Pralatrexate, a dihydrofolate reductase inhibitor for the potential treatment of several malignancies

Pralatrexate, a 10-deazaaminopterin derivative, is being developed by Allos Therapeutics Inc for the potential treatment of malignancies. The folate analog inhibits dihydrofolate reductase and was developed to overcome the limitations of the folate analog methotrexate. Compared with methotrexate in preclinical studies, pralatrexate demonstrated superior intracellular transport via the reduced folate carrier, and increased accumulation within cells by enhanced polyglutamylation. Preclinical studies in vitro and in models of B-cell lymphomas, T-cell lymphomas and NSCLC indicated that pralatrexate exhibited antitumor activity that was superior to the activity of other antifolates. In phase I clinical trials, the DLT for pralatrexate was mucositis, which could be abrogated with folic acid and vitamin B12 supplementation. The administration of pralatrexate to patients with T-cell lymphomas and NSCLC resulted in significant tumor remissions. At the time of publication, pralatrexate was in phase II clinical trials for the treatment of peripheral T-cell lymphoma, a phase I/II trial in combination with gemcitabine for the treatment of non-Hodgkin's lymphoma, and a phase IIb trial in comparison with erlotinib in patients with NSCLC. Because of the limited therapies available for peripheral T-cell lymphoma, pralatrexate could have a secure niche for the treatment of this indication, if ongoing clinical trials and future phase III trials confirm the efficacy of the drug. In contrast, for pralatrexate to be incorporated into the accepted treatment options for NSCLC, the drug will need to prove clear superiority to established agents.