JP2015504080A - Egfr阻害剤と組み合わせたテトラヒドロフォレート - Google Patents
Egfr阻害剤と組み合わせたテトラヒドロフォレート Download PDFInfo
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Abstract
Description
目的:大腸腺癌の異種移植モデルであるLoVoにおいて、セツキシマブと組み合わせたメチレン−THFの抗腫瘍性効力を決定すること。LoVoは、セツキシマブおよび5−FUに感受性の細胞系である。
腫瘍体積の中央値の経時的経過を図1に示す。ビヒクル群、すなわち群1の動物は、より速くエンドポイントに到達した。この図は、メチレン−THFは腫瘍成長に対して有益な効果を有し、セツキシマブの抗腫瘍効果を増強することを示す。驚いたことに、メチレン−THFの有益な効果は5−FUがなくても見られる。
それぞれの群において、エンドポイントまでの時間、すなわち1000mm3の腫瘍量または75日に達した時を示すカプラン−マイヤープロットを図2に示す。このカプラン−マイヤー曲線(エンドポイントまでの時間)は、メチレン−THFの有益な効果、メチレン−THFがセツキシマブの有益な効果を増強することを示す。ログランク検定は、ビヒクル群を除外する場合も、治療群の間に統計的に有意な差があることを示す。
体重は治療の副作用の重篤度の指標となり、体重の不十分な発達は、より有害な副作用を示す。図3に見られるように、メチレン−THFを用いた両治療群、すなわち群3および5は、よく似た体重の発達を示す。28日目以降体重の発達が最も不十分な群は、セツキシマブおよび5−FUを与えた群4であった。
腫瘍体積、すなわち腫瘍成長阻害と、体重、すなわち重篤な副作用がより少ない、の両方を考慮すると、5−FUおよびメチレン−THFと組み合わせてセツキシマブを与えた群が最も良好な成果があったように思われる。腫瘍体積を考慮すると、セツキシマブのみを与えた群は良好な成果が最も少なかったが、ビヒクルを含めた他の群よりも重量が増加した。驚いたことに、メチレン−THFは、5−FUがなくても、セツキシマブの抗腫瘍成長効果を増強する。
Claims (26)
- 成分として、
a.メチレン−テトラヒドロフォレート、テトラヒドロフォレートまたはメチル−テトラヒドロフォレートと、
b.EGFR阻害剤と
を含む、がん治療における使用のための医薬組成物。 - 前記組成物が5−フルオロウラシルと分離して投与するためのものである、請求項1に記載の使用のための医薬組成物。
- 前記組成物が5−フルオロウラシルの類似体、プロドラッグおよび/または代謝物と分離して投与するためのものである、請求項1または2に記載の使用のための医薬組成物。
- 前記5−フルオロウラシルおよび/または前記5−フルオロウラシルの類似体、プロドラッグおよび/または代謝物がFdUMPに代謝される、請求項2または3に記載の使用のための医薬組成物。
- 前記がん治療が腫瘍成長の阻害である、先行する請求項のいずれか一項に記載の使用のための医薬組成物。
- 前記がん治療が腫瘍体積の減少である、請求項1〜4のいずれか一項に記載の使用のための医薬組成物。
- 成分b)が、表1に列挙されるEGFR阻害剤、ならびにゲフィチニブ、エルロチニブおよびラパチニブ、ならびにポリクローナルもしくはモノクローナル抗体のEGFR阻害剤、たとえばセツキシマブ、パニツムマブ、ザルツムマブ、ニモツズマブおよびマツズマブまたはそれらの組み合わせから選択される、先行する請求項のいずれか一項に記載の使用のための医薬組成物。
- 成分b)がモノクローナル抗体のEGFR阻害剤である、請求項7に記載の使用のための医薬組成物。
- 成分b)がセツキシマブおよび/またはパニツムマブである、請求項8に記載の使用のための医薬組成物。
- 成分a)がメチレン−テトラヒドロフォレートである、先行する請求項のいずれか一項に記載の使用のための医薬組成物。
- 成分a)が、5−FUならびに/またはその類似体、プロドラッグおよび/もしくはその代謝物の投与前、遅くとも24時間前までに投与するためのものである、先行する請求項のいずれか一項に記載の使用のための医薬組成物。
- 成分a)が、5−FUならびに/またはその類似体、プロドラッグおよび/もしくはその代謝物の投与前、遅くとも36時間前までに投与するためのものである、請求項1〜10のいずれか一項に記載の使用のための医薬組成物。
- 成分a)が、5−FUならびに/またはその類似体、プロドラッグおよび/もしくはその代謝物の投与前、遅くとも48時間前までに投与するためのものである、請求項1〜10のいずれか一項に記載の使用のための医薬組成物。
- 成分a)が、5−FUならびに/またはその類似体、プロドラッグおよび/もしくはその代謝物を投与してから早くとも6時間で投与するためのものである、請求項1〜13のいずれか一項に記載の使用のための医薬組成物。
- 成分a)が、5−FUならびに/またはその類似体、プロドラッグおよび/もしくはその代謝物を投与してから早くとも24時間で投与するためのものである、請求項1〜13のいずれか一項に記載の使用のための医薬組成物。
- 成分a)が、5−FUならびに/またはその類似体、プロドラッグおよび/もしくはその代謝物を投与してから早くとも48時間で投与するためのものである、請求項1〜13のいずれか一項に記載の使用のための医薬組成物。
- 成分a)が、5−FUならびに/またはその類似体、プロドラッグおよび/もしくはその代謝物を投与してから早くとも1週間で投与するためのものである、請求項1〜13のいずれか一項に記載の使用のための医薬組成物。
- 成分a)が、5−FUならびに/またはその類似体、プロドラッグおよび/もしくはその代謝物を投与してから早くとも12日で投与するためのものである、請求項1〜13のいずれか一項に記載の使用のための医薬組成物。
- 前記組成物が、5−FUならびに/またはその類似体、プロドラッグおよび/もしくはその代謝物の投与前、遅くとも1週間前までに投与するためのものである、請求項1〜13のいずれか一項に記載の使用のための医薬組成物。
- 前記組成物が、5−FUならびに/またはその類似体、プロドラッグおよび/もしくはその代謝物を投与してから早くとも1週間で投与するためのものである、請求項1〜13のいずれか一項に記載の使用のための医薬組成物。
- 前記組成物が、少なくとも3カ月の期間中、5−FUおよび/またはその類似体、プロドラッグおよび/または代謝物から分離して投与するためのものである、先行する請求項のいずれか一項に記載の使用のための医薬組成物。
- 成分a)および成分b)が異なる医薬組成物に製剤化される、先行する請求項のいずれか一項に記載の使用のための医薬組成物。
- 成分a)および成分b)が共通の医薬組成物に製剤化される、請求項1〜21のいずれか一項に記載の使用のための医薬組成物。
- 成分b)がセツキシマブであり、少なくとも50mg/m2、好ましくは少なくとも100mg/m2、より好ましくは少なくとも250mg/m2、400mg/m2または500mg/m2、および最大で1000mg/m2の量で投与するためのものである、先行する請求項のいずれか一項に記載の使用のための医薬組成物。
- 成分a)が、少なくとも10mg/m2、好ましくは少なくとも20mg/m2、より好ましくは少なくとも50mg/m2、最も好ましくは少なくとも100mg/m2、200mg/m2または500mg/m2、および最大で5g/m2の量で投与するためのものである、先行する請求項のいずれか一項に記載の使用のための医薬組成物。
- 前記がんが、乳がん、胃がん、胃腸がん、胆嚢がん、胆管がん、結腸がん、直腸がん、肝臓がん、膵臓がん、頭頸部がん、食道がん、中皮腫がん、非小細胞肺がんを含めた肺がん、卵巣がん、子宮内膜がん、子宮頸がん、末梢T細胞リンパ腫(PTCL)、黒色腫、脳腫瘍、腺癌、食道がんおよび骨肉腫から選択される、先行する請求項のいずれか一項に記載の使用のための医薬組成物。
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EP3446704A1 (en) * | 2017-08-24 | 2019-02-27 | Isofol Medical AB | [6r]-mthf - an efficient folate alternative in 5-fluorouracil based chemotherapy |
EP3848036A3 (en) | 2017-02-14 | 2021-08-18 | Isofol Medical AB | Methods for increasing blood plasma 2'-deoxyuridine (durd) and thymidylate synthase inhibition |
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NZ626271A (en) | 2016-07-29 |
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