JP5461200B2 - 抗がん剤感受性判定マーカー - Google Patents
抗がん剤感受性判定マーカー Download PDFInfo
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- JP5461200B2 JP5461200B2 JP2009551436A JP2009551436A JP5461200B2 JP 5461200 B2 JP5461200 B2 JP 5461200B2 JP 2009551436 A JP2009551436 A JP 2009551436A JP 2009551436 A JP2009551436 A JP 2009551436A JP 5461200 B2 JP5461200 B2 JP 5461200B2
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- Prior art keywords
- cancer
- dimethylglycine
- phenylalanine
- cpt
- sensitivity
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Description
進行性・転移大腸癌に対する化学療法は、1990年代に登場したCPT−11、オキサリプラチンなどのkey drugと、それまで大腸癌治療の中心的薬剤であったフルオロウラシル(5−FU)を中心とするフッ化ピリミジン製剤とを併用することにより、生存率をはじめとする臨床成績が劇的に改善された。しかしそれでもなお奏効率はおよそ50%程度であり、重篤な副作用という高リスクを冒して抗がん剤が投与された患者の半分では効果が得られていないのが現状であり、個々の治療反応性(レスポンダー・ノンレスポンダー)を判別する抗がん剤感受性予測マーカーの確立は急務である。
一般的に、がん化学療法の治療スケジュールは長期に渡り、副作用の発現を見ながら何クールか繰り返し治療を行った後で、効果が得られているか、そのまま投与を続けるべきか判断するが、それまでには長い時間と高額な医療費がかかり、副作用の発現も起こっているのが事実である。よって、個々の患者に対し、効果が得られるかどうかを治療早期に予測できる手段があれば、患者の負担や副作用の発現を軽減し、医療費を削減することができる。
重篤な下痢や好中球減少症などの副作用は、UGT1A1遺伝多型がもたらすSN−38体内曝露量の変化が一因であることが示されている。しかし治療効果に関しては、プロドラッグであるCPT−11から活性代謝物SN−38への変換とその解毒、さらに腸管循環の過程におけるSN−38の再生成や、CPT−11自体の代謝と代謝物からのSN−38の生成といった体内動態の複雑性により、薬物動態により治療効果を予測できるとする報告は未だなされていない。末梢血単核球細胞のカルボキシルエステラーゼmRNA発現量がSN−38とSN−38GのAUC比とは相関するものの腫瘍縮小効果とは相関がなかったとする報告もなされている(非特許文献8)。
また、本発明は、検体中のL−フェニルアラニン及び/又はN,N−ジメチルグリシンが関与する代謝系上の物質を測定することを特徴とする抗がん剤感受性の判定方法を提供するものである。
また、本発明は、検体中のL−フェニルアラニン及び/又はN,N−ジメチルグリシンが関与する代謝系上の物質を測定するためのプロトコールを含むことを特徴とする抗がん剤感受性の判定方法を実施するためのキットを提供するものである。
さらに本発明は、L−フェニルアラニン及び/又はN,N−ジメチルグリシンが関与する代謝系上の物質の発現抑制を指標とする抗がん剤感受性亢進剤のスクリーニング方法を提供するものである。
さらにまた本発明は、上記のスクリーニング方法により得られた抗がん剤感受性亢進剤を提供するものである。
さらに本発明は、上記の抗がん剤感受性亢進剤と、感受性亢進の対象となる抗がん剤とを組み合せてなるがん治療用組成物を提供するものである。
さらに本発明は、上記の抗がん剤感受性亢進剤と、感受性亢進の対象となる抗がん剤との組み合せの、がん治療薬製造のための使用を提供するものである。
さらに本発明は、上記の抗がん剤感受性亢進剤と、感受性亢進の対象となる抗がん剤とを投与することを特徴とするがん治療方法を提供するものである。
また、抗がん剤投与前あるいは投与後初期の段階において、L−フェニルアラニン及び/又はN,N−ジメチルグリシン代謝系物質の濃度が所定の標準濃度より高いと判断される濃度を有する場合は、そのがんは対象とする抗がん剤に対して感受性ではないと判定できる。対象とする抗がん剤に対して感受性を有さない場合は、その薬効を期待することができず、このような薬効の期待できない抗がん剤の投与が続けられた場合、がんの進行、副作用の増大が危惧される。このように、本発明における抗がん剤感受性判定マーカーは、抗がん剤治療反応性の判定のみならず、薬効の期待できない抗がん剤の継続投与に伴う副作用の増大を防ぐことにも大きく貢献する。
(1)方法
(a)動物
日本クレア社から購入したヌードマウス(BALB/cAJcl−nu/nu)、6週齢の雄性マウスを使用し、恒温室で自由に摂食可能な状態で通常の餌と飲水を与えた。本検討は慶應義塾大学医学部動物実験ガイドラインに沿ったプロトコルを申請し、承認を得て愛護的に行った。
(b)ヒト培養大腸癌細胞
SN−38高感受性であるヒト培養大腸癌細胞HCT−116とSN−38低感受性であるヒト培養大腸癌細胞HT−29は、株式会社ヤクルト本社より入手した。
(c)薬剤
CPT−11の製剤であるカンプトTMとカンプト溶解剤は、株式会社ヤクルト本社より入手した。
6週齢のヌードマウスの後背部に、SN−38低感受性であるヒト培養大腸癌細胞HT−29とSN−38高感受性であるヒト培養大腸癌細胞HCT−116を200万個/100μL/マウスで皮下移植した。移植後、腫瘍サイズを長径×短径2/2の式を用いて測定し、腫瘍サイズが300−400mm3となった時点でCPT−11投与群と溶解剤投与群に無作為に割り付け、day0とし、CPT−11投与群には、CPT−11の製剤であるカンプトTMを4.5mL/kg(CPT−11量として90mg/kg)、CPT−11非投与群としては、カンプトTMの溶解剤(D−ソルビトール、乳酸、pH調節剤)を尾静脈より、緩徐に投与した。day0、投与12時間後、24時間後、72時間後、7日後に腫瘍サイズを測定し、解剖後採血を行った。採取した血液は、10,000rpmにて10分間遠心分離後、血清画分を液体窒素にて凍結し、メタボローム用サンプルの調製に使用するまで−80℃で保存した。コントロール群として癌細胞非移植群も作製し、同様の処置を施した。
マウス解剖後−80℃で保存してある血清に、内部標準物質(IS)を添加したメタノール溶液を加え、タンパク質を変性させた後、クロロホルムとミリQ水を加え液―液抽出を行い、夾雑成分を除去した。代謝物を含む水―メタノール層を採取し、分画分子量5000kDaの遠心限外ろ過フィルターを用いて除タンパクを行った後、ろ液を減圧乾燥し、−80℃に保存した。測定直前にミリQ水に溶解させ、メタボローム測定に供した。
血清中代謝物の網羅的測定はAgilent Technologies社のキャピラリー電気泳動―飛行時間型質量分析計(CE−TOFMS)にて行った。本検討では、キャピラリーの出口が陰極となるように電圧を印加し、陽イオン性の代謝物を網羅的に測定した。
得られたピークは、ピーク自動抽出ソフトであるMolecular Feature Extratcor(Agilent technologies,Inc.)を用いて、m/z 50−1000、RT 0−50分、S/N比2以上の条件でピークを自動抽出させ、Microsoft excelTM上にて横軸にm/z、縦軸にピーク強度のIS ratioをプロットさせた。解析方法としては、Microsoft excelTM上に横軸m/zを細かくプロットし、一つずつピークの発現量の差を確認して行った。
ヌードマウスの後背部に、SN−38高感受性であるヒト培養大腸癌細胞HCT−116とSN−38低感受性であるヒト培養大腸癌細胞HT−29を移植した後、腫瘍サイズを、長径×短径2/2の式を用いて測定を行った。腫瘍サイズが300−400mm3となった時点でCPT−11投与群と溶解剤投与群に無作為に割り付け、day0と投与12時間後、24時間後、72時間後、及び7日後の腫瘍サイズを測定し、その結果を図1に示した。投与後7日後において、SN−38高感受性であるヒト培養大腸癌細胞HCT−116を移植し、CPT−11を投与した群と、溶解剤を投与した群において有意な差が認められた(p=0.01319)。また、SN−38高感受性であるヒト培養大腸癌細胞HCT−116を移植し、CPT−11を投与した群と、SN−38低感受性であるヒト培養大腸癌細胞HT−29を移植し、CPT−11を投与した群においても有意な差が認められた(p=0.04979)。よって、本検討で使用したヒト培養大腸癌細胞HCT−116はヒト培養大腸癌細胞HT−29と比較して、CPT−11に対する感受性が高く、逆に、ヒト培養大腸癌細胞HT−29はヒト培養大腸癌細胞HCT−116と比較して、CPT−11に対する感受性が低いことを確認することができた。
Claims (6)
- L−フェニルアラニン及び/又はN,N−ジメチルグリシンからなる、イリノテカン、SN−38及びそれらの塩から選ばれる抗がん剤の大腸がん感受性判定マーカー。
- イリノテカン、SN−38及びそれらの塩から選ばれる抗がん剤の大腸がん感受性を判定する目的で、検体中のL−フェニルアラニン及び/又はN,N−ジメチルグリシンを測定する方法。
- 検体が、大腸がんを有する被験者由来の生体試料である請求項2記載の測定方法。
- 検体が、抗がん剤を投与された、大腸がんを有する被験者由来の生体試料である請求項2又は3記載の測定方法。
- 検体中のL−フェニルアラニン及び/又はN,N−ジメチルグリシンを測定するためのプロトコールを含むことを特徴とする請求項2〜4のいずれか1項記載の測定方法を実施するためのキット。
- L−フェニルアラニン及び/又はN,N−ジメチルグリシンの発現抑制を指標とする、イリノテカン、SN−38及びこれらの塩から選ばれる抗がん剤の大腸がん感受性亢進剤のスクリーニング方法。
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EP3858344A4 (en) | 2018-09-28 | 2022-07-06 | Keio University | MARKER TO EVALUATE SENSITIVITY TO A COMBINATION OF ANTICANCER DRUGS |
CN112129938B (zh) * | 2019-06-25 | 2023-08-18 | 中国科学院分子细胞科学卓越创新中心 | UDP-Glc在肺癌转移评估中的应用 |
CN113325057B (zh) * | 2021-07-01 | 2022-03-04 | 上海碧云天生物技术有限公司 | 提高聚丙烯酰胺凝胶预混液稳定性的方法、预混液及其应用 |
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EP2237042A1 (en) | 2010-10-06 |
WO2009096189A1 (ja) | 2009-08-06 |
CN101932939A (zh) | 2010-12-29 |
AU2009208519A1 (en) | 2009-08-06 |
SG192544A1 (en) | 2013-08-30 |
EP2237042B1 (en) | 2014-03-12 |
US20110003842A1 (en) | 2011-01-06 |
CA2712966A1 (en) | 2009-08-06 |
EP2698637A1 (en) | 2014-02-19 |
JPWO2009096189A1 (ja) | 2011-05-26 |
EP2698637B1 (en) | 2015-08-12 |
EP2237042A4 (en) | 2011-07-06 |
CN101932939B (zh) | 2014-01-08 |
US8945929B2 (en) | 2015-02-03 |
KR20110003464A (ko) | 2011-01-12 |
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