JP7406990B2 - ヒト血漿様培地 - Google Patents
ヒト血漿様培地 Download PDFInfo
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- JP7406990B2 JP7406990B2 JP2019524430A JP2019524430A JP7406990B2 JP 7406990 B2 JP7406990 B2 JP 7406990B2 JP 2019524430 A JP2019524430 A JP 2019524430A JP 2019524430 A JP2019524430 A JP 2019524430A JP 7406990 B2 JP7406990 B2 JP 7406990B2
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- 235000019375 tylosin Nutrition 0.000 description 1
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 1
- 229960001055 uracil mustard Drugs 0.000 description 1
- 229940005267 urate oxidase Drugs 0.000 description 1
- 239000003383 uricosuric agent Substances 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 230000036325 urinary excretion Effects 0.000 description 1
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 1
- 229910052720 vanadium Inorganic materials 0.000 description 1
- LEONUFNNVUYDNQ-UHFFFAOYSA-N vanadium atom Chemical compound [V] LEONUFNNVUYDNQ-UHFFFAOYSA-N 0.000 description 1
- 229960003165 vancomycin Drugs 0.000 description 1
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 description 1
- MYPYJXKWCTUITO-LYRMYLQWSA-O vancomycin(1+) Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C([O-])=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)[NH2+]C)[C@H]1C[C@](C)([NH3+])[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-O 0.000 description 1
- 229960000241 vandetanib Drugs 0.000 description 1
- UHTHHESEBZOYNR-UHFFFAOYSA-N vandetanib Chemical compound COC1=CC(C(/N=CN2)=N/C=3C(=CC(Br)=CC=3)F)=C2C=C1OCC1CCN(C)CC1 UHTHHESEBZOYNR-UHFFFAOYSA-N 0.000 description 1
- ZQFGRJWRSLZCSQ-ZSFNYQMMSA-N verteporfin Chemical compound C=1C([C@@]2([C@H](C(=O)OC)C(=CC=C22)C(=O)OC)C)=NC2=CC(C(=C2C=C)C)=NC2=CC(C(=C2CCC(O)=O)C)=NC2=CC2=NC=1C(C)=C2CCC(=O)OC ZQFGRJWRSLZCSQ-ZSFNYQMMSA-N 0.000 description 1
- 229960003895 verteporfin Drugs 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- 238000011179 visual inspection Methods 0.000 description 1
- 235000019155 vitamin A Nutrition 0.000 description 1
- 239000011719 vitamin A Substances 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 235000019166 vitamin D Nutrition 0.000 description 1
- 239000011710 vitamin D Substances 0.000 description 1
- 150000003710 vitamin D derivatives Chemical class 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 235000012711 vitamin K3 Nutrition 0.000 description 1
- 239000011652 vitamin K3 Substances 0.000 description 1
- 229940045997 vitamin a Drugs 0.000 description 1
- 229940046008 vitamin d Drugs 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
- 229940075420 xanthine Drugs 0.000 description 1
- UBORTCNDUKBEOP-UUOKFMHZSA-N xanthosine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(NC(=O)NC2=O)=C2N=C1 UBORTCNDUKBEOP-UUOKFMHZSA-N 0.000 description 1
- 108091005957 yellow fluorescent proteins Proteins 0.000 description 1
- NWONKYPBYAMBJT-UHFFFAOYSA-L zinc sulfate Chemical compound [Zn+2].[O-]S([O-])(=O)=O NWONKYPBYAMBJT-UHFFFAOYSA-L 0.000 description 1
- 229910000368 zinc sulfate Inorganic materials 0.000 description 1
- 239000011686 zinc sulphate Substances 0.000 description 1
- 235000009529 zinc sulphate Nutrition 0.000 description 1
- 150000003952 β-lactams Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/0018—Culture media for cell or tissue culture
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
- C12M41/00—Means for regulation, monitoring, measurement or control, e.g. flow regulation
- C12M41/30—Means for regulation, monitoring, measurement or control, e.g. flow regulation of concentration
- C12M41/32—Means for regulation, monitoring, measurement or control, e.g. flow regulation of concentration of substances in solution
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2500/00—Specific components of cell culture medium
- C12N2500/30—Organic components
- C12N2500/32—Amino acids
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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- C12N2500/00—Specific components of cell culture medium
- C12N2500/30—Organic components
- C12N2500/32—Amino acids
- C12N2500/33—Amino acids other than alpha-amino carboxylic acids, e.g. beta-amino acids, taurine
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2500/00—Specific components of cell culture medium
- C12N2500/30—Organic components
- C12N2500/34—Sugars
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2500/00—Specific components of cell culture medium
- C12N2500/30—Organic components
- C12N2500/38—Vitamins
Description
いくつかの態様では、本開示は、広く使用される哺乳動物細胞培養培地の組成が身体の外側の哺乳動物細胞の生存および増殖のために必要な栄養分を提供するように設計されながら、in vivoでの栄養状態を不十分にしか反映しないという認識に関する。いくつかの態様では、本開示は、哺乳動物細胞表現型に対しておよびアッセイにおける哺乳動物細胞の挙動に対して重大な効果を有する、ヒト血液において見出される特定の代謝産物の培養培地中の存在に関する。例えば、培養培地中のこのような代謝産物の存在は、公知または潜在的な治療剤などの外因性物質に対する細胞の応答を有意に変更し得る。
II.使用の方法
III.さらなる方法および組成物
ヒト血漿の極性代謝産物組成を反映する細胞培養培地
公知の合成細胞培養培地、BME、MEM、DMEM、およびRPMI 1640はグルコース、アミノ酸、ビタミン、および塩をヒト血漿の濃度を大部分反映していない濃度で含有する(図1A)。これらの培地は、血漿の質量分析およびNMR分析により存在していることが明らかにされた追加の構成成分も欠く(Psychogiosら、2011年)。代わりに、基本培地は多くの場合、熱不活化したウシ胎仔血清(IFS)を補充され、この血清は未定義で多くの場合非説明の(unaccounted for)代謝産物のカクテル、ならびに細胞増殖に必要な成長因子およびホルモンを与える(Freshney、2010年)。したがって、細胞代謝に対する環境因子の影響はよく認識されている(Davidsonら、2016年;DeNicolaおよびCantley、2015年;Hensleyら、2016年;Maddocksら、2013年;Mayersら、2016年;PavlovaおよびThompson、2016年;Yunevaら、2012年)が、ヒト血漿の代謝産物組成をよりよく反映する培地中の培養細胞の疑問(interrogation)は大部分が未調査である(図1B)。
表5Aおよび5Bにおけるすべての濃度は、他の方法で指示されていなければマイクロモル濃度である。
表5Aおよび5Bにおける平均および標準偏差値は4つの生物学的複製物から計算される。
N/D:検出されず
(実施例2)
HPLMでの細胞の培養はその代謝ランドスケープおよびグルコース炭素の運命を広範囲に変える
(実施例3)
HPLMの尿酸構成成分はデノボピリミジン生合成に対して著しい効果を有する
(実施例4)
尿酸はUMPSの直接の阻害因子である
(実施例5)
尿酸は5-フルオロウラシルの細胞傷害性と拮抗する
材料および方法
細胞系および試薬
1.レンチウイルスプラスミドpLJC2の構築
2.UMPSプラスミドの構築
プライマー
HPLMの設計
細胞培養培地調合
細胞培養条件
代謝産物プロファイリングおよび代謝産物存在量の定量
グルコース追跡
LC/MSのための5-FU処置
高度標的化メタボロミクス
消費および分泌速度
組換えUMPSの発現および免疫精製
UMPS活性アッセイ
薬物処置アッセイ
マウス血漿の収集
統計分析
参考文献
(項目1)
少なくとも9種のタンパク質構成性アミノ酸と、
1種または複数種のビタミンと、
1種または複数種の無機イオンと、
グルコースと、
4-ヒドロキシプロリン、アセチルグリシン、アルファ-アミノブチレート、ベタイン、カルニチン、シトルリン、オルニチン、タウリン、2-ヒドロキシブチレート、3-ヒドロキシブチレート、アセテート、シトレート、ホルメート、ラクテート、マロネート、ピルベート、スクシネート、アセトン、クレアチン、クレアチニン、グルタチオン、グリセロール、尿素、ガラクトース、フルクトース、ヒポキサンチンおよび尿酸から選択される少なくとも10種の小有機化合物と
を含む、基礎培養培地。
(項目2)
前記少なくとも10種の小有機化合物が、
4-ヒドロキシプロリン、アセチルグリシン、アルファ-アミノブチレート、ベタイン、カルニチン、シトルリン、オルニチン、タウリンから選択される少なくとも4種のアミノ酸またはアミノ酸誘導体と、
2-ヒドロキシブチレート、3-ヒドロキシブチレート、アセテート、シトレート、ホルメート、ラクテート、マロネート、ピルベートおよびスクシネートから選択される少なくとも6種の小有機化合物と
を含む、項目1に記載の基礎培養培地。
(項目3)
前記少なくとも10種の小有機化合物が、4-ヒドロキシプロリン、アセチルグリシン、アルファ-アミノブチレート、ベタイン、カルニチン、シトルリン、オルニチンおよびタウリンから選択される少なくとも6種のアミノ酸またはアミノ酸誘導体を含む、項目1または項目2に記載の基礎培養培地。
(項目4)
前記少なくとも10種の小有機化合物が、4-ヒドロキシプロリン、アセチルグリシン、アルファ-アミノブチレート、ベタイン、カルニチン、シトルリン、オルニチンおよびタウリンを含む、前記項目のいずれかに記載の基礎培養培地。
(項目5)
前記少なくとも10種の小有機化合物が、2-ヒドロキシブチレート、3-ヒドロキシブチレート、アセテート、シトレート、ホルメート、ラクテート、マロネート、ピルベートおよびスクシネートから選択される少なくとも8種の小有機化合物を含む、前記項目のいずれかに記載の基礎培養培地。
(項目6)
前記少なくとも10種の小有機化合物が、アセトン、クレアチン、クレアチニン、グルタチオン、グリセロールおよび尿素から選択される少なくとも3種の小有機化合物を含む、前記項目のいずれかに記載の基礎培養培地。
(項目7)
前記少なくとも10種の小有機化合物が、アセトン、クレアチン、クレアチニン、グルタチオン、グリセロールおよび尿素を含む、前記項目のいずれかに記載の基礎培養培地。
(項目8)
前記少なくとも10種の小有機化合物が、ヒポキサンチン、尿酸または両方を含む、前記項目のいずれかに記載の基礎培養培地。
(項目9)
前記少なくとも10種の小有機化合物が、ガラクトース、フルクトースまたは両方を含む、前記項目のいずれかに記載の基礎培養培地。
(項目10)
前記少なくとも10種の小有機化合物が、2-ヒドロキシブチレート、3-ヒドロキシブチレート、4-ヒドロキシプロリン、アセテート、アセトン、アセチルグリシン、アルファ-アミノブチレート、ベタイン、カルニチン、シトレート、シトルリン、クレアチン、クレアチニン、ホルメート、フルクトース、ガラクトース、グルタチオン、グリセロール、ヒポキサンチン、ラクテート、マロネート、オルニチン、ピルベート、スクシネート、タウリン、尿素および尿酸を含む、前記項目のいずれかに記載の基礎培養培地。
(項目11)
前記少なくとも9種のタンパク質構成性アミノ酸が、グリシン、L-アラニン、L-アルギニン、L-アスパラギン、L-アスパルテート、L-システイン、L-グルタメート、L-グルタミン、L-ヒスチジン、L-イソロイシン、L-ロイシン、L-リシン、L-メチオニン、L-フェニルアラニン、L-プロリン、L-セリン、L-トレオニン、L-トリプトファン、L-チロシン、L-バリンおよびL-シスチンを含む、前記項目のいずれかに記載の基礎培養培地。
(項目12)
前記1種または複数種のビタミンが、以下のビタミン:D-ビオチン、コリン、葉酸、ミオ-イノシトール、ナイアシンアミド、p-アミノ安息香酸、D-パントテン酸、ビタミンB6、リボフラビン、チアミンおよびビタミンB12のうち少なくとも8種を含む、前記項目のいずれかに記載の基礎培養培地。
(項目13)
前記1種または複数種の無機イオンが、以下のイオン:Na + 、K + 、Ca 2+ 、Mg 2+ 、NH 4 + 、Cl - 、HCO 3 - 、PO 4 3- 、SO 4 2- およびNO 3 - のうち少なくとも8種を含む、前記項目のいずれかに記載の基礎培養培地。
(項目14)
前記培地中に存在する前記イオンの各々の濃度が、表1においてそのイオンについて列挙される濃度の±50%以内である、項目13に記載の基礎培養培地。
(項目15)
前記培地中に存在する前記イオンの各々の濃度が、表1においてそのイオンについて列挙される濃度の±25%以内である、項目13に記載の基礎培養培地。
(項目16)
前記培地中に存在する前記イオンの各々の濃度が、表1においてそのイオンについて列挙される濃度の±10%以内である、項目13に記載の基礎培養培地。
(項目17)
前記培地中に存在する前記イオンの各々の濃度が、表1においてそのイオンについて列挙される濃度である、項目13に記載の基礎培養培地。
(項目18)
前記1種または複数種の無機イオンが、Na + 、K + 、Ca 2+ 、Mg 2+ 、NH 4 + 、Cl - 、HCO 3 - 、PO 4 3- 、SO 4 2- およびNO 3 - を含む、前記項目のいずれかに記載の基礎培養培地。
(項目19)
前記1種または複数種の無機イオンが、無機塩として存在し、該無機塩のうち少なくとも6種が、CaCl 2 、KCl、MgCl 2 、MgSO 4 、NaCl、NaHCO 3 、Na 2 HPO 4 、Ca(NO 3 ) 2 ・4H 2 OおよびNH 4 Clから選択される、前記項目のいずれかに記載の基礎培養培地。
(項目20)
表2中に列挙される前記基礎培養培地中に存在する前記構成成分の各々の濃度が、表2においてその構成成分について列挙される濃度の±50%以内である、前記項目のいずれかに記載の基礎培養培地。
(項目21)
表2中に列挙される前記基礎培養培地中に存在する前記構成成分の各々の濃度が、表2においてその構成成分について列挙される濃度の±25%以内である、前記項目のいずれかに記載の培養培地。
(項目22)
表2中に列挙される前記基礎培養培地中に存在する前記構成成分の各々の濃度が、表2においてその構成成分について列挙される濃度の±10%以内である、前記項目のいずれかに記載の基礎培養培地。
(項目23)
表2中に列挙される前記基礎培養培地中に存在する前記構成成分の各々の濃度が、表2においてその構成成分について列挙される濃度で存在する、前記項目のいずれかに記載の基礎培養培地。
(項目24)
表2中に列挙される前記構成成分の各々が、前記培地中に存在する、前記項目のいずれかに記載の基礎培養培地。
(項目25)
1種または複数種の抗生物質、pH指示薬または両方をさらに含む、前記項目のいずれかに記載の基礎培養培地。
(項目26)
前記項目のいずれかに記載の基礎培養培地を含む培養培地であって、血清または血清代用品をさらに含む培養培地。
(項目27)
1%~20%の血清を含む、項目26に記載の培養培地。
(項目28)
1%~5%の血清または5%~10%の血清または10%~20%の血清を含む、項目27に記載の培養培地。
(項目29)
およそ10%の血清を含む、項目27に記載の培養培地。
(項目30)
前記血清が、ウシ胎仔血清である、項目26から29のいずれかに記載の培養培地。
(項目31)
前記血清が、透析された血清である、項目26から30のいずれかに記載の培養培地。
(項目32)
前記血清が、熱不活化血清である、項目26から31のいずれかに記載の培養培地。
(項目33)
項目1から25に記載の基礎培養培地または項目26から32に記載の培養培地の構成成分をまとめて含有する1つまたは複数の容器を含むキット。
(項目34)
前記培養培地の複数の相互に適合性である構成成分を各々が含有する少なくとも2つの容器を含む、項目33に記載のキット。
(項目35)
前記培養培地を調製するための指示、該培養培地において細胞を培養するための指示または両方をさらに含む、項目33または項目34に記載のキット。
(項目36)
項目1から25に記載の基礎培養培地または項目26から32に記載の培養培地を調製する方法であって、そのそれぞれの構成成分を組み合わせることを含む、方法。
(項目37)
項目1から25に記載の基礎培養培地または項目26から32に記載の培養培地および1種もしくは複数種の哺乳動物細胞を含む組成物。
(項目38)
前記哺乳動物細胞が、ヒト細胞を含む、項目37に記載の組成物。
(項目39)
前記細胞が、血液細胞を含む、項目37または項目38に記載の組成物。
(項目40)
前記細胞が、がん細胞を含む、項目37から39のいずれかに記載の組成物。
(項目41)
試験薬剤をさらに含む、項目1から25に記載の基礎培養培地、項目26から32に記載の培養培地、または項目37から40に記載の組成物。
(項目42)
前記試験薬剤が、小分子である、項目41に記載の基礎培養培地、培養培地または組成物。
(項目43)
前記試験薬剤が、化学療法剤である、項目41または項目42に記載の基礎培養培地、培養培地または組成物。
(項目44)
1種または複数種の哺乳動物細胞を培養する方法であって、項目1から25に記載の基礎培養培地、項目26から32に記載の培養培地、または項目37から40に記載の組成物を提供することと、該培養培地において1種または複数種の哺乳動物細胞を培養することとを含む、方法。
(項目45)
前記1種または複数種の哺乳動物細胞が、ヒト細胞を含む、項目44に記載の方法。
(項目46)
前記1種または複数種の哺乳動物細胞が、血液細胞を含む、項目44または項目45に記載の方法。
(項目47)
前記1種または複数種の哺乳動物細胞が、がん細胞を含む、項目44から46のいずれかに記載の方法。
(項目48)
前記培養培地に試験薬剤を添加することをさらに含む、項目44から47のいずれかに記載の方法。
(項目49)
哺乳動物細胞集団または細胞系を特徴付ける方法であって、(a)項目1から25に記載の基礎培養培地または項目26から32に記載の培養培地中で哺乳動物細胞集団または細胞系の1種または複数種の細胞を培養することと、(b)該培養培地で培養された該細胞の表現型を検出すること、または該培養培地で培養された細胞を用いて実施したアッセイの結果を得ることとを含む、方法。
(項目50)
(c)第2の培養培地において同一集団または細胞系に由来する1種または複数種の細胞を培養することと、(d)該第2の培養培地において培養された該細胞の表現型を検出すること、または該第2の培養培地において培養された該細胞を用いて実施したアッセイの結果を得ることと、(e)ステップ(b)において検出された前記表現型を、第2の培養培地で培養されている同一集団もしくは細胞系に由来する1種もしくは複数種の細胞の該表現型と比較すること、または該アッセイの結果を、第2の培養培地において培養されている同一集団もしくは細胞系に由来する1種もしくは複数種の細胞を用いて実施した同一アッセイの結果と比較することとをさらに含む、項目49に記載の方法。
(項目51)
前記第1の培養培地で培養された細胞から得た前記表現型またはアッセイの結果と、前記第2の培養培地において培養された細胞から得た前記表現型またはアッセイの結果との間の差を検出することを含む、項目49または項目50に記載の方法。
(項目52)
前記細胞を、前記培養培地において該細胞が培養される期間の一部またはすべての間、試験薬剤と接触させることを含む、項目49から51のいずれかに記載の方法。
(項目53)
前記試験薬剤の存在下で前記培養培地において培養された細胞の前記表現型を、前記試験薬剤の存在下で前記第2の培養培地において培養されている同一集団もしくは細胞系に由来する細胞の前記表現型と比較すること、または前記試験薬剤の存在下で前記培養培地において培養された細胞を用いて実施した前記アッセイの結果を、前記試験薬剤の存在下で前記第2の培養培地において培養されている同一集団もしくは細胞系に由来する細胞を用いて実施した同一アッセイの結果と比較することを含む、項目52に記載の方法。
(項目54)
前記第2の培養培地が、標準培養培地である、項目50から53のいずれかに記載の方法。
(項目55)
前記アッセイが、生存率アッセイ、増殖アッセイ、アポトーシスアッセイ、オートファジーアッセイ、レポーターアッセイまたは細胞毒性アッセイである、項目49から54のいずれかに記載の方法。
(項目56)
試験薬剤を特徴付ける方法であって、(a)前記試験薬剤の存在下で、項目1から25に記載の基礎培養培地または項目26から32に記載の培養培地において1種もしくは複数種の哺乳動物細胞を培養することと、(b)該細胞を用いて実施したアッセイの結果を得ることとを含む、方法。
(項目57)
(c)前記試験薬剤の存在下で第2の培養培地において同一集団または細胞系に由来する1種または複数種の細胞を培養することと、(d)該第2の培養培地において培養した該細胞を用いて実施したアッセイの結果を得ることとをさらに含む、項目56に記載の方法。
(項目58)
前記アッセイの結果を、前記試験薬剤の存在下で第2の培養培地において培養されている同一集団または細胞系に由来する1種または複数種の細胞を用いて実施した同一アッセイの結果と比較することをさらに含む、項目56または項目57に記載の方法。
(項目59)
前記細胞を、前記試験薬剤と少なくとも24時間接触させることを含む、項目56から58のいずれかに記載の方法。
(項目60)
前記第2の培養培地が、標準培養培地である、項目56から59のいずれかに記載の方法。
(項目61)
前記試験薬剤の存在下で前記第1の培養培地において培養された細胞から得た前記アッセイの結果と、前記試験薬剤の存在下で前記2の培養培地において培養された細胞から得た前記アッセイの結果との間の差を検出することを含む、項目56から60のいずれかに記載の方法。
(項目62)
前記1種または複数種の細胞が、ヒト細胞を含む、項目49から61のいずれかに記載の方法。
(項目63)
前記1種または複数種の細胞が、血液細胞を含む、項目49から62のいずれかに記載の方法。
(項目64)
前記1種または複数種の細胞が、がん細胞を含む、項目49から63のいずれかに記載の方法。
(項目65)
前記アッセイが、生存率アッセイ、増殖アッセイ、アポトーシスアッセイ、
オートファジーアッセイ、レポーターアッセイまたは細胞毒性アッセイである、項目56から64のいずれかに記載の方法。
(項目66)
前記試験薬剤が、小分子である、項目56から65のいずれかに記載の方法。
(項目67)
前記試験薬剤が、化学療法剤である、項目56から66のいずれかに記載の方法。
(項目68)
がんを処置することを必要とする被験体においてがんを処置する方法であって、該被験体に、(a)5-フルオロウラシル(5-FU)または5-FUプロドラッグの一方または両方、および(b)尿酸低下剤を投与し、その結果、該被験体が5-FUおよび尿酸低下剤の両方に曝露されることを含む、方法。
(項目69)
前記尿酸低下剤がウリカーゼである、項目68に記載の方法。
(項目70)
前記尿酸低下剤が、尿酸排泄剤であり、必要に応じて、該尿酸排泄剤が、プロベネシド、ベンズブロマロンまたはスルフィンピラゾンである、項目69に記載の方法。
(項目71)
前記尿酸低下剤が、アンプロジピン、アトルバスタチン、フェノフィブラート、グアイフェネシンまたはレシヌラドである、項目70に記載の方法。
(項目72)
前記5-FUプロドラッグが、テガフールまたはカペシタビンである、項目68から71のいずれかに記載の方法。
(項目73)
5-FUまたは5-FUプロドラッグを、尿酸低下剤が投与されている被験体に投与することを含む、項目68から72のいずれかに記載の方法。
Claims (67)
- 少なくとも9種のタンパク質構成性アミノ酸と、
1種または複数種のビタミンと、
1種または複数種の無機イオンと、
グルコースと、
4-ヒドロキシプロリン、アセチルグリシン、アルファ-アミノブチレート、ベタイン、カルニチン、シトルリン、オルニチン、タウリン、2-ヒドロキシブチレート、3-ヒドロキシブチレート、アセテート、シトレート、ホルメート、ラクテート、マロネート、ピルベート、スクシネート、アセトン、クレアチン、クレアチニン、グルタチオン、グリセロール、尿素、ガラクトース、フルクトース、ヒポキサンチンおよび尿酸から選択される少なくとも10種の小有機化合物と
を含む、基礎培養培地であって、
20マイクロモル濃度(μM)の0.3から3倍の濃度の4-ヒドロキシプロリンを含み、
350μMの0.3から3倍の濃度の尿酸を含む、基礎培養培地。 - 前記少なくとも10種の小有機化合物が、
4-ヒドロキシプロリン、アセチルグリシン、アルファ-アミノブチレート、ベタイン、カルニチン、シトルリン、オルニチン、タウリンから選択される少なくとも4種のアミノ酸またはアミノ酸誘導体と、
2-ヒドロキシブチレート、3-ヒドロキシブチレート、アセテート、シトレート、ホルメート、ラクテート、マロネート、ピルベートおよびスクシネートから選択される少なくとも6種の小有機化合物と
を含む、請求項1に記載の基礎培養培地。 - 前記少なくとも10種の小有機化合物が、4-ヒドロキシプロリン、アセチルグリシン、アルファ-アミノブチレート、ベタイン、カルニチン、シトルリン、オルニチンおよびタウリンから選択される少なくとも6種のアミノ酸またはアミノ酸誘導体を含む、請求項1または請求項2に記載の基礎培養培地。
- 前記少なくとも10種の小有機化合物が、4-ヒドロキシプロリン、アセチルグリシン、アルファ-アミノブチレート、ベタイン、カルニチン、シトルリン、オルニチンおよびタウリンを含む、請求項1~3のいずれかに記載の基礎培養培地。
- 前記少なくとも10種の小有機化合物が、2-ヒドロキシブチレート、3-ヒドロキシブチレート、アセテート、シトレート、ホルメート、ラクテート、マロネート、ピルベートおよびスクシネートから選択される少なくとも8種の小有機化合物を含む、請求項1~4のいずれかに記載の基礎培養培地。
- 前記少なくとも10種の小有機化合物が、アセトン、クレアチン、クレアチニン、グルタチオン、グリセロールおよび尿素から選択される少なくとも3種の小有機化合物を含む、請求項1~5のいずれかに記載の基礎培養培地。
- 前記少なくとも10種の小有機化合物が、アセトン、クレアチン、クレアチニン、グルタチオン、グリセロールおよび尿素を含む、請求項1~6のいずれかに記載の基礎培養培地。
- 前記少なくとも10種の小有機化合物が、ヒポキサンチン、尿酸または両方を含む、請求項1~7のいずれかに記載の基礎培養培地。
- 前記少なくとも10種の小有機化合物が、ガラクトース、フルクトースまたは両方を含む、請求項1~8のいずれかに記載の基礎培養培地。
- 前記少なくとも10種の小有機化合物が、2-ヒドロキシブチレート、3-ヒドロキシブチレート、4-ヒドロキシプロリン、アセテート、アセトン、アセチルグリシン、アルファ-アミノブチレート、ベタイン、カルニチン、シトレート、シトルリン、クレアチン、クレアチニン、ホルメート、フルクトース、ガラクトース、グルタチオン、グリセロール、ヒポキサンチン、ラクテート、マロネート、オルニチン、ピルベート、スクシネート、タウリン、尿素および尿酸を含む、請求項1~9のいずれかに記載の基礎培養培地。
- 前記少なくとも9種のタンパク質構成性アミノ酸が、グリシン、L-アラニン、L-アルギニン、L-アスパラギン、L-アスパルテート、L-システイン、L-グルタメート、L-グルタミン、L-ヒスチジン、L-イソロイシン、L-ロイシン、L-リシン、L-メチオニン、L-フェニルアラニン、L-プロリン、L-セリン、L-トレオニン、L-トリプトファン、L-チロシン、L-バリンおよびL-シスチンを含む、請求項1~10のいずれかに記載の基礎培養培地。
- 前記1種または複数種のビタミンが、以下のビタミン:D-ビオチン、コリン、葉酸、ミオ-イノシトール、ナイアシンアミド、p-アミノ安息香酸、D-パントテン酸、ビタミンB6、リボフラビン、チアミンおよびビタミンB12のうち少なくとも8種を含む、請求項1~11のいずれかに記載の基礎培養培地。
- 前記1種または複数種の無機イオンが、以下のイオン:Na+、K+、Ca2+、Mg2+、NH4 +、Cl-、HCO3 -、PO4 3-、SO4 2-およびNO3 -のうち少なくとも8種を含む、請求項1~12のいずれかに記載の基礎培養培地。
- 前記培地中に存在する前記イオンの各々の濃度が、表1においてそのイオンについて列挙される濃度の±50%以内である、請求項13に記載の基礎培養培地。
- 前記培地中に存在する前記イオンの各々の濃度が、表1においてそのイオンについて列挙される濃度の±25%以内である、請求項13に記載の基礎培養培地。
- 前記培地中に存在する前記イオンの各々の濃度が、表1においてそのイオンについて列挙される濃度の±10%以内である、請求項13に記載の基礎培養培地。
- 前記培地中に存在する前記イオンの各々の濃度が、表1においてそのイオンについて列挙される濃度である、請求項13に記載の基礎培養培地。
- 前記1種または複数種の無機イオンが、Na+、K+、Ca2+、Mg2+、NH4 +、Cl-、HCO3 -、PO4 3-、SO4 2-およびNO3 -を含む、請求項1~17のいずれかに記載の基礎培養培地。
- 前記1種または複数種の無機イオンが、無機塩として存在し、該無機塩のうち少なくとも6種が、CaCl2、KCl、MgCl2、MgSO4、NaCl、NaHCO3、Na2HPO4、Ca(NO3)2・4H2OおよびNH4Clから選択される、請求項1~18のいずれかに記載の基礎培養培地。
- 表2中に列挙される前記基礎培養培地中に存在する各々の構成成分の濃度が、表2においてその構成成分について列挙される濃度の±50%以内である、請求項1~19のいずれかに記載の基礎培養培地。
- 表2中に列挙される前記基礎培養培地中に存在する各々の構成成分の濃度が、表2においてその構成成分について列挙される濃度の±25%以内である、請求項1~20のいずれかに記載の培養培地。
- 表2中に列挙される前記基礎培養培地中に存在する各々の構成成分の濃度が、表2においてその構成成分について列挙される濃度の±10%以内である、請求項1~21のいずれかに記載の基礎培養培地。
- 表2中に列挙される前記基礎培養培地中に存在する各々の構成成分の濃度が、表2においてその構成成分について列挙される濃度で存在する、請求項1~22のいずれかに記載の基礎培養培地。
- 表2中に列挙される各々の構成成分が、前記培地中に存在する、請求項1~23のいずれかに記載の基礎培養培地。
- 1種または複数種の抗生物質、pH指示薬または両方をさらに含む、請求項1~24のいずれかに記載の基礎培養培地。
- 請求項1~25のいずれかに記載の基礎培養培地を含む培養培地であって、血清または血清代用品をさらに含む培養培地。
- 1%~20%の血清を含む、請求項26に記載の培養培地。
- 1%~5%の血清または5%~10%の血清または10%~20%の血清を含む、請求項27に記載の培養培地。
- およそ10%の血清を含む、請求項27に記載の培養培地。
- 前記血清が、ウシ胎仔血清である、請求項26から29のいずれかに記載の培養培地。
- 前記血清が、透析された血清である、請求項26から30のいずれかに記載の培養培地。
- 前記血清が、熱不活化血清である、請求項26から31のいずれかに記載の培養培地。
- 請求項1から25のいずれかに記載の基礎培養培地または請求項26から32のいずれかに記載の培養培地の構成成分をまとめて含有する1つまたは複数の容器を含むキット。
- 前記培養培地の複数の相互に適合性である構成成分を各々が含有する少なくとも2つの容器を含む、請求項33に記載のキット。
- 前記培養培地を調製するための指示、該培養培地において細胞を培養するための指示または両方をさらに含む、請求項33または請求項34に記載のキット。
- 請求項1から25のいずれかに記載の基礎培養培地または請求項26から32のいずれかに記載の培養培地を調製する方法であって、そのそれぞれの構成成分を組み合わせることを含む、方法。
- 請求項1から25のいずれかに記載の基礎培養培地または請求項26から32のいずれかに記載の培養培地および1種もしくは複数種の哺乳動物細胞を含む組成物。
- 前記哺乳動物細胞が、ヒト細胞を含む、請求項37に記載の組成物。
- 前記細胞が、血液細胞を含む、請求項37または請求項38に記載の組成物。
- 前記細胞が、がん細胞を含む、請求項37から39のいずれかに記載の組成物。
- 試験薬剤をさらに含む、請求項1から25のいずれかに記載の基礎培養培地、請求項26から32のいずれかに記載の培養培地、または請求項37から40のいずれかに記載の組成物。
- 前記試験薬剤が、小分子である、請求項41に記載の基礎培養培地、培養培地または組成物。
- 前記試験薬剤が、化学療法剤である、請求項41または請求項42に記載の基礎培養培地、培養培地または組成物。
- 1種または複数種の哺乳動物細胞を培養する方法であって、請求項1から25のいずれかに記載の基礎培養培地、請求項26から32のいずれかに記載の培養培地、または請求項37から40のいずれかに記載の組成物を提供することと、該培養培地において1種または複数種の哺乳動物細胞を培養することとを含む、方法。
- 前記1種または複数種の哺乳動物細胞が、ヒト細胞を含む、請求項44に記載の方法。
- 前記1種または複数種の哺乳動物細胞が、血液細胞を含む、請求項44または請求項45に記載の方法。
- 前記1種または複数種の哺乳動物細胞が、がん細胞を含む、請求項44から46のいずれかに記載の方法。
- 前記培養培地に試験薬剤を添加することをさらに含む、請求項44から47のいずれかに記載の方法。
- 哺乳動物細胞集団または細胞系を特徴付ける方法であって、(a)請求項1から25のいずれかに記載の基礎培養培地または請求項26から32のいずれかに記載の培養培地中で哺乳動物細胞集団または細胞系の1種または複数種の細胞を培養することと、(b)該培養培地で培養された該細胞の表現型を検出すること、または該培養培地で培養された細胞を用いて実施したアッセイの結果を得ることとを含む、方法。
- (c)第2の培養培地において同一集団または細胞系に由来する1種または複数種の細胞を培養することと、(d)該第2の培養培地において培養された該細胞の表現型を検出すること、または該第2の培養培地において培養された該細胞を用いて実施したアッセイの結果を得ることと、(e)ステップ(b)において検出された前記表現型を、第2の培養培地で培養されている同一集団もしくは細胞系に由来する1種もしくは複数種の細胞の該表現型と比較すること、または該アッセイの結果を、第2の培養培地において培養されている同一集団もしくは細胞系に由来する1種もしくは複数種の細胞を用いて実施した同一アッセイの結果と比較することとをさらに含む、請求項49に記載の方法。
- ステップ(b)において得た前記表現型またはアッセイの結果と、ステップ(d)において得た前記表現型またはアッセイの結果との間の差を検出することを含む、請求項50に記載の方法。
- 前記細胞を、前記培養培地において該細胞が培養される期間の一部またはすべての間、試験薬剤と接触させることを含む、請求項50から51のいずれかに記載の方法。
- ステップ(b)において得た前記表現型またはアッセイの結果、およびステップ(d)において得た前記表現型またはアッセイの結果が、試験薬剤の存在下で培養された前記細胞または前記細胞系に由来する、請求項50に記載の方法。
- 前記第2の培養培地が、標準培養培地である、請求項50から53のいずれかに記載の方法。
- 前記アッセイが、生存率アッセイ、増殖アッセイ、アポトーシスアッセイ、オートファジーアッセイ、レポーターアッセイまたは細胞毒性アッセイである、請求項49から54のいずれかに記載の方法。
- 試験薬剤を特徴付ける方法であって、(a)前記試験薬剤の存在下で、請求項1から25のいずれかに記載の基礎培養培地または請求項26から32のいずれかに記載の培養培地において1種もしくは複数種の哺乳動物細胞を培養することと、(b)該細胞を用いて実施したアッセイの結果を得ることとを含む、方法。
- (c)前記試験薬剤の存在下で第2の培養培地において同一集団または細胞系に由来する1種または複数種の細胞を培養することと、(d)該第2の培養培地において培養した該細胞を用いて実施したアッセイの結果を得ることとをさらに含む、請求項56に記載の方法。
- 前記アッセイの結果を、前記試験薬剤の存在下で第2の培養培地において培養されている同一集団または細胞系に由来する1種または複数種の細胞を用いて実施した同一アッセイの結果と比較することをさらに含む、請求項56または請求項57に記載の方法。
- 前記細胞を、前記試験薬剤と少なくとも24時間接触させることを含む、請求項57から58のいずれかに記載の方法。
- 前記第2の培養培地が、標準培養培地である、請求項57から59のいずれかに記載の方法。
- 前記試験薬剤の存在下で培養された前記細胞または前記細胞系から得た前記アッセイの結果と、前記試験薬剤の存在下で前記2の培養培地において培養された前記細胞または前記細胞系から得た前記アッセイの結果との間の差を検出することを含む、請求項58から60のいずれかに記載の方法。
- 前記1種または複数種の細胞が、ヒト細胞を含む、請求項49から61のいずれかに記載の方法。
- 前記1種または複数種の細胞が、血液細胞を含む、請求項49から62のいずれかに記載の方法。
- 前記1種または複数種の細胞が、がん細胞を含む、請求項49から63のいずれかに記載の方法。
- 前記アッセイが、生存率アッセイ、増殖アッセイ、アポトーシスアッセイ、オートファジーアッセイ、レポーターアッセイまたは細胞毒性アッセイである、請求項56から64のいずれかに記載の方法。
- 前記試験薬剤が、小分子である、請求項56から65のいずれかに記載の方法。
- 前記試験薬剤が、化学療法剤である、請求項56から66のいずれかに記載の方法。
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US20230051644A1 (en) | 2023-02-16 |
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