Drug evaluation: forodesine - PNP inhibitor for the treatment of leukemia, lymphoma and solid tumor.
Purine nucleoside phosphorylase (PNP) is a key enzyme in the purine-salvage metabolic pathway. In humans, the loss of functional PNP results in significant T-cell-mediated immunodeficiency (and may also affect B-cell function). Forodesine is a potent PNP inhibitor that acts by elevating plasma 2'-deoxyguanosine (dGuo) and intracellular deoxyguanosine triphosphate, which in turn affects deoxynucleotide-triphosphate pools and induces cell death by apoptosis. BioCryst Pharmaceuticals Inc, under license from the Albert Einstein College of Medicine, is developing intravenous and oral formulations of forodesine for the potential treatment of various T-cell and B-cell lymphomas and leukemias, as well as for solid tumors; MundiPharma AG is also investigating the drug for leukemia. Forodesine effectively inhibits T-cell proliferation in vitro in the presence of dGuo. In early clinical trials, forodesine has demonstrated an acceptable safety profile and indications of biological activity. Few drug-related serious adverse events have been reported, and generally only mild-to-moderate nonhematological toxicity has been observed. Forodesine has the potential to lead the development of other novel therapies with broad-based activity for hematological malignancies; the drug may also be useful for the treatment of a wide variety of other T-cell-mediated disorders, as well as for the potential treatment for other B-cell lymphomas/leukemias.
Galmarini
Carlos M
CM
Université Claude Bernard Lyon 1, Unité d'Oncologie Moléculaire, Centre Léon Bérard, 69373 Lyon CEDEX 08, France. carlos.galmarini@recherche.univ-lyon1.fr
D000818:Animals; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006801:Humans; D007938:Leukemia / Q000188:drug therapy*; D008223:Lymphoma / Q000188:drug therapy*; D009369:Neoplasms / Q000188:drug therapy*; D011684:Purine Nucleosides / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors*; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D011684:Purine Nucleosides; D011744:Pyrimidinones; C113101:forodesine; D011683:Purine-Nucleoside Phosphorylase