JP6234553B2 - 抗癌剤および副作用軽減剤 - Google Patents
抗癌剤および副作用軽減剤 Download PDFInfo
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- JP6234553B2 JP6234553B2 JP2016512802A JP2016512802A JP6234553B2 JP 6234553 B2 JP6234553 B2 JP 6234553B2 JP 2016512802 A JP2016512802 A JP 2016512802A JP 2016512802 A JP2016512802 A JP 2016512802A JP 6234553 B2 JP6234553 B2 JP 6234553B2
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Description
本発明の抗癌剤は、有効成分として、アルクチゲニンと、アルクチゲニン以外の抗癌作用を有する成分とを組み合わせたものである。換言すれば、本発明の抗癌剤は、有効成分として、アルクチゲニン以外の抗癌作用を有する成分と、当該成分の腫瘍組織への薬剤送達の増強剤としてのアルクチゲニンとを組み合わせたものである。すなわち、本発明の抗癌剤は、アルクチゲニンと抗癌作用を有する成分とを併用して投与する併用剤である。
本発明は、アルクチゲニンを有効成分として含有する、アルクチゲニン以外の抗癌作用を有する成分と組み合わせて併用投与するための製剤をも包含する。本発明の製剤は、上述した抗癌剤において説明したアルクチゲニンを含む製剤と同様の構成であることができる。この製剤は、たとえば上述した抗癌剤の一部として使用することが可能である。
本発明はまた、アルクチゲニン以外の抗癌作用を有する成分による副作用を軽減するための副作用軽減剤をも包含する。本発明の副作用軽減剤は、アルクチゲニンを有効成分として含有する。本発明の副作用軽減剤は、上述した抗癌剤において説明したアルクチゲニンを含む製剤と同様の製剤形態、用量および投与方法であることができる。また、本発明の副作用軽減剤は、抗癌作用を有する成分と混合されて配合剤を構成してもよい。
本発明はまた、腫瘍内の血管を正常化する、腫瘍内血管正常化剤をも包含する。
本発明はまた、アルクチゲニン以外の抗癌作用を有する成分の腫瘍組織への薬剤送達の増強剤をも包含する。
本発明はまた、癌を治療、改善または予防する方法をも包含する。本発明の癌を治療、改善または予防する方法は、アルクチゲニンの有効量と、アルクチゲニン以外の抗癌作用を有する成分の有効量とを組み合わせて対象に投与する工程を含む。
本発明の抗癌剤、製剤および副作用軽減剤に適したゴボウシ抽出物は、生薬切裁工程、抽出工程(酵素変換工程および有機溶媒による抽出工程)、固液分離工程、濃縮工程および乾燥工程を経て製造される。
生薬切裁工程では、原料とするゴボウシを抽出に適した大きさに切裁する。原料となる生薬は、植物の様々な部位や鉱物、動物など種々の大きさ、形状、固さがあり、その特質に応じた切裁が必要となる。ゴボウシは、当業者に公知の任意の手段を使用して切裁することができる。たとえば、市販の切裁機を使用することができる。
抽出工程は、生薬抽出物粉末製造工程中で、品質上最も重要な工程である。この抽出工程により、生薬抽出物粉末の品質が決まる。本発明の抗癌剤に用いるのに適したゴボウシ抽出物の製造方法では、ゴボウシ抽出物を抽出するために、酵素変換工程と有機溶媒による抽出工程の2段階に分けて抽出を行う。
酵素変換工程は、本発明に適したゴボウシ抽出物の製造方法において重要な工程である。酵素変換工程は、ゴボウシに内在する酵素であるβ-グルコシダーゼにより、ゴボウシに含まれているアルクチインをアルクチゲニンに酵素変換する工程である。
有機溶媒による抽出工程は、任意の適切な有機溶媒を使用して、ゴボウシからアルクチゲニンおよびアルクチインを抽出する工程である。すなわち、上記の酵素変換工程によりアルクチゲニンが高含量となった状態で、適切な溶媒を添加して、ゴボウシ抽出物を抽出する工程である。たとえば、ゴボウシ抽出物に適切な溶媒を添加して、適切な時間加熱攪拌してゴボウシ抽出物を抽出する。また、加熱攪拌以外にも、加熱還流、ドリップ式抽出、浸漬式抽出または加圧式抽出法などの当業者に公知の任意の抽出法を使用して、ゴボウシ抽出物を抽出することができる。
固液分離工程は、抽出の終わったゴボウシを抽出液から分離する工程である。固液分離は、当業者に公知の任意の方法を使用して行うことができる。固液分離法には、たとえば濾過法、沈降法および遠心分離法などがある。工業的には、遠心分離法が望ましい。
濃縮工程は、乾燥に先立ちゴボウシ抽出液から溶媒を除去する工程である。ゴボウシ抽出液からの溶媒の除去は、当業者に公知の任意の方法を使用して行うことができる。しかし、上記工程によって得られたゴボウシからの抽出液が、さらに高温に長時間曝されることがないようにすることが好ましい。たとえば、減圧濃縮法を使用することにより、高温に長時間曝されることなく、ゴボウシ抽出液を濃縮することができる。
上記工程によって得られたゴボウシ抽出物を粉末状に仕上げる工程である。乾燥は、当業者に公知の任意の方法を使用して行うことができる。たとえば、乾燥法として、凍結乾燥および噴霧乾燥などが知られているが、実験室レベルであれば前者、量産レベルであれば後者を用いるのが一般的である。
以下の方法により、アルクチゲニンを含有するゴボウシエキスを調製した。
アルクチゲニン含有ゴボウシエキス、ベバシズマブおよびゲムシタビンの反復投与による腫瘍内の血流を評価した。ベバシズマブとして、アバスチンを用いた。
治療開始4週間後の各群の平均腫瘍サイズは、(a)未治療群が228mm2、(b)ゴボウシエキス投与群が189mm2、(c)ベバシズマブ投与群が56mm2、および(d)ゲムシタビン投与群が68mm2であった。
治療開始4週間後に、各群のマウス腫瘍組織におけるガドリニウムDTPAの取り込みを評価した。ガドリニウムDTPAを急速静注した後120秒まで、9.4テスラMRI装置(BIOSPEC 94/20USR)を用いて、腫瘍のダイナミック造影T1強調画像(時間分解能1.8-5.3秒)を撮影した。この画像から、腫瘍組織内のガドリニウムDTPAのシグナル強度を測定した。図1は、ガドリニウムDTPA静注後0秒のシグナル強度を100としたときの、30秒ごとのシグナル強度の平均値を示すグラフである。腫瘍組織内のガドリニウムDTPAのシグナル強度の増加は、腫瘍組織内へのガドリニウムDTPAの取り込みを意味する。腫瘍組織内へのガドリニウムDTPAの取り込みの度合いは、腫瘍組織内の血流状態の指標となる。
図1に示すように、ガドリニウムDTPA静注後90〜120秒において、ゴボウシエキス投与群における治療後の腫瘍組織中心部のシグナル強度は、118.1 ± 13.7%まで増加した。一方、未治療群では、90〜120秒において102.6 ± 3.4%であり、増加しなかった。したがって、ゴボウシエキス投与群では、未治療群と比較して血流が良い傾向であった(P <0.05, t-test)。また、抗腫瘍効果が見られたゲムシタビン治療群では、未治療群と同様に腫瘍組織中心部のシグナル強度が増加していなかった。一方、血管新生阻害作用を持つベバシズマブ治療群では、シグナル強度が増加する傾向にあった。
腫瘍が増大する過程においては、増大した腫瘍組織全体にわたって栄養や酸素が血管を通して供給されていなければならない。しかしながら、多くの腫瘍においては、未熟な血管形成のため、これらが十分に供給されておらず、部分的な組織壊死を起こし、組織が潰瘍状になる部位が発生すると考えられている。そこで、前述のゴボウシエキスの腫瘍内血流正常化効果を組織状態から検証するため、それぞれの治療後の腫瘍組織における潰瘍形成を観察した。
5週間にわたり、腫瘍組織に対し、ゴボウシエキスの単独投与、ベバシズマブの単独投与およびゴボウシエキスとベバシズマブの併用投与を実施した。未治療群(Control)およびそれぞれの投与群について、腫瘍に潰瘍を生じたマウスの比率(%)を図2に示す。図2に示すように、50%潰瘍形成率は、未治療群が8日、ゴボウシエキス投与群が20日、ベバシズマブ投与群が10日、併用投与群が24日であった。したがって、ゴボウシエキス投与群および併用投与群では、未治療群およびベバシズマブ投与群と比較して、腫瘍における潰瘍形成の抑制効果が認められた。ベバシズマブ投与群では、未治療群と比較して潰瘍形成の抑制効果が認められたが、一過性であった。この効果は、ベバシズマブの持つ血管新生阻害作用による効果と考えられる。一方、ベバシズマブに加えてゴボウシエキスを併用投与した場合、潰瘍形成の阻害が増強された。これは、ベバシズマブ単剤での腫瘍に対する血流改善効果に対して、ゴボウシエキス治療による低酸素・低栄養領域の形成抑制と血管新生抑制による血流改善効果が、併用増強されたためであると考えられる。このように、アルクチゲニンとの併用投与により、低酸素および低栄養状態にある領域を顕著に縮小することができるため、癌の悪性化を抑制することが期待される。
上述した治療を5週間継続した後に、治療を中止し、生存期間の追跡を実施した。各群における生存率を図3に示した。その結果、50%生存期間は、図3に示すように未治療群が103日、ゴボウシエキス投与群が114日、ベバシズマブ投与群が107日、併用投与群が137日であった。したがって、併用投与群では、未治療群および単独投与群と比較して、それぞれ33%および20-28%の生存期間延長効果が認められた。
ゴボウシエキスおよびゲムシタビンの併用投与による抗腫瘍効果を調べた。
ヒト膵臓癌細胞Miapaca-2(ATCC CRL 1420)5×106 Cells/200μlを、BALB/cAJcl nu/nuマウス(日本クレア)の脇下皮下に移植した。その後、約2〜3週間飼育し、100mm3程度になったものを選別し、治療対象マウスとした。
治療対象マウスを、(a)未治療群、(b)ゲムシタビン投与群、(c)ゴボウシエキス投与群、並びに(d)ゴボウシエキスおよびゲムシタビンを併用して投与する群(併用投与群)、の4つの群に分け、4週間治療を継続した。ゴボウシエキスは、実施例1のゴボウシエキスの250mg/kg(アルクチゲニンとして25mg/kg以上)を連日(週5回)、経口投与した。ゲムシタビンは、点滴用ゲムシタビン製剤(イーライリリー社)を使用して、150mg/kgを週2回、腹腔内投与した。
治療試験後、各投与群について腫瘍重量を測定した。その結果、治療試験後の腫瘍重量は、未治療群では2.05g、ゲムシタビン投与群では1.24g、ゴボウシエキス投与群では0.98g、および併用投与群では0.82gであった。したがって、ゲムシタビン投与群、ゴボウシエキス投与群および併用投与群のいずれにおいても、未治療群と比較して、40〜60%程度の腫瘍重量の抑制が認められた。
治療試験後の腫瘍組織から癌細胞を回収し、CD24、CD44およびESA(CD326)の3重陽性マーカー並びにCD133およびCD44の2重陽性マーカーを使用して、治療試験後の腫瘍内のCD44+, CD24+, CD326+細胞(3重陽性)およびCD133+, CD44+細胞(2重陽性)の比率を評価した。評価には、FACS ARIA IIフローサイトメーター(BD bioscience)を用いた。CD44+, CD24+, CD326+細胞(3重陽性)は、腫瘍内の癌幹細胞のうち、造腫瘍能に優れた癌幹細胞であり、CD133+, CD44+細胞(2重陽性)は、極めて転移性の高い癌幹細胞である。比率は、腫瘍内に存在する細胞をTruStain fcX(mouse, biolegend)で処理後、死細胞をSytox-Red(Invitrogen)で除き、また、マウス由来の細胞をmouse lineage cocktail(biolegend), anti-H2-Kd(biolegend)で除き、残った2.5X104の膵臓癌細胞における比率とした。
膵臓癌の診断後の5年生存率は2013年時点で5%を切っており、またその平均生存時間は、4-6ヶ月に止まっている。これは他の癌に比べて極端に低い数値であり、有効な対策が求められている。上述した実施例3において、膵臓腫瘍移植モデルに対するアルクチゲニン高含有ゴボウシエキスとゲムシタビンとの併用治療により、単剤治療に比べて腫瘍の増大抑制傾向が認められた。そこで、より実際の病巣に近いモデルとして、マウス膵臓への膵臓癌同所移植モデルを作製し、ゲムシタビンおよびゴボウシエキスによる併用治療が生存率に与える影響を評価した。
ヒト膵臓癌細胞Miapaca-2細胞を5×106cells/50μlにて高濃度マトリゲル溶液(BD bioscience)に懸濁した。8週齢、メスのBALB/cAJcl-nu/nu(日本クレア)を麻酔下に開腹し、上記細胞懸濁液を膵臓組織へ注入および固化させた後、縫合・閉腹した。
移植後のマウスを、未治療群(Non treat)、10%アルクチゲニンを含むゴボウシエキス(クラシエ製薬、GBS-01)250mg/kgを連日経口投与する群(GBS-01)、150mg/kgのゲムシタビン(イーライリリー社)を週2回腹腔投与する群(Gemcitabine)、およびこれらを併用投与する群(Combination)の4群各7匹に分け、マウスがすべて死亡するまで治療を継続した。
生存率は、Kaplan-Mayer法を使って生存率曲線および生存率中央値MSTを計算および描出することにより算出した(GraphPad-PRISM 6.2, MDF社)。有意差は、Logrank(Mantel-COX)およびGehan-Breslow-Wilcoxon検定で評価した。算出した結果を図5の上のグラフに示した。
癌細胞に対して様々な機序で傷害作用を持つ種々の薬剤について、ゴボウシ由来のアルクチゲニンと併用投与したときの、薬剤の殺傷効果の増強作用を検討した。
膵臓癌移植モデルを用いて、既存の各種抗癌剤、アルクチゲニン高含有ゴボウシエキスおよびこれらの組み合わせによる治療を行い、腫瘍サイズの変動を評価した。
5×106 Cells/200μlのMiapaca-2細胞をBALB/cAJcl-nu/nuマウス(日本クレア)の脇下皮下に移植し、約2週間飼育後、約100mm3または約600mm3程度のサイズになったものを、治療対象マウスとした。
作製した移植マウスを、未治療群、各種の抗癌作用を有する成分である既存抗癌剤投与群、ゴボウシエキス投与群およびこれらの併用投与群の各群に分け、各群の5〜6腫瘍に対して、約4週間程度にわたって治療を継続した。既存抗癌剤としては、カルボプラチン(CBDCA、Bristol-Myers、60mg/kgを週1回腹腔投与)、ドキソルビシン(Doxorubicin、協和発酵、10mg/kgを週2回腹腔投与)、オキサリプラチン(Oxaliplatin、ヤクルト、8mg/kgを週1回腹腔投与)、エベロリムス(Everolimus、ノバルティス、5mg/kgを週5回経口投与)、ボルテゾミブ(Bortezomib、ヤンセンファーマ、1mg/kgを週2回腹腔投与)、イリノテカン(Irinotecan、ヤクルト、25mg/kgを週2回腹腔投与)およびヒドロキシクロロキン(Hydroxychloroquine、サノフィー、100mg/kgを週5回腹腔投与)を用いた。ゴボウシエキスは、10%アルクチゲニンを含むゴボウシエキス(クラシエ製薬、GBS-01)を用い、750mg/kgを週5日経口投与した。
治療開始後、3-4日毎に、マウスを保定して精密デジタルノギスで腫瘍の長径(L)、短径(W)および高さ(H)を測定し、腫瘍サイズ= 4/3 * pi * L/2 * H/2 * W/2 (pi=3.14)の式を用いてサイズを求めた。また、高さが測定できない場合は、簡易的に、腫瘍サイズ = 4/3 * pi * L/2 * (W/2)2を使用した。測定結果を図6に示した。
アルクチゲニン高含有ゴボウシエキスおよびベバシズマブの併用治療による大腸癌に対する効果を調べた。ベバシズマブとして、アバスチンを用いた。
ヒト大腸癌細胞LS174T(ATCC. CL-188)の5×105細胞をBALB/cAJc1-nu/nuマウス(日本クレア)の皮下に移植した。移植14日目に、移植マウスを、(a)未治療群、(b)ベバシズマブ投与群、(c)ゴボウシエキス投与群、並びに(d)ゴボウシエキスおよびベバシズマブを併用して投与する群(併用投与群)、の4つの群に分け、4週間治療を継続した。ゴボウシエキスを投与する場合は、実施例1のゴボウシエキスの250mg/kg(アルクチゲニンとして25mg/kg)を週6回、経口投与した。ベバシズマブは、アバスチン点滴静注用100mg/4ml(中外製薬)を使用して、5mg/kgを週1回、腹腔内投与した。
治療試験後、各投与群について腫瘍重量を測定した。その結果、治療試験後の腫瘍重量は、未治療群では2.51g、ベバシズマブ投与群では1.33g、ゴボウシエキス投与群では1.25g、および併用投与群では0.68gであった。したがって、ベバシズマブ投与群、ゴボウシエキス投与群および併用投与群のいずれにおいても、未治療群と比較して、腫瘍重量増大の抑制が認められた。また、併用投与群では、単独で投与した場合と比較して、腫瘍重量増大がより強く抑制された。
次いで、腫瘍組織から癌細胞を回収し、CD133およびCD44の2重陽性マーカーを使用して、治療試験後の腫瘍内のCD133+, CD44+細胞の比率をFACS ARIA IIフローサイトメーター(BD bioscience)を使用して評価した。また、比率は、腫瘍内に存在する細胞をTruStain fcX(mouse, biolegend)で処理後、死細胞をSytox-Red(Invitrogen)で除き、また、マウス由来の細胞をmouse lineage cocktail(biolegend), anti-H2-Kd(biolegend)で除き、残った2.5X104の膵臓癌細胞における比率とした。
ゴボウシエキスおよびゲムシタビンの併用反復投与による毒性試験を行った。
Claims (2)
- アルクチゲニンを有効成分として含有する、ゲムシタビンによる副作用を軽減するための副作用軽減剤であって、
前記副作用は、肝障害である、副作用軽減剤。 - 前記アルクチゲニンがゴボウシ抽出物として含有される、請求項1に記載の副作用軽減剤。
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