有することを特徴とする、悪性腫瘍の転移を抑制又は予防するための医薬組成物であって、
(iii)グレリン又はその誘導体が、配列番号1又は2に示されるアミノ酸配列を有するペプチドであり、アミノ末端から3番目のアミノ酸残基はその側鎖がn−オクタン酸によりアシル化された修飾アミノ酸残基であるペプチドであって、成長ホルモン分泌促進因子レセプター1aに対するアゴニスト作用を有するペプチドであり、
(iv)アドレノメデュリン又はその誘導体が、配列番号13に示されるアミノ酸配列を有するポリペプチドであって、血小板中のcAMPを増加させる作用か、又は血管拡張作用及び/又は降圧作用を有するポリペプチドである
医薬組成物。 - (iii)グレリン又はその誘導体及び(iv)アドレノメデュリン又はその誘導体から選択される少なくとも一種類の血管保護剤又はその薬理的に許容される塩を有効成分として含有することを特徴とする、抗癌剤及び/又は抗腫瘍剤による悪性腫瘍の転移の増悪及び/又は増大を抑制又は予防するための医薬組成物であって、
(iii)グレリン又はその誘導体が、配列番号1又は2に示されるアミノ酸配列を有するペプチドであり、アミノ末端から3番目のアミノ酸残基はその側鎖がn−オクタン酸によりアシル化された修飾アミノ酸残基であるペプチドであって、成長ホルモン分泌促進因子レセプター1aに対するアゴニスト作用を有するペプチドであり、
(iv)アドレノメデュリン又はその誘導体が、配列番号13に示されるアミノ酸配列を有するポリペプチドであって、血小板中のcAMPを増加させる作用か、又は血管拡張作用及び/又は降圧作用を有するポリペプチドである
医薬組成物。 - 悪性腫瘍の転移が、肺、骨、肝臓または脳への転移である、請求項1又は2に記載の医薬組成物。
- 悪性腫瘍の転移が、肺または肝臓への転移である、請求項3に記載の医薬組成物。
- 悪性腫瘍が、上皮系悪性腫瘍、非上皮性悪性腫瘍及びメラノーマから選択される悪性腫瘍である、請求項1〜4のいずれか1項に記載の医薬組成物。
- 悪性腫瘍が、メラノーマである、請求項5に記載の医薬組成物。
- 投与対象患者が、悪性腫瘍の切除手術を受けるか又は切除手術を受けた患者である、請求項1〜6のいずれか1項に記載の医薬組成物。
- 投与対象患者が、抗癌剤及び/又は抗腫瘍剤の投与を受けているか又は投与を受けた患者である、請求項1〜7のいずれか1項に記載の医薬組成物。
- 抗癌剤及び/又は抗腫瘍剤とともに用いられるためのものである、請求項1〜8のいずれか1項に記載の医薬組成物。
- 抗癌剤及び/又は抗腫瘍剤が白金系抗腫瘍剤である、請求項9に記載の医薬組成物。
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