JP2012144512A - 脳腫瘍を治療するための医薬組成物又は脳腫瘍細胞のテモゾロミド耐性を低減させるための医薬組成物、及びその使用 - Google Patents
脳腫瘍を治療するための医薬組成物又は脳腫瘍細胞のテモゾロミド耐性を低減させるための医薬組成物、及びその使用 Download PDFInfo
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- JP2012144512A JP2012144512A JP2011144450A JP2011144450A JP2012144512A JP 2012144512 A JP2012144512 A JP 2012144512A JP 2011144450 A JP2011144450 A JP 2011144450A JP 2011144450 A JP2011144450 A JP 2011144450A JP 2012144512 A JP2012144512 A JP 2012144512A
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- JP
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- Prior art keywords
- temozolomide
- butylidenephthalide
- pharmaceutical composition
- brain tumor
- pharmaceutically acceptable
- 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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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
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- General Chemical & Material Sciences (AREA)
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- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Furan Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
【解決手段】薬剤的に許容可能なキャリアと、化学式(I)の(Z)−ブチリデンフタリド、(Z)−ブチリデンフタリドの薬剤的に許容可能な塩、(Z)−ブチリデンフタリドの薬剤的に許容可能なエステル、及びこれらの組み合わせからなる群より選択された有効量の活性成分と、を含む、脳腫瘍を治療するための医薬組成物、又は脳腫瘍細胞のテモゾロミド耐性を低減させるための医薬組成物。
【選択図】なし
Description
直径10cmのペトリ皿で、脳腫瘍細胞株8401,8901,DBTRG,U87MG,及びG5T/VGHを各々培養した。皿の60%の容量まで細胞が増殖した後、リン酸緩衝生理食塩水(PBS)溶液を用いて細胞を洗浄した。最後に、細胞と細胞内タンパク質を収集した。ドデシル硫酸ナトリウム−ポリアクリルアミドゲル電気泳動(SDS−PAGE)及びウェスタンブロッティングを用いて、各々の脳腫瘍細胞株におけるMGMTタンパク質の発現を分析した。結果を図1に示す。
MTT(3−[4,5−ジメチルチアゾール−2−イル]−2,4−ジフェニルテトラゾリウムブロミド)細胞生存試験を用いて、テモゾロミドの種々の脳腫瘍細胞株に対する死亡率効果を検討した(Pauwels et al.,J.Virol.Methods,1988,20,309−321を参照、この内容は参照により本明細書に取り込まれる)。
この実験では、脳腫瘍細胞における(Z)−ブチリデンフタリド及び(E)−ブチリデンフタリドのMGMT発現抑制効果を示した。
(Z)−ブチリデンフタリドがテモゾロミドの脳腫瘍細胞に対する細胞毒性感受性を亢進させるかについて、MTT細胞生存アッセイを用いて試験した。
実施例4での実験工程を繰り返した。ただし、脳腫瘍細胞株はテモゾロミド耐性を有するGBM22−TMZに変更した。(Z)−ブチリデンフタリド濃度を0〜600μM(200μL)に変更する一方で、テモゾロミド濃度を0〜3200μM(200μL)に変更した。結果を図7に示す。
MTT細胞生存アッセイを用いて、(Z)−ブチリデンフタリド及び(E)−ブチリデンフタリドの抗脳腫瘍活性を試験した。
実施例6での実験工程を繰り返した。ただし、腫瘍細胞株を腫瘍細胞株DBTRG,8401,8901,及びG5T/VGHに置き換えた。(Z)−ブチリデンフタリド濃度を0〜400μM(200μL)に変更した。結果を図10に示す。
MTT細胞生存アッセイを用いて、異なる濃度の(Z)−ブチリデンフタリドとテモゾロミドとの組み合わせの抗脳腫瘍細胞活性について試験した。(Z)−ブチリデンフタリドとテモゾロミドとの間で相乗効果があるかについて、コンビネーションインデックス(combination index)(CI)を用いて分析した。
皮下腫瘍移植モデルによりin vivo試験を行い、in vivoでの(Z)−ブチリデンフタリド、テモゾロミド、又はそれらの組み合わせの抗腫瘍活性を評価した。
(Z)−ブチリデンフタリド及びポリ(乳酸−グリコール酸供重合体)(p(CPP−co−SA))を物理的手法により均一に混合した。得られた混合粉末を直径1〜13mmの円形の型に置き、プレスして厚さ1〜2mmの円形ウエハー(又は錠剤)に成型した。ジクロロメタン(10% w/v)を用いてテモゾロミド及びp(CPP−co−SA)を混合し、その後真空ポンプでジクロロメタンを蒸発させた。最後に、得られた粉末を円形のウエハー(又は錠剤)を成型するようにプレスして、テモゾロミドのウエハーを調製した。
生存分析を行ってin vivoでの(Z)−ブチリデンフタリド及びテモゾロミドの組み合わせによる抗グリオーマ効果について評価した。脳腫瘍細胞株GBM22−TMZ由来の膠芽細胞腫の同所性異種移植片が定着しているマウスをランダム化して、示されているテモゾロミド(66mg/kg/日;5日間)、(Z)−ブチリデンフタリド(50又は100mg/kg/日;5日間)、又はこれらの組み合わせでの治療を行った。マウスが瀕死状態に至るまで観察及び記録を行い、生存結果をカプラン−マイヤー生存曲線で示す。生存率を表8に示す。
本出願は、台湾特許出願100100673(出願日2011年1月7日)に基づく優先権を主張しており、その内容は本明細書に参照として取り込まれる。
Claims (13)
- 薬剤的に許容可能なキャリアと、
化学式(I)の(Z)−ブチリデンフタリド、(Z)−ブチリデンフタリドの薬剤的に許容可能な塩、(Z)−ブチリデンフタリドの薬剤的に許容可能なエステル、及びこれらの組み合わせからなる群より選択された有効量の活性成分と、
を含む、脳腫瘍細胞のテモゾロミド耐性を低減させるための医薬組成物。
- 前記活性成分が、(Z)−ブチリデンフタリドである、
ことを特徴とする請求項1に記載の医薬組成物。 - 前記脳腫瘍細胞が、ヒト悪性神経膠腫である、
ことを特徴とする請求項1又は2に記載の医薬組成物。 - テモゾロミドのテモゾロミド耐性脳腫瘍細胞に対する細胞毒性感受性を亢進させるために用いられる、請求項1乃至3のいずれか1項に記載の医薬組成物。
- 薬剤的に許容可能なキャリアと、
化学式(I)の(Z)−ブチリデンフタリド、(Z)−ブチリデンフタリドの薬剤的に許容可能な塩、(Z)−ブチリデンフタリドの薬剤的に許容可能なエステル、及びこれらの組み合わせからなる群より選択された有効量の活性成分と、
を含む、脳腫瘍を治療するための医薬組成物。
- テモゾロミド、テモゾロミドの水和物、テモゾロミドのアイソスター、テモゾロミドの薬剤的に許容可能な塩、及びこれらの組み合わせからなる群より選択された有効量の抗腫瘍成分をさらに含む、請求項5に記載の医薬組成物。
- 前記抗腫瘍成分が、テモゾロミドである、
ことを特徴とする請求項6に記載の医薬組成物。 - テモゾロミドと前記活性成分とが組み合わされて1未満のコンビネーションインデックス(combination index)をもたらす、
ことを特徴とする請求項7に記載の医薬組成物。 - 前記活性成分((Z)−ブチリデンフタリドとして)の用量が1日約30mg/kg−体重から約500mg/kg−体重であり、テモゾロミドの用量が1日約10mg/kg−体重から約100mg/kg−体重である、
ことを特徴とする請求項7に記載の医薬組成物。 - 前記活性成分((Z)−ブチリデンフタリドとして)の用量が1日約40mg/kg−体重から約120mg/kg−体重であり、テモゾロミドの用量が1日約40mg/kg−体重から約80mg/kg−体重である、
ことを特徴とする請求項9に記載の医薬組成物。 - 前記脳腫瘍が、ヒト悪性神経膠腫である、
ことを特徴とする請求項5乃至10のいずれか1項に記載の医薬組成物。 - 前記活性成分及び前記抗腫瘍成分が一緒に、別々に、又は引き続いて投与される、
ことを特徴とする請求項6乃至11のいずれか1項に記載の医薬組成物。 - 前記活性成分が、(Z)−ブチリデンフタリドである、
ことを特徴とする請求項5乃至12のいずれか1項に記載の医薬組成物。
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