Pemetrexed (sodium salt hydrate)

Pemetrexed is an antifolate with anticancer activity.^1,2,3 It is an inhibitor of folate-dependent enzymes involved in purine synthesis, including thymidylate synthase and dihydrofolate reductase (K_is = 109 and 7 nM, respectively, for the human recombinant enzymes), and the potency for thymidylate kinase is increased following polyglutamination of pemetrexed (K_i = 1.3 nM for pemetrexed-glu5).^1,2 Pemetrexed is an inhibitor of other nucleotide metabolism enzymes in a polyglutamination-dependent manner, including glycinamide ribonucleotide formyltransferase, with K_i values of 9,300 and 65 nM for the non-glutaminated and polyglutaminated mouse recombinant enzyme, respectively, and aminoimidazole carboxamide ribonucleotide formyltransferase, with K_i values of 3,600 and 265 nM for the non-glutaminated and polyglutaminated human enzyme, respectively. It inhibits proliferation of CCRF-CEM cells but not 5,10-dideazatetrahydrofolate-resistant CR15 cells (IC₅₀s = 0.254 and 200 µM, respectively).¹ Pemetrexed (100 mg/kg, i.p.) reduces tumor growth in A549, H1299, and PC-9 non-small cell lung cancer cell (NSCLC) mouse xenograft models but not in models using the same cell lines overexpressing thymidylate kinase.³

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1. Shih, C., Chen, V.J., Gossett, L.S., et al. LY231514, a pyrrolo[2,3-d]pyrimidine-based antifolate that inhibits multiple folate-requiring enzymes. Cancer Res. 57(6), 1116-1123 (1997).

2. Hanauske, A.R., Chen, V., Paoletti, P., et al. Pemetrexed disodium: A novel antifolate clinically active against multiple solid tumors. Oncologist 6(4), 363-373 (2001).

3. Takezawa, K., Okamoto, I., Okamoto, W., et al. Thymidylate synthase as a determinant of pemetrexed sensitivity in non-small cell lung cancer. Br. J. Cancer 104(10), 1594-1601 (2011).