JP6294459B2 - 骨髄性白血病の処置方法 - Google Patents
骨髄性白血病の処置方法 Download PDFInfo
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- JP6294459B2 JP6294459B2 JP2016503780A JP2016503780A JP6294459B2 JP 6294459 B2 JP6294459 B2 JP 6294459B2 JP 2016503780 A JP2016503780 A JP 2016503780A JP 2016503780 A JP2016503780 A JP 2016503780A JP 6294459 B2 JP6294459 B2 JP 6294459B2
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- myeloid leukemia
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Classifications
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/10—Peptides having 12 to 20 amino acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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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
- A61P35/02—Antineoplastic agents specific for leukemia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Gastroenterology & Hepatology (AREA)
- Molecular Biology (AREA)
- Dermatology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
図1〜7は、処置後5日目に検査した血球に対する4F−ベンゾイル−TN14003(配列番号1、ここではBL−8040とも呼ばれる;2.4、4.8、9.6、又は、12mg/kgの濃度で)、シタラビン(ARA−C;200mg/kgの濃度で)、又は、それらの組合せの正常C57BL/6マウスへの処置の効果を説明する棒グラフである。
1 2 3 4 5 6 7 8 9 10 11 12 13 14
A1−A2−A3−Cys−Tyr−A4−A5−A6−A7−A8−A9−A10−Cys−A11 (I)
式中、
A1はアルギニン、リシン、オルニチン、シトルリン、アラニン又はグルタミン酸残基又はこれらのアミノ酸のN−α−置換誘導体であるか、A1は存在せず;
A1が存在する場合、A2はアルギニン又はグルタミン酸残基であり、もしくは、A1が存在しない場合、A2はアルギニン又はグルタミン酸残基又はこれらのアミノ酸のN−α−置換誘導体であり;
A3は芳香族アミノ酸残基であり;
A4、A5、A9は、それぞれ独立して、アルギニン、リシン、オルニチン、シトルリン、アラニン又はグルタミン酸残基であり;
A6はプロリン、グリシン、オルニチン、リシン、アラニン、シトルリン、アルギニン又はグルタミン酸残基であり;
A7はプロリン、グリシン、オルニチン、リシン、アラニン、シトルリン又はアルギニン残基であり;
A8はチロシン、フェニルアラニン、アラニン、ナフチルアラニン、シトルリン又はグルタミン酸残基であり;
A10はシトルリン、グルタミン酸、アルギニン又はリシン残基であり;
A11はアルギニン、グルタミン酸、リシン又はシトルリン残基で、この場合、C−末端カルボキシルを誘導体化していてもよく;
4−位又は13−位のシステイン残基は、ジスルフィド結合を形成でき、当該アミノ酸はL又はD型を取ることができる。
Tan NC, Yu P, Kwon Y−U, Kodadek T. High−throughput evaluation of relative cell permeability between peptoids and Peptides(ペプトイドとペプチドとの間での相対細胞透過性のハイ−スループット評価),Bioorg Med Chem. 2008;16:5853〜61。
ここで、上記の記述と合わせて、非限定的な方式で本発明を説明する以下の実施例を参考にする。
材料及び方法
試薬
4F−ベンゾイル−TN14003
凍結乾燥4F−ベンゾイル−TN14003は、MSD N.V.によって製造された。前記化合物を、最終保存濃度25mg/mLで注射用水(WFI)に溶解し、使用時まで−20℃で保存した。マウスに注射する前に、4F−ベンゾイル−TN14003を融解し、PBSで希釈し、最終濃度5mg/mLとした。注射直前にPBS中5mg/mL保存溶液(塩を含む合計用量)を希釈して、実際の用量決定溶液を調製した。200μLの一定用量体積で4F−ベンゾイル−TN14003を投与した。
シタラビン(シトシンアラビノシド;ARA−C)は、Hadassah cytotoxica pharmacy(イスラエル)から購入した。ARA−Cは、100mg/mLの濃度でHadassah cytotoxica pharmacyから提供された。100mg/mL保存溶液をPBSで希釈して、実際の投与液(200mg/kg)を調製した。
正常なC57BL/6 メスのマウス − 9〜10週令、体重約20g、を使用した。前記マウス最大10匹の群を、固形の床を備え、寝床用材としてかんな屑を敷いたポリスルホンケージ(425x266x185mm)で飼育した。前記マウスには、市販のげっ歯類用飼料(Harland Tekland(商標) Ra/Mouse Diet)を任意に与え、少量を供給するステンレスシッパーチューブを備えたポリスルホンボトルから各ケージに供給する高圧蒸気滅菌水を自由に摂取できるようにした。ARA−C用量決定初日から、ケージの床に吸湿の餌を置いた。1処置群当たり10匹を無作為に割付けた。
処置群は次の通りであった(1処置群当たり10匹):
・A群:非処置対照
・B群:1日目から7日目まで毎日、用量2.4、4.8、9.6又は12mg/kgで4FB−TN14003を投与されたマウス
・C群:3日目から7日目まで毎日200mg/kgの用量でARA−Cを投与されたマウス
・D群:B群と同じく4FB−TN14003を投与され(1日目から7日目まで毎日、用量2.4、4.8、9.6又は12mg/kg)、C群と同じくARA−Cも投与された(3日目から7日目まで毎日200mg/kgの用量で)マウス。
ARA−Cの単独処置は、非処置対照と比較すると、予想通り、白血球(図1)、赤血球(図2)、ヘマトクリット(図3)、ヘモグロビン(図4)、血小板(図5)、リンパ球絶対数(図6)及び好中球絶対数(図7)の劇的な減少を生じた。
以下に、本願の出願当初の請求項を実施の態様として付記する。
[1] 治療有効量のCXCR4−拮抗ペプチド及び治療有効量の化学療法剤を、それを必要とする対象に投与し、それによって、骨髄性白血病を処置することを含む、骨髄性白血病の処置方法。
[2] 前記骨髄性白血病が急性骨髄性白血病である、[1]に記載の方法。
[3] 前記CXCR4−拮抗ペプチドが配列番号1で示され、前記化学療法剤がシタラビンである、[1]又は[2]に記載の方法。
[4] 前記CXCR4−拮抗ペプチドが配列番号1で示されるアミノ酸配列を有する、[1]に記載の方法。
[5] 前記化学療法剤がシタラビンである、[1]に記載の方法。
[6] 前記CXCR4−拮抗ペプチドが0.1mg/kg体重〜10mg/kg体重の1日量で前記対象に投与される、[1]又は[3]に記載の方法。
[7] シタラビンが1g/m 2 体表面積〜10g/m 2 体表面積の1日量で前記対象に投与される、[5]又は[3]に記載の方法。
[8] 前記CXCR4−拮抗ペプチドが皮下投与される、[1]又は[3]に記載の方法。
[9] 前記シタラビンが静脈内投与される、[5]に記載の方法。
[10] 前記CXCR4−拮抗ペプチドが前記化学療法剤投与の少なくとも1日前に前記対象に投与される、[1]又は[3]に記載の方法。
[11] 前記CXCR4−拮抗ペプチドが前記化学療法剤投与の少なくとも1時間前に前記対象に投与される、[1]又は[3]に記載の方法。
Claims (2)
- 骨髄性白血病の処置における治療有効量のCXCR4−拮抗ペプチド及び治療有効量の化学療法剤であって、前記CXCR4−拮抗ペプチドが配列番号1で示され、前記化学療法剤がシタラビンである、治療有効量のCXCR4−拮抗ペプチド及び化学療法剤。
- 前記骨髄性白血病が急性骨髄性白血病である、請求項1に記載の治療有効量のCXCR4−拮抗ペプチド及び化学療法剤。
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JP2020203919A (ja) * | 2013-10-31 | 2020-12-24 | バイオカイン セラピューティックス リミテッド | Flt3変異を有する急性骨髄性白血病の治療用の医薬組成物 |
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