Pralatrexate

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Background

Pralatrexate is an inhibitor of DHFR with Ki value of 45 nM [1].
Dihydrofolate reductase (DHFR) is an enzyme that reduces dihydrofolic acid to tetrahydrofolic acid, a methyl group shuttle required for the synthesis of purines, thymidylic acid, and certain amino acids.
Pralatrexate is a DHFR inhibitor with high affinity for folylpolyglutamate synthetase (FPGS) and reduced folate carrier 1 (RFC-1), resulting in extensive internalization and accumulation in tumour cells. In 15 human cancer cell lines, pralatrexate showed antiproliferative effects with IC50 < 0.1 μM in PC3, SCC61, DU145, HT29, HOP62, SQ20B, HOP92, HEP2 and IGROV1 cells. While it showed antiproliferative effects with IC50≥ 9 μM in Colo205, HCC2998, MCF7, HCT116, OVCAR3 and MDA-MB-435 cells [2].
In MV522 human non-small cell lung cancer (NSCLC) xenograft, pralatrexate showed increased antitumor activity. In the 2 mg/kg pralatrexate-treated group, the 38% tumor growth inhibition (TGI) was observed. In NCI-H460 NSCLC xenograft, pralatrexate showed antitumor activity in a dose-dependent way. TGI of 1 mg/kg and 2 mg/kg pralatrexate-treated groups was 34% and 52%, respectively. In the two xenografts, pralatrexate resulted in weight loss, which suggested its toxicity [1].

[1]. Izbicka E, Diaz A, Streeper R, et al. Distinct mechanistic activity profile of pralatrexate in comparison to other antifolates in in vitro and in vivo models of human cancers. Cancer Chemother Pharmacol, 2009, 64(5): 993-999.
[2]. Serova M, Bieche I, Sablin MP, et al. Single agent and combination studies of pralatrexate and molecular correlates of sensitivity. Br J Cancer, 2011, 104(2): 272-280.