Publication Date:
2007-11-16
Description:
Forodesine (BCX-1777) is a potent purine nucleoside phosphorylase (PNP) inhibitor. PNP inhibition results in elevation of plasma 2′-deoxyguanosine (dGuo) and intracellular accumulation of deoxyguanosine triphosphate (dGTP), which in turn affects deoxynucleotide-triphosphate pools and induces cell death. It has been reported that forodesine exerts a cytotoxic effect in cells from CLL probably due to high deoxycytidine kinase (dCK) activity in these cells. dCK is the primary enzyme for the conversion of dGuo to dGMP (dGuo monophosphate), which is then converted to dGTP. Several markers such as ZAP-70 and p53 status (17p deletions) identify CLL patients with a different biological and clinical behaviour. High ZAP-70 expression levels are associated with poorer overall survival and shorter time to disease progression, whereas p53 alterations convey drug resistance and short survival. We analyzed the in vitro cytotoxic effect of forodesine in primary cells from 29 patients with CLL, 11 of them carrying 17p deletions. Forodesine (2 μM) and dGuo (10–20 μM) induced apoptosis at 24–48 hours in CLL cells (56.7±14.3% of mean cytotoxicity in respect to control). As per the individual cytotoxic effect, this was higher than 60% in 17 cases (58.6%), 40–60% in 8 cases (27,5%), and lower than 40% in 4 cases (13.8%). No significant differences were observed between CLL cells with low levels of ZAP-70 (11 cases; 61.85±11.2% mean cytotoxicity) and CLL cells with high levels of ZAP-70 (16 cases; 55.7±16.8% mean cytotoxicity). Cases with 17p deletion showed good response to forodesine (11 cases; 58.5± 20% of mean cytoxicity vs. 18 CLL cases with no 17p deletion, 55.2±10.3 of mean cytotoxicity). Next, we analyzed the effect of combination of forodesine with fludarabine (3.75–7.5 μM) or bendamustine (10–25 μM). A significant synergistic effect (Chou Talalay Combination Index CI
Print ISSN:
0006-4971
Electronic ISSN:
1528-0020
Topics:
Biology
,
Medicine
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