JP2022553298A - 癌を処置する方法 - Google Patents
癌を処置する方法 Download PDFInfo
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- JP2022553298A JP2022553298A JP2022523392A JP2022523392A JP2022553298A JP 2022553298 A JP2022553298 A JP 2022553298A JP 2022523392 A JP2022523392 A JP 2022523392A JP 2022523392 A JP2022523392 A JP 2022523392A JP 2022553298 A JP2022553298 A JP 2022553298A
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- cancer
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- gemcitabine
- treatment
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- 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
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
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Abstract
Description
本出願は、2019年10月21日に出願された米国仮出願第62/923,629号及び第62/923,631号に対して優先権を主張する。これらの出願は、参照によりそれらの全体がここに取り込まれる。
便宜上、明細書、実施例及び付随する特許請求の範囲において採用される所定の用語をここにまとめる。ここで特に断りがない限り、本開示で採用される科学的及び技術的用語は、当業者に一般的に理解及び使用される意味を有するものとする。
本発明は、化合物の所定の組合せが癌性細胞の生存能力を低下させることがあり、したがって癌の処置に有用であるという発見に、少なくともある程度基づく。本開示の一態様は、被検体における癌を処置する方法を提供することにある。本方法は、癌の生存能力を低下させるために、抗寄生虫剤及びオートファジー阻害剤の有効量を被検体に投与するステップを含む。
本発明は、化合物の所定の組合せが、癌、特に薬物耐性癌の抗癌剤(例えば、化学療法)に対する感受性を増強し得るという発見に少なくともある程度基づく。したがって、本発明は、薬物耐性癌が処置されることを可能とするだけでなく、抗癌剤によって処置され得る癌に対してより低用量の抗癌剤が使用されることを可能とする。
本開示の更なる態様は、本方法における使用のための製剤を提供することである。いくつかの実施形態では、抗癌剤に対する癌の感受性を増強するのに適した前述の増感物質(例えば、抗寄生虫剤、オートファジー阻害剤及びHDAC阻害剤のいずれかである少なくとも2剤)が、被検体に投与するための投与量形態に製剤される。
本増感物質(すなわち、抗寄生虫剤、オートファジー阻害剤及びHDAC阻害剤からなる群から選択される少なくとも2剤)は、経口摂取に適した組成物に製剤され得る。(例えば、摂取による)経口投与に適した製剤は、カプセル、カシェ剤又はタブレットのような別個のユニットとして提示されてもよく、各々が粉末若しくは顆粒として、水性若しくは非水性液体中の溶液若しくは懸濁液として、水中油型乳濁液若しくは油中水型乳濁液として、ボーラスとして、舐剤として又はペーストとして所定量の活性化合物を含有する。
(例えば、皮膚、皮下、筋肉内、静脈内及び皮内を含む注入による)非経口投与に適した製剤は、抗酸化剤、緩衝液、防腐剤、安定剤、静菌剤、及び目的のレシピエントの血液と製剤を等張にする溶質を含有し得る水性及び非水性の等張性のパイロジェンフリーの滅菌注射溶液と、懸濁剤及び増粘剤、並びに化合物を血液成分又は1以上の器官を標的とするように設計されたリポソーム又は他のマイクロ粒子系を含み得る水性及び非水性の滅菌懸濁体とを含む。そのような製剤で使用されるのに適した等張性ビヒクルの例は、塩化ナトリウム注射液、リンゲル液又は乳酸加リンゲル液を含む。製剤は、単位用量又は複数用量の密封容器、例えば、アンプル及びバイアルで提示されてもよく、使用直前に滅菌液体担体、例えば、注射用の水の添加だけを必要とするフリーズドライ(凍結乾燥)状態で保存されてもよい。即時注入溶液及び懸濁体は、滅菌粉末、顆粒及びタブレットから調製され得る。製剤は、活性化合物を血液成分又は1以上の器官を標的とするように設計されたリポソーム又は他のナノ粒子若しくはマイクロ粒子系の形態となり得る。
膜透過製剤は、局所及び経粘膜使用に適したものであり、点眼液、スプレー、エアロゾル、クリーム、ローション、軟膏、ジェル、溶液、懸濁体、皮膚パッチなどを含むが、これに限定されない。パッチは、リザーバー型及びマトリックス型の皮膚パッチを含み、活性成分が被検体の体内に吸着されることを可能とするように、所定期間にわたって皮膚に付着し得る。
癌、特に、化学療法に非応答性である癌の処置に有用な材料を含む製品又は「キット」も、本開示内に包含する。
細胞培養及び動物
本開示で使用される細胞株は、ヒト膵臓癌細胞株BxPC-3、Mia-Paca-2/R(ゲムシタビン耐性細胞株)及びPanc-1/R(ゲムシタビン耐性細胞株)、ヒト肝癌細胞株SK-Hep-1及びHep3B並びにTMZ耐性細胞株であるヒト脳膠芽腫細胞株GBM8401を含む。細胞を10%の熱不活化ウシ胎児血清(FBS)、50単位/mLのペニシリンG、50μg/mLのストレプトマイシン(pH7.4)を添加したダルベッコ改変イーグル培地(DMEM)中で培養し、細胞を37℃で5%のCO2/95%の空気からなる加湿環境で維持した。
薬物耐性Panc-1/Gem細胞を、連続的な低用量のゲムシタビン(20μM)の存在下でPanc-1細胞を培養することによって誘導してゲムシタビンに対するそれらの耐性を発生させた。操作中、ゲムシタビン耐性Panc-1細胞(Panc-1/Gem)を、10%のウシ胎児血清(FCS)、100IU/mlのペニシリン、100μg/mlのストレプトマイシン、2mMのグルタミン及び20μMのゲムシタビンを添加したDMEM中で、5%のCO2中で37℃で維持した。
MTTアッセイは、(3-(4,5-ジメチルチアゾール-2イル)-2,5-ジフェニルテトラゾリウムブロミド(MTT)の黄色テトラゾールを紫色ホルマザンに生細胞内で還元する酵素(すなわち、レダクターゼ)の活性を測定する比色アッセイである。この還元は細胞が生存している場合にのみ起こり、よって、MTTアッセイは一般に細胞の生存能力及び増殖を査定するのに使用される。簡潔には、細胞を種々の用量の試験化合物(例えば、MB、4-PB、CQ、HCQなど)で48時間又は72時間検証した。そして、MTT色素(500μg/ml)を添加し、反応を500μlのイソプロパノールの添加によって終了させる前に4時間進行させた。溶液の570nmでの吸光度を分光光度計によって測定した。
原発性膵臓癌モデルについて、xx週齢の合計30匹のマウスを、各グループに5匹のマウスでランダムに6つのグループに分割した。実験を開始するために、各マウスに7×106個のMia-Paca-2/R細胞を皮下注射して0日目の薬物耐性膵臓癌を発生させ、そしてさらに14日間、培養に戻して腫瘍を約200mm3のサイズまで進行させた。試験化合物の有効性を評価するために、2日目に開始された処置後28日間にわたって、試験グループのマウスにゲムシタビン(50mg/Kg/用量、腹腔内投与、週1回)、MBZ(100mg/Kg/用量、経口投与、週3回)、CQ(100mg/Kg/用量、経口投与、週3回)、MBZ+CQ(経口投与、週3回)又はMBZ+CQ+ゲムシタビン(MBZ及びCQを週3回の頻度で経口投与し、注入を介してゲムシタビンを週1回投与した)を与えた。腫瘍サイズを、キャリパーを使用して測定した。各マウスの体重及び白血球数を、実験全体を通じて毎日それぞれ記録した。腫瘍体積を、体積=幅2×長さ×0.52の式を使用して計算した。
膵臓癌BxPC-3細胞、薬物耐性膵臓癌Mia-Paca-2/R細胞及び膠芽腫GBM8401細胞の細胞生存能力に対するMBZ及びHCQ/CQの併用処置の効果をMTTアッセイによって調べた。結果を図1~3に示す。
MBZ(5μM)及びHCQ(50又は100μM)の併用処置後の膵臓癌BxPC-3細胞の細胞生存能力を示す図1をまず参照する。BxPC-3細胞の細胞生存能力は、HCQ(20又は50μM)単独の処置によってわずかにしか及び/又は全く影響を受けないことが見出された。BxPC-3細胞をMBZ(5μM)の組合せで処置した場合、細胞生存能力は約60%まで低下した。驚くことに、BxPC-3細胞をMBZ(5μM)及びHCQ(50又は100μM)で同時に処置した場合、細胞生存能力は、コントロールのものと比較して、約55~38%の低いレベルまでさらに低下した。
薬物耐性膵臓癌Mia-Paca-2/R細胞の細胞生存能力に対するMBZ及びCQの併用処置の効果を調べ、結果を図3に示す。
抗癌剤(例えば、ゲムシタビン、ドキソルビシン、ソラフェニブ又はTMZ)に対する、膵臓癌BxPC-3細胞、薬物耐性膵臓癌Mia-Paca-2/R細胞、Pan-1/Gem細胞、肝細胞癌Sk-Hep-1細胞又は膠芽腫GBM8401細胞の細胞生存能力に対する本増感物質の効果をMTTアッセイによって調べた。結果を図4~9に示す。
MBZ(5μM)及びCQ(100μM)を含む本増感物質の処置後の、化学療法剤-ゲムシタビン(0.05μM)に対するBxPC-3細胞の細胞生存能力を示す図4をまず参照する。BxPC-3細胞をMBZ(5μM)及びCQ(100μM)の組合せで処置した場合、細胞生存能力は約38%まで低下することが見出された。驚くべきことに、BxPC-3細胞をMBZ(5μM)、CQ(100μM)及びゲムシタビン(0.05μM)で同時に処置した場合、MBZ及びCQの併用処置又はゲムシタビン単独の処置のものと比較して、細胞生存能力はさらに低下した(図4)。換言すると、本増感物質(すなわち、MBZ及びCQ)は、化学療法剤-ゲムシタビンに対する膵臓癌細胞の感受性を増強した。同様の結果は、薬物耐性膵臓癌Mia-Paca-2/R細胞(図5)、肝細胞癌Sk-Hep-1細胞(図6及び7)及び膠芽腫GBM8401細胞(図8A及び8B)でも見出され、各癌細胞株は、抗癌剤(例えば、ドキソルビシン、ソラフェニブ又はTMZ)の処置に対して感受性がより高くなった。
実施例2.1に記載された手順と同様に、本実施例では、ゲムシタビン耐性膵臓癌細胞(Panc-1/Gem細胞)に対するMBZ、CQ及び4-PBの処置を調べた。結果を図9に示す。
薬物耐性膵臓癌Mia-Paca-2/R細胞を移植されたマウスに対する本開示の増感物質の効果を、「材料及び方法」の章に記載されたステップに従って、移植された腫瘍体積及び腫瘍重量を測定することによって調べた。結果を図10及び11に示す。
Claims (17)
- 癌を処置するための医薬品を製造するための抗寄生虫剤及びオートファジー阻害剤の使用。
- 前記抗寄生虫剤が、アルベンダゾール、アンフォテリシンB、ベンズイミダゾール、ジエチルカルバマジン、エフロルニチン、フェバンテル、フェンベンダゾール、フルベンダゾール、フマギリン、イベルメクチン、メベンダゾール(MBZ)、メラルソプロール、メトロニダゾール、ミルテホシン、ネトビミン、ニクロサミド、ニタゾキサニド、オクスフェンダゾール、オキシフェンダゾール、オキシベンダゾール、プラジカンテル、ピランテルパモ酸塩、リファンピン、チアベンダゾール、チオファネート、チニダゾール及びトリクラベンダゾールからなる群から選択され、
前記オートファジー阻害剤が、バフィロマイシンA1、ボルテゾミブ、クロロキン(CQ)、ヒドロキシクロロキン(HCQ)、3-メチルアデニン(3-MA)及びキナクリンからなる群から選択される、請求項1に記載の使用。 - 前記癌が、膀胱癌、乳癌、脳腫瘍、結腸癌、頭頸部癌、白血病、肺癌、肝臓癌、リンパ腫、腎臓癌、メラノーマ、神経上皮腫、卵巣癌、膵臓癌、前立腺癌、直腸癌、胃癌及び子宮癌からなる群から選択される、請求項2に記載の使用。
- 前記癌が、ゲムシタビン、ドキソルビシン、ソラフェニブ及びテモゾロミド(TMZ)からなる群から選択される抗癌剤に耐性である、請求項3に記載の使用。
- 前記医薬品がヒストン脱アセチル化酵素(HDAC)阻害剤をさらに含む、請求項3又は4に記載の使用。
- 前記HDAC阻害剤が、ベリノスタット、4-フェニル酪酸(4-PB)、ロミデプシン及びボリノスタットからなる群から選択される、請求項5に記載の使用。
- 前記癌が膵臓癌であり、前記抗寄生虫剤がMBZであり、前記オートファジー阻害剤がCQ又はHCQである、請求項3に記載の使用。
- 前記癌がゲムシタビン耐性膵臓癌であり、前記抗寄生虫剤がMBZであり、前記オートファジー阻害剤がCQ又はHCQである、請求項4に記載の使用。
- 前記癌が肝臓癌であり、前記抗寄生虫剤がMBZであり、前記オートファジー阻害剤がCQ又はHCQである、請求項3に記載の使用。
- 前記癌が脳腫瘍であり、前記抗寄生虫剤がMBZであり、前記オートファジー阻害剤がCQ又はHCQである、請求項3に記載の使用。
- 前記医薬品が、ベリノスタット、4-フェニル酪酸(4-PB)、ロミデプシン及びボリノスタットからなる群から選択されるヒストン脱アセチル化酵素(HDAC)阻害剤をさらに含む、請求項7から10のいずれか一項に記載の使用。
- 前記癌がゲムシタビンに耐性である膵臓癌であり、前記抗癌剤がゲムシタビンであり、前記医薬品がMBZ、CQ及び4-PBを含む、請求項11に記載の使用。
- 抗寄生虫剤、オートファジー阻害剤及び薬学的に許容可能な賦形剤を含む、癌を処置するための薬学的組成物。
- 前記抗寄生虫剤が、アルベンダゾール、アンフォテリシンB、ベンズイミダゾール、ジエチルカルバマジン、エフロルニチン、フェバンテル、フェンベンダゾール、フルベンダゾール、フマギリン、イベルメクチン、メベンダゾール(MBZ)、メラルソプロール、メトロニダゾール、ミルテホシン、ネトビミン、ニクロサミド、ニタゾキサニド、オクスフェンダゾール、オキシフェンダゾール、オキシベンダゾール、プラジカンテル、ピランテルパモ酸塩、リファンピン、チアベンダゾール、チオファネート、チニダゾール及びトリクラベンダゾールからなる群から選択され、
前記オートファジー阻害剤が、バフィロマイシンA1、ボルテゾミブ、クロロキン(CQ)、ヒドロキシクロロキン(HCQ)、3-メチルアデニン(3-MA)及びキナクリンからなる群から選択される、請求項13に記載の薬学的組成物。 - ベリノスタット、4-フェニル酪酸(4-PB)、ロミデプシン及びボリノスタットからなる群から選択されるHDAC阻害剤をさらに含む請求項14に記載の薬学的組成物。
- 前記癌が、膀胱癌、乳癌、脳腫瘍、結腸癌、頭頸部癌、白血病、肺癌、肝臓癌、リンパ腫、腎臓癌、メラノーマ、神経上皮腫、卵巣癌、膵臓癌、前立腺癌、直腸癌、胃癌及び子宮癌からなる群から選択される、請求項13から15のいずれか一項に記載の薬学的組成物。
- 前記癌が、ゲムシタビン、ドキソルビシン、ソラフェニブ及びテモゾロミド(TMZ)からなる群から選択される抗癌剤に耐性である、請求項16に記載の使用。
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