Pemetrexed disodium

Alias: Pemetrexed; LY-231514; LY231514; HSDB-7316; LY 231514; Alimta; HSDB 7316; HSDB7316; ALIMTA. Abbreviation: MTA.
Cat No.:V0846 Purity: ≥98%
Pemetrexed disodium (formerly HSDB-7316; LY-231514; Alimta), the disodium salt ofPemetrexed, is a marketed anticancer drug of the antifolate and antimetabolite class.
Pemetrexed disodium Chemical Structure CAS No.: 150399-23-8
Product category: DNA(RNA) Synthesis
This product is for research use only, not for human use. We do not sell to patients.
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Purity & Quality Control Documentation

Purity: ≥98%

Product Description

Pemetrexed disodium (formerly HSDB-7316; LY-231514; Alimta), the disodium salt of Pemetrexed, is a marketed anticancer drug of the antifolate and antimetabolite class. In cell-free assays, it inhibits DHFR, GARFT, and thymidylate synthase/TS with Ki values of 1.3 nM, 7.2 nM, and 65 nM, respectively. In a wide variety of tumor types, including malignant mesothelioma, NSCLC (non-small cell lung carcinoma), carcinomas of the breast, colorectum, uterine cervix, head and neck, and bladder, pemetrexed shows strong antitumor activity.

Biological Activity I Assay Protocols (From Reference)
Targets
TS ( Ki = 1.3 nM ); DHFR ( Ki = 7.2 nM ); GARFT ( Ki = 1.3 nM )
ln Vitro

Pemetrexed (LY231514) disodium is a novel classical antifolate. Its polyglutamated metabolites may simultaneously and multiplexly inhibit several important folate-requiring enzymes, thereby mediating antitumor activity. One of the best substrates for the enzyme FPGS that is currently known to exist is pemetrexed (LY231514) (Km=1.6 μM and Vmax/Km=621). The selectivity and antitumor activity of LY231514 are probably greatly influenced by polyglutamation and the polyglutamated metabolites of this novel agent. Although LY23l5l4 only exhibits a moderate inhibitory effect on TS (Ki=340 nM, recombinant mouse), LY23l5l4's pentaglutamate has 100-fold greater potency (Ki=3.4 nM), making LY231514 one of the most effective folate-based TS inhibitors[1].

ln Vivo
Statistically speaking, the mice in the PC61 plus Pemetrexed group survive longer than the other groups. The mice treated with PC61 plus Pemetrexed showed a significantly higher survival rate in a survival analysis when compared to the mice treated with PC61 alone, rat IgG plus Pemetrexed, or no treatment[2].
Enzyme Assay
TS activity is measured by spectrophotometric means, which entails tracking the rise in absorbance at 340 nm brought about by the production of 7,8-dihydrofolate. The assay buffer has the following contents: 25 mM MgC12, 6.5 mM formaldehyde, 1 mM EDTA, 75 mM 2-mercaptoethanol, 50 mM N-tris[hydroxymethyljmethyl-2-aminoethanesulfonic acid]. The concentrations of hIS, 6R-MTHF, and deoxyuridylate monophosphate are 30 μM, 100 μM, and 30 nM (1.7 milliunits/mL), respectively. An uninhibited reaction and six inhibitor concentrations are tested at the 6R-MTHF concentration. Ki app values are obtained by applying nonlinear regression analysis, with the assistance of the ENZFITTER program, to fit the data to the Morrison equation. Ki app= Ki(1 + [S]/Km is the formula used to calculate Ki values, where [S] is equivalent to 30 μM and Km is equivalent to 3 μM. Using spectrophotometry, DHFR activity is measured by tracking the disappearance of 7,8-dihydrofolate and NADPH at 340 nm. In 0.5 mL of 50 mM potassium phosphate buffer, pH 7.5, 150 mM KC1, 10 nM 2-mercaptoethanol, and 14 nM (0.34 milliunitlmL) DHFR are present during the reaction, which occurs at 25°C. 10, μM is the concentration of NADPH, while 5, 10, or 15 μM is the concentration of 7,8-dihydrofolate. Seven inhibitor concentrations and an uninhibited reaction are measured at each 7,8-dihydrofolate concentration. Ki app values are obtained by fitting the data to the Morrison equation using nonlinear regression analysis and the ENZFITI'ER microcomputer program. Ki app= Ki(1 + [S]/Km), where Km of 7,8-dihydrofolate is equal to 0.15 μM and [S] is the concentration of 7,8-dihydrofolate used. GARFT activity is measured spectrophotometrically by tracking the rise in absorbance at 295 nm that is brought about by the formation of the product 5,8-dideazafolate. At 25°C and pH 7.5, the reaction solvent is composed of 50% a-thioglycerol, 20% glycerol, and 75 mM HEPES. Substrates and enzyme were used at the following concentrations: 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 determined using the Beckman DU640 spectrophotometer's Enzyme Mechanism program, which fits data to the Michaelis-Menten equation for competitive inhibition using nonlinear regression analysis.
Cell Assay
To ascertain the concentration necessary for 50% inhibition of growth, dose-response curves are produced (IC50). Initially, 4 mg/mL of pemetrexed disodium is dissolved in DMSO, and the concentration is then further diluted with cell culture medium. 24-well Cluster plates are filled to a total capacity of 2.0 mL with CCRF-CEM leukemia cells in complete medium. Duplicate wells are filled with varying concentrations of pemetrexed disodium until the total volume of DMSO is 0.5%. The plates are incubated for seventy-two hours at 37 °C in an air atmosphere containing 5% CO2. Cell counts on a ZBI Coulter counter are measured at the conclusion of the incubation. AICA at 300 μM, thymidine at 5 μM, hypoxanthine at 100 μM, or a combination of 5 μM hymidine and 100 μM hypoxanthine are the conditions under which the IC50s for each compound are discovered for a number of investigations. The MTT colorimetric assay is modified to quantify the cytotoxicity of adherent tumor cells. 96-well tissue culture plates with a flat bottom are used to seed the human tumor cells at a density of 100 μL assay medium/well. In the assay medium, the only sources of folate are 2.3 μM or 2 nM folic acid, along with 10% FCS and folic acid-free RPMI 1640. It is left empty in Well 1A. Antifolate stock solutions (one milligram per milliliter) are prepared in Dulbecco's PBS, and then successive 2-fold dilutions are made in PBS. Triplicate wells are filled with ten-μL aliquots of each concentration. Plates are incubated at 37 °C for 72 hours in an atmosphere that is humidified with 5% CO2 in the air. 10 μL of stock MTF solution is added to each well of an assay after MTT has been dissolved in PBS at a concentration of 5 mg/mL. The plates are then incubated for an additional two hours at 37 °C. 100 μL of DMSO is added to each well after incubation. The plates are read on a Dynatech MR600 reader using a test wavelength of 570 nm and a reference wavelength of 630 nm following complete formazan solubilization. The amount of medication needed to impede cell growth by 50% in comparison to untreated controls is known as the IC50.
Animal Protocol
Mice: The mice used are female CBA mice and female NOD/SCID mice (NOD.CB17-Prkdcscid) that are 6–8 weeks old. In order to investigate the synergistic effect of premetrexed (100 mg/kg) in combination with anti-CD25 Ab or IgG control, tumor-bearing mice receive it intraperitoneally (i.p.) from days 4–8 (5 consecutive days). Based on earlier research conducted on mice, the current study's Pemetrexed dosage and schedule were chosen.
References

[1]. Cancer Res . 1997 Mar 15;57(6):1116-23.

[2]. Int J Cancer . 2013 Jan 15;132(2):459-71.

[3]. Clin Cancer Res . 2000 Mar;6(3):1016-23.

These protocols are for reference only. InvivoChem does not independently validate these methods.
Physicochemical Properties
Molecular Formula
C20H19N5NA2O6
Molecular Weight
471.37
Exact Mass
471.11
CAS #
150399-23-8
Appearance
Powder
SMILES
C1=CC(=CC=C1CCC2=CNC3=C2C(=O)NC(=N3)N)C(=O)N[C@@H](CCC(=O)[O-])C(=O)[O-].[Na+].[Na+]
InChi Key
NYDXNILOWQXUOF-GXKRWWSZSA-L
InChi Code
InChI=1S/C20H21N5O6.2Na/c21-20-24-16-15(18(29)25-20)12(9-22-16)6-3-10-1-4-11(5-2-10)17(28)23-13(19(30)31)7-8-14(26)27;;/h1-2,4-5,9,13H,3,6-8H2,(H,23,28)(H,26,27)(H,30,31)(H4,21,22,24,25,29);;/q;2*+1/p-2/t13-;;/m0../s1
Chemical Name
disodium;(2S)-2-[[4-[2-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]amino]pentanedioate
Synonyms
Pemetrexed; LY-231514; LY231514; HSDB-7316; LY 231514; Alimta; HSDB 7316; HSDB7316; ALIMTA. Abbreviation: MTA.
Storage

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Shipping Condition
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
Solubility Data
Solubility (In Vitro)
DMSO: ~94 mg/mL (~199.4 mM)
Water: <1 mg/mL
Ethanol: <1 mg/mL
Solubility (In Vivo)
Saline: 30 mg/mL
 (Please use freshly prepared in vivo formulations for optimal results.)
Preparing Stock Solutions 1 mg 5 mg 10 mg
1 mM 2.1215 mL 10.6074 mL 21.2148 mL
5 mM 0.4243 mL 2.1215 mL 4.2430 mL
10 mM 0.2121 mL 1.0607 mL 2.1215 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.

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Working concentration mg/mL;

Method for preparing DMSO stock solution mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.

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Clinical Trial Information
NCT Number Recruitment interventions Conditions Sponsor/Collaborators Start Date Phases
NCT02588781 Active
Recruiting
Drug: Pemetrexed Colorectal Cancer Samsung Medical Center October 2015 Phase 2
NCT03809637 Active
Recruiting
Drug: Pemetrexed, cisplatin Sarcoma Yonsei University January 10, 2017 Phase 2
NCT04683965 Active
Recruiting
Drug: Pemetrexed
Drug: TAS-102
Colorectal Neoplasms The First Affiliated Hospital
with Nanjing Medical University
January 1, 2021 Phase 2
NCT03952403 Active
Recruiting
Drug: Carboplatin
Drug: Pemetrexed
Carcinoma
Non-Small-Cell Lung
Shanghai Henlius Biotech December 2, 2019 Phase 3
NCT03623776 Active
Recruiting
Drug: JS001
Drug: Pemetrexed
Efficacy and Safety Sun Yat-sen University February 1, 2019 Phase 2
Biological Data
  • Pemetrexed

    Pemetrexed

  • Pemetrexed

    Growth delay of the human H460 non-small cell lung carcinoma grown as a xenograft in male nude mice after treatment with MTA (Pemetrexed, LY-231514)); gemcita-bine (GEM; 60 mg/kg).Clin Cancer Res.2000 Mar;6(3):1016-23.
  • Pemetrexed

    Growth delay of the human MX-1 breast carcinoma xenograft grown in female nude mice.Clin Cancer Res.2000 Mar;6(3):1016-23.
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