Recently a few new
purine nucleoside analogues (PNA) have been synthesized and introduced into preclinical and clinical trials. The transition-state theory has led to the design of 9-deazanucleotide analogues that are
purine nucleoside phosphorylase (PNP) inhibitors, termed immucillins. Among them the most promising results have been obtained with
forodesine.
Forodesine (BCX-1777, Immucillin H, 1-(9-deazahypoxanthin)-1,4-dideoxy-1,4-imino-D-ribitol) has
carbon-
carbon linkage between a cyclic
amine moiety that replaces
ribose and 9-deaza-hypixanthine. The
drug is a novel T-cell selective
immunosuppressive agent which in the presence of 2'-deoxyguanosine (dGuo) inhibits human lymphocyte proliferation activated by various agents such as
interleukin-2 (IL-2), mixed lymphocyte reaction and
phytohemagglutinin. In the mechanism of
forodesine action two
enzymes are involved: PNP and
deoxycytidine kinase (dCK). PNP catalyzes the phosphorolysis of dGuo to
guanine (Gu) and 2'-deoxyribose-1-phosphate, whereas dCK converts dGuo to deoxyguanosino-5'-monophosphate (
dGMP) and finally to deoxyguanosino-5'-triphosphate (
dGTP). The affinity of dGuo is higher for PNP than for dCK. Nevertheless, if PNP is blocked by
forodesine, plasma dGuo is not cleaved to Gu, but instead it is intracellularly converted to
dGTP by high dCK activity, which leads to inhibition of
ribonucleotide reductase (RR), an
enzyme required for
DNA synthesis and cell replication, which eventually results in apoptosis.
Forodesine is active in some experimental
tumors in mice, however it could be used for the treatment of human T-cell proliferative disorders and it is undergoing phase II clinical trials for the treatment of T-cell
non-Hodgkin's lymphoma, which includes
cutaneous T-cell lymphoma (CTCL). Moreover, recent preclinical and clinical data showed activity of
forodesine in B-cell acute lympholastic
leukemia (ALL).