Pemetrexed disodium (LY231514) is an antineoplastic, multitargeted antifolate which inhibits TS (thymidylate synthase), DHFR and GARFT as well as other folate dependent enzymes. By inhibiting the formation of precursor purine and pyrimidine nucleotides, pemetrexed prevents the formation of DNA and RNA, which are required for the growth and survival of both normal cells and cancer cells. 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. In the human H460 non-small cell lung carcinoma xenograft, Pemetrexed disodium produces a duration-dependent tumor growth delay (TGD). Pemetrexed has demonstrated antitumor activity in various tumor types as a single agent and in combination with other chemotherapeutic agents. In a phase III trial, pemetrexed (LY231514) demonstrated equivalent efficacy to docetaxel, but with significantly less toxicity, in second-line treatment of non-small-cell lung cancer.
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Source | Biochem Biophys Res Commun (2014). Figure 2. Pemetrexed disodium |
| Method | apoptosis assay | |
| Cell Lines | OS cell | |
| Concentrations | 1 μM | |
| Incubation Time | 72 h | |
| Results | Through Annexin V FACS assay, we showed that pemetrexed (1 μM) or C6 ceramide (5 μg/ml) alone only slightly induced apoptosis of U2OS cells and MG-63 cells (5–10%), combination of the two led to a significant increase of cell apoptosis. |
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Source | Biochem Biophys Res Commun (2014). Figure 1. Pemetrexed disodium |
| Method | MTT assay | |
| Cell Lines | OS cells | |
| Concentrations | 1 μM | |
| Incubation Time | 72 h | |
| Results | C6 ceramide showed most significant sensitization effect with pemetrexed at 1 μM, this concentration was chosen for further experiments. |
| Cell Experiment | |
|---|---|
| Cell lines | Human OS cell |
| Preparation method | U2OS cells were treated with pemetrexed (PMX, 1 lM) and/or C6 ceramide (C6, 5 lg/ml) for 24 h, phospho-/regular Akt and S6K1 were tested by Western blots (A). |
| Concentrations | 1 µM |
| Incubation time | 24 h |
| Animal Experiment | |
|---|---|
| Animal models | nude mice |
| Formulation | Pemetrexed disodium is dissolved in DMSO and then diluted in water. |
| Dosages | 100 mg/kg or 150 mg/kg |
| Administration | i.p. |
| Molecular Weight | 471.37 |
| Formula | C20H19N5Na2O6 |
| CAS Number | 150399-23-8 |
| Solubility (25°C) | Water 84 mg/mL |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
| Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
| Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
| Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
| Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
| Animal A (mg/kg) = Animal B (mg/kg) multiplied by | Animal B Km |
| Animal A Km |
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
| Related Antifolate Products |
|---|
| Methotrexate hydrate
Methotrexate hydrate is an antimetabolite and antifolate that inhibits dihydrofolate reductase, thereby preventing the conversion of folic acid to tetrahydrofolate and inhibiting DNA synthesis. In addition, Methotrexate hydrate is an immunosuppressant and antitumor agent used in studies related to rheumatoid arthritis and various cancers such as acute lymphoblastic leukemia. |
| Trimetrexate glucuronate
Trimetrexate glucuronate (NSC 352122) is a folic acid antagonist. Trimetrexate glucuronate affects DNA and RNA synthesis by inhibiting dihydrofolate reductase and preventing the synthesis of purine nucleotides and thymidylate. Trimetrexate glucuronate has potential antitumour activity and can also be used to inhibit Pneumocystis carinii pneumonia. |
| Pemetrexed disodium heptahydrate
Pemetrexed disodium heptahydrate is a novel antifolate, the Ki values of the pentaglutamate of LY231514 are 1.3, 7.2, and 65 nM for inhibits thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT), respectively. |
| Fanotaprim
Fanotaprim is a dihydrofolate reductase (DHFR) inhibitor with IC50s of 1.57 and 308 nM for tgDHFR (Toxoplasma gondii DHFR) and hDHFR (human DHFR), respectively. Fanotaprim has the potential for the research of toxoplasmosis. |
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