JP6830255B2 - 抗腫瘍剤 - Google Patents
抗腫瘍剤 Download PDFInfo
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- JP6830255B2 JP6830255B2 JP2017562903A JP2017562903A JP6830255B2 JP 6830255 B2 JP6830255 B2 JP 6830255B2 JP 2017562903 A JP2017562903 A JP 2017562903A JP 2017562903 A JP2017562903 A JP 2017562903A JP 6830255 B2 JP6830255 B2 JP 6830255B2
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- A—HUMAN NECESSITIES
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- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/26—Iron; Compounds thereof
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- A—HUMAN NECESSITIES
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- A61K38/00—Medicinal preparations containing peptides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Proteomics, Peptides & Aminoacids (AREA)
- Gastroenterology & Hepatology (AREA)
- Inorganic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
(2)式中、R1及びR2が水素原子、並びにR3〜R5がいずれもメチル基である、(1)に記載の抗腫瘍剤。
(3)腫瘍が消化器がんである、(1)又は(2)に記載の抗腫瘍剤。
大腸がん細胞株であるCaco2/bbe(ATCC)、SKCO−1(ATCC)及びSW620(ATCC)、膵臓がん細胞株であるbxpc3(ATCC)及びSuit2(ヒューマンサイエンス資源バンク)、胃がん細胞株であるMKN45(国立研究開発法人 医薬基盤・健康・栄養研究所 JCRB細胞バンク)及びSH−10−TC(医療細胞資源センター・細胞バンク)、食道がん細胞株であるOE33(DSファーマ)、並びにラット腸上皮細胞(intestinal epitherial cell)株IEC−18(ATCC)を評価に用いた。
96穴プレートに1.0×104個/ウェルとなるように分注した被験細胞(以下、特に指定がないかぎりn=5)を24時間培養した後、測定試料を終濃度10ng〜10μg/mLとなるようにDMEMに添加してインキュベーションを開始し、24時間、48時間、72時間又は96時間後にプレートを回収した。培地を除去した後、各ウェルに5%TCAを添加して4℃で1時間静置し、純水で4回洗浄した。室温でプレートを乾燥させ、0.057重量%のSRB水溶液100μLを各ウェルに加えて細胞を染色し、0.1%酢酸で4回洗浄してから乾燥させた。染色された細胞を10mMのTris緩衝液に溶解したときの510nmにおけるODを測定することで、各インキュベーション時間における細胞密度を測定した。
1)培養上清の抗腫瘍活性
大腸がん細胞株Caco2/bbe、SKCO−1及びSW620を被験細胞とし、LGG ATCC53103、L.casei ATCC334、L.coryniformis ATCC25600及びL.fermentis ATCC23271の各培養上清を測定試料として、各上清の抗腫瘍活性をSRBアッセイにより測定した。その結果を図1に示す。いずれの大腸がん細胞株に対しても、L.casei ATCC334の培養上清は強い抗腫瘍活性を示すことが確認された。
L.casei ATCC334の培養上清から、分子量3kDaのカットオフスピンカラム(GE Healthcare)を用いて分子量3kDa以下の画分を得、次いでこの画分に対してMicro Float−A−Lyzer Dialysis Device(Spectrum Laboratories)を用いた透析を行うことで、分子量0.5kDa〜3kDaの画分を回収した。
被験細胞としてCaco2/bbe及びSW620を用い、フェリクロームの抗腫瘍活性の用量依存性をSRBアッセイにより試験した。同時に、ラット腸上皮細胞株IEC−18及びマウスプライマリー腸上皮細胞に対するフェリクロームの影響を調べた。その結果、フェリクロームはCaco2/bbe及びSW620に対して用量依存的に抗腫瘍活性を示した(図4)が、IEC−18及びマウスプライマリー腸上皮細胞に対しては、細胞密度をあまり低下させなかった(図5)。また、フェリクロームは別の大腸がん細胞株HT29、HCT116及びSKCO1に対しても、Caco2/bbe及びSW620同様に抗腫瘍活性を示すことが確認された。
2×106個の大腸がん細胞株SW620を、BALB/cヌードマウスの背部皮下に注射して移植した。移植の翌日から毎日、10μg/日のフェリクローム(n=16)又はPBS(n=16)を移植部位に投与し、各移植部位における腫瘍塊の成長を9日間観察した。移植後1日目及び移植後9日目のマウスの外観を図6に、腫瘍塊の体積変化を図7にそれぞれ示す。図6及び図7に示されるように、フェリクロームは移植細胞による腫瘍塊の成長を顕著に阻害した。
被験細胞を大腸がん細胞株SW620及び腸上皮細胞IEC−18とし、フェリクローム、抗がん剤として利用されている5−フルオロウラシル(5−FU)及びシスプラチンを測定試料として、SRBアッセイにより抗腫瘍活性を比較した。その結果、フェリクロームは5−FU及びシスプラチンを上回るSW620に対する抗腫瘍活性を示した(図8)。一方、IEC−18に対しては、5−FU及びシスプラチンは特に高濃度で用いた際に細胞密度を低下させたが、フェリクロームは細胞密度に大きく影響しないことが確認された(図9)。
C57/BL6マウス(n=5)に7日間に亘ってフェリクローム10μg又は100μg/日を経口投与又は静脈投与したときの血中AST(アスパラギン酸アミノトランスフェラーゼ)、ALT(アラニンアミノトランスフェラーゼ)及び血清鉄を測定したが、コントロールと比較して有意な変化は観察されなかった(図10)。
フェリクロームで処理した大腸がん細胞株SW620からmammalian cell extraction kit(BioVision)を用いて回収した総タンパク質に対して、cleaved caspase−3及びPARPそれぞれに対する特異抗体(Cell Signaling)を用いたウェスタンブロッティングを行った。その結果、フェリクロームの添加によってcleaved caspase−3及びPARPは用量依存的に増加しており、アポトーシスの誘導が認められた(図11)。アポトーシスの誘導は、TUNEL染色(In Situ Cell Death Detection Kit and TMR red(Roche Diagnostic))によっても確認された。図12に0.1μg/mLのフェリクロームで処理したSW620のTUNEL染色陽性細胞数の結果を示す。
被験細胞として膵臓がん細胞株bxpc3及びsuit2、胃がん細胞株MKN45及びSH−10−TC、並びに食道がん細胞株OE33を用い、フェリクロームの抗腫瘍活性の用量依存性をSRBアッセイにより試験した。フェリクロームはいずれの被験細胞に対しても用量依存的に抗腫瘍活性を示した(図16〜18)。また、フェリクロームは上記以外の膵臓がん細胞株(KP3、KP1N、KP3L、Miapaca)、胃がん細胞株(MKN7、MKN74)及び食道がん細胞株(OE19)に対しても同様に抗腫瘍活性を示すことが確認された。
2群のBALB/cヌードマウス(n=6/群)の背部皮下に1×106個の胃がん細胞MKN45を注射して移植した。移植の翌日から毎日、1群にはPBSに溶解したフェリクローム100μgを、他の1群にはPBSのみをそれぞれ移植部位に投与しながら、通常の飼育環境下で21日間飼育した。移植1日後と19日後の移植部位の写真を図19に、移植1日後の腫瘍体積を1としたときの腫瘍体積比の変化を図20に示す。
2群のヌードマウス(n=5/群)に1×106個の膵臓がん細胞Suit2を皮下移植した2日後から、1群にはPBSに溶解したフェリクローム100μgを、他の1群にはPBSのみをそれぞれ2日に1回、腹腔内投与しながら、通常の飼育環境下で12日間飼育した。移植12日後の移植部位の写真を図21に、腫瘍塊の体積変化を図22に示す。
BALB/cマウス(6週齢、♂)にアゾキシメタン(AOM)10mg/kgを腹腔内投与した。AOM処置後1週間飼育し、蒸留水で1.5%に希釈したデキストラン硫酸ナトリウム(DSS、MP bio社製)を1週間自由飲水によりマウスに投与した。1週間休薬したのち、蒸留水で1%に希釈したデキストラン硫酸ナトリウム(DSS、MP bio社製)を1週間自由飲水によりマウスに投与することで、化学発癌モデルを作製した。再度1週間休薬したのち、PBSに希釈したフェリクローム50μgを毎日経口投与しながら通常の飼育環境下で28日間飼育した。飼育終了後、マウスから大腸を摘出して、腫瘍面積を測定した。
BALB/cマウス(6週齢、♂)にアゾキシメタン(AOM)10mg/kgを腹腔内投与した。AOM処置後1週間飼育し、蒸留水で1%に希釈したデキストラン硫酸ナトリウム(DSS、MP bio社製)を1週間自由飲水によりマウスに投与した。1週間休薬したのち、PBSに溶解したフェリクローム100μgを2日に1回の頻度で腹腔内投与しながら通常の飼育環境下で49日間飼育した。飼育終了後、マウスから大腸を摘出して、腫瘍面積を測定した。
Claims (3)
- 式中、R1及びR2が水素原子、並びにR3〜R5がいずれもメチル基である、請求項1に記載の抗腫瘍剤。
- 消化器がんが、大腸がん、膵臓がん、胃がん又は食道がんである、請求項1又は2に記載の抗腫瘍剤。
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