From cell biology to therapy: forodesine

  • M Duvic

Abstract

Introduction and rationale Forodesine [(BCX-1777; immucillin H; (1S)-1-(9-deazahypoxanthin- 9-y-l)-1,4-dideoxy- 1,4-imino-D-ribitol hydrochloride), BioCryst Pharmaceuticals, Birmingham, AL, USA] is a rationally designed, novel transition- state analog inhibitor of purine nucleoside phosphorylase (PNP)(Miles 1998; Bantia 2001; Bantia 2004). This designer small molecule has a molecular formula weight of 302.73 and the structure of a nucleoside analogue (such as fludarabine, 2-CDA, nelarabine, gemcitabine) that are active in cutaneous T-cell lymphoma (Korycka 2008) (Figure 1). However, as a transition state analogue, forodesine is unique in that it is not incorporated into DNA as are the other cytotoxic nucleoside analogues that are also active in Tcell malignancies (Galmarini 2008) (Figure 1). The rational for the clinical development of forodesine stems from the observation that children who have inherited a deficiency of purine nucleoside phosphorylase (PNP) have selective depletion of their T-lymphocytes. PNP deficiency alters the normal nucleoside pathway leading to accumunation of plasma 2'-deoxyguanosine (dGuo) and intra-cellular intracellular dGuo triphosphate (dGTP) that is toxic to lymphocytes resulting in their undergoing apoptosis(Gandhi 2007) (Figure 2). A nucleoside kinase, deoxycytidine kinase (dCK) found in activated T-lymphocytes, is required and lends specificity to the effect of PNP inhibition.
Published
2009-06-23
How to Cite
Duvic, M. (2009). From cell biology to therapy: forodesine. Hematology Meeting Reports (formerly Haematologica Reports), 2(5). https://doi.org/10.4081/hmr.v2i5.746