IN-VIVO AND IN-VITRO PHARMACOLOGICAL ACTIVITY OF THE PURINE NUCLEOSIDE PHOSPHORYLASE INHIBITOR BCX-34 - THE ROLE OF GTP AND DGTP

BCX-34 inhibits RBC PNP in vitro from humans, rats, and, mice with IC( 50)s ranging from 5 to 36 nM. BCX-34 also, in the presence but not in the absence of deoxyguanosine, inhibits human CCRF-CEM T-cell prolifer ation with an IC50 of 0.57 mu M but not rat or mouse T-cell proliferat ion up to 30 mu M. Inhibition of human T-cell proliferation is accompa nied by an accumulation of intracellular dGTP with an associated reduc tion in GTP. These nucleotide changes do not occur in BC16A mouse T-ce lls and explain why proliferation is not inhibited by PNP inhibitors i n this case. Reduction in intracellular GTP is not essential for the a ntiproliferative action of BCX-34. Oral bioavailability of BCX-34 in r ats is 76%. BCX-34 is orally active in elevating plasma inosine in rat s (2-fold at 30 mg/kg), in suppressing ex vivo RBC PNP activity in rat s (98% at 3 h, 100 mg/kg), and in suppressing ex vivo skin PNP in mice (39% at 3 h, 100 mg/kg). The results demonstrate that BCX-34 inhibits human PNP and T-cell proliferation, is orally bioavailable in rodents , and pharmacologically active in vivo in rodents after oral dosing wi th no apparent side effects or toxicity. BCX-34 may, therefore, be use ful in treating human T-cell proliferative inflammatory disorders.