Pemetrexed Disodium Hydrate

別名:LY-231514 Disodium Hydrate

Pemetrexed Disodium Hydrate (LY-231514) is a novel antifolate and antimetabolite for TS, DHFR and GARFT with Ki of 1.3 nM, 7.2 nM and 65 nM, respectively. Pemetrexed Disodium Hydrate stimulates autophagy and apoptosis.

Pemetrexed Disodium Hydrate化学構造

CAS No. 357166-30-4

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Pemetrexed Disodium Hydrate関連製品

シグナル伝達経路

DHFR阻害剤の選択性比較

生物活性

製品説明 Pemetrexed Disodium Hydrate (LY-231514) is a novel antifolate and antimetabolite for TS, DHFR and GARFT with Ki of 1.3 nM, 7.2 nM and 65 nM, respectively. Pemetrexed Disodium Hydrate stimulates autophagy and apoptosis.
Targets
TS [1] DHFR [1] GARFT [1]
1.3 nM(Ki) 7.2 nM(Ki) 65 nM(Ki)
In Vitro
In vitro Pemetrexed disodium shows the antiproliferative activity in CCRF-CEM leukemia, GC3/C1 colon carcinoma, and HCT-8 ileocecal carcinoma cells with IC50 of 25 nM, 34 nM and 220 nM, respectively. [1] A recent study shows that cisplatin plus Pemetrexed combined with SOCS-1 gene delivery shows the antitumor effect by inhibition of cell proliferation, invasiveness, and induction of apoptosis in MPM cells infected with adenovirus-expressing SOCS-1 vector. [2]
Kinase Assay Enzyme Assays and Methods.
TS activity is assayed using a spectrophotometric method, which involved monitoring the increase in absorbance at 340 nm resulting from formation of the product, 7,8-dihydrofolate. The assay buffer contains 50 mM N-tris[hydroxymethyljmethyl-2-aminoethanesulfonic acid, 25 mM MgC12, 6.5 mM formaldehyde, 1 mM EDTA, and 75 mM 2-mercaptoethanol, pH 7.4. The concentrations of deoxyuridylate monophosphate, 6R-MTHF, and hIS are 100 μM, 30μM and 30 nM (1.7 milliunits/mL), respectively. At the 6R-MTHF concentration, an uninhibited reaction and six concentrations of inhibitor are assayed. Ki app values are determined by fitting the data to the Morrison equation using nonlinear regression analysis with the aid of the program ENZFITTER. Ki values are calculated using the equation: Ki app= Ki(1 + [S]/Km), where [S] is equal to 30 μM and Km is equal to 3 μM. DHFR activity is assayed spectrophotometrically by monitoring the dis appearance of the substrates NADPH and 7,8-dihydrofolate at 340 nm. The reaction takes place at 25°C in 0.5 mL of 50 mM potassium phosphate buffer, which contains 150 mM KC1 and 10 nM 2-mercaptoethanol, pH 7.5, and 14 nM (0.34 milliunitlmL) DHFR. The NADPH concentration is 10 μM and 7,8-dihydrofolate is varied at 5, 10, or 15 μM. At each 7,8-dihydrofolate concentration, an uninhibited reaction and seven concentrations of inhibitor are assayed. The ENZFITI'ER microcomputer program is used to obtain Ki app values by fitting the data to the Morrison equation by nonlinear regression analysis. Ki app= Ki(1 + [S]/Km), where [S] is equal to the concentration of 7,8-dihydrofolate used and Km of 7,8-dihydrofolate is equal to 0.15 μM. GARFT activity is assayed spectrophotometrically by monitoring the increase of absorbance resulting from formation of the product 5,8-dideazafolate at 295 nm. The reaction solvent contains 75 mM HEPES, 20% glycerol, and 50 mM a-thioglygerol, pH 7.5, at 25°C. The concentrations of substrates and enzyme used are 10 μM α,β-glycinamide ribonucleotide, 0-10 μM 10-formyl-5,8-dideazafolic acid, and 10 nM (1.9 milliunits/mL) GARFT. Ki values are calculated using the Enzyme Mechanism program of the Beckman DU640 spectrophotometer, which uses nonlinear regression analysis to fit data to the Michaelis-Menten equation for competitive inhibition.
細胞実験 細胞株 CCRF-CEM leukemia, GC3/C1 colon carcinoma, and HCT-8 ileocecal carcinoma cells.
濃度 0-30 μM
反応時間 72 hours
実験の流れ Dose-response curves are generated to determine the concentration required for 50% inhibition of growth (IC50). Pemetrexed disodium is dissolved initially in DMSO at a concentration of 4 mg/mL and further diluted with cell culture medium to the desired concentration. CCRF-CEM leukemia cells in complete medium are added to 24-well Cluster plates in a total volume of 2.0 mL. Pemetrexed disodium at various concentrations are added to duplicate wells so that the final volume of DMSO is 0.5%. The plates are incubated for 72 hour at 37 °C in an atmosphere of 5% CO2 in air. At the end of the incubation, cell numbers are determined on a ZBI Coulter counter. For several studies, IC50s are determined for each compound in the presence of either 300 μM AICA, 5 μM thymidine, 100 μM hypoxanthine, or combination of 5 μM hymidine plus 100 μM hypoxanthine. For adherent tumor cells, a modification of the original MTT colorimetric assay is used to measure cell cytotoxicity. The human tumor cells are seeded in 100 μL assay medium/well in 96-well flat-bottomed tissue culture plates. The assay medium contains folic acid-free RPMI 1640 supplemented with 10% FCS and either 2 nM folinic acid or 2.3 μM folic acid as the sole folate source. Well 1A is left blank. Stock solutions of antifolates are prepared in Dulbecco's PBS at 1 mg/mL, and a series of 2-fold dilutions are subsequently made in PBS. Ten-μL aliquots of each concentration are added to triplicate wells. Plates are incubated for 72 hours at 37 °C in a humidified atmosphere of 5% CO2-in-air. MTT is dissolved in PBS at 5 mg/mL, 10 μL of stock MTF solution are added to each well of an assay, and the plates are incubated at 37 °C for 2 additional hours. Following incubation, 100 μL of DMSO are added to each well. After thorough formazan solubilization, the plates are read on a Dynatech MR600 reader, using a test wavelength of 570 nm and a reference wavelength of 630 nm. The IC50 is determined as the concentration of drug required to inhibit cell growth by 50% compared to an untreated controls.
実験結果図 Methods Biomarkers 結果図 PMID
Western blot EGFR / p-EGFR AKT / p-AKT / GSK3β / p-GSK3β Topo IIα / Topo I / γH2AX / Cleaved PARP / Survivin p-Chk1 / Chk1 / Cyclin D / Cyclin E / p-Histone H3 / Histone H3 / Cyclin B1 / p-Cdc2 / Cdc2 30953548
Growth inhibition assay Cell viability 28719077
Immunofluorescence p-AKT 24847863
In Vivo
In Vivo In the human H460 non-small cell lung carcinoma xenograft, Pemetrexed disodium produces a duration-dependent tumor growth delay (TGD). [3]
動物実験 動物モデル EMT-6 mammary carcinoma, the human HCT 116 colon carcinoma, and the human H460 non-small cell lung carcinoma are injected s.c. into the nude mice.
投与量 100 mg/kg or 150 mg/kg
投与経路 Administered via i.p.
NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT06378892 Recruiting
Non Small Cell Lung Cancer Metastatic|ALK Gene Mutation
Centro di Riferimento Oncologico - Aviano
March 15 2024 Phase 2
NCT06010277 Recruiting
NSCLC|Mesothelioma|Thymoma
Amphia Hospital|Albert Schweitzer Hospital
February 6 2023 Phase 4

化学情報

分子量 516.42 化学式

C20H21N5O6.5/2H2O.2Na

CAS No. 357166-30-4 SDF Download Pemetrexed Disodium Hydrate SDFをダウンロードする
Smiles C1=CC(=CC=C1CCC2=CNC3=C2C(=O)NC(=N3)N)C(=O)NC(CCC(=O)[O-])C(=O)[O-].C1=CC(=CC=C1CCC2=CNC3=C2C(=O)NC(=N3)N)C(=O)NC(CCC(=O)[O-])C(=O)[O-].O.O.O.O.O.[Na+].[Na+].[Na+].[Na+]
保管

In vitro
Batch:

Water : 100 mg/mL

DMSO : Insoluble ( 吸湿したDMSOは溶解度を減少させます。新しいDMSOをご使用ください。)

Ethanol : Insoluble

モル濃度計算器

in vivo
Batch:

Add solvents to the product individually and in order.

投与溶液組成計算機

実験計算

モル濃度計算器

質量 濃度 体積 分子量

投与溶液組成計算機(クリア溶液)

ステップ1:実験データを入力してください。(実験操作によるロスを考慮し、動物数を1匹分多くして計算・調製することを推奨します)

mg/kg g μL

ステップ2:投与溶媒の組成を入力してください。(ロット毎に適した溶解組成が異なる場合があります。詳細については弊社までお問い合わせください)

% DMSO % % Tween 80 % ddH2O
%DMSO %

計算結果:

投与溶媒濃度: mg/ml;

DMSOストック溶液調製方法: mg 試薬を μL DMSOに溶解する(濃度 mg/mL, 注:濃度が当該ロットのDMSO溶解度を超える場合はご連絡ください。 )

投与溶媒調製方法:Take μL DMSOストック溶液に μL PEG300,を加え、完全溶解後μL Tween 80,を加えて完全溶解させた後 μL ddH2O,を加え完全に溶解させます。

投与溶媒調製方法:μL DMSOストック溶液に μL Corn oil,を加え、完全溶解。

注意:1.ストック溶液に沈殿、混濁などがないことをご確認ください;
2.順番通りに溶剤を加えてください。次のステップに進む前に溶液に沈殿、混濁などがないことを確認してから加えてください。ボルテックス、ソニケーション、水浴加熱など物理的な方法で溶解を早めることは可能です。

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