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.