Potentiating effect of {2-[2-[(2-amino-1,6-dihydro-6-oxo-9h-purin-9-yl)methyl]-phenyl]ethenyl}-phosphoric acid (MDL 74,428), a potent inhibitor of purine nucleoside phosphorylase, on the antiretro viral activities of 2′,3′-dideoxyinosine combined to ribavirin in mice

Abstract

2′,3′ dideoxyinosine (ddI) has potent activity against human immunodeficiency virus (HIV) but is rapidly metabolized by erythrocytic purine nucleoside phosphorylase (PNP), and therefore has a very short plasma half-life in rodents, monkeys and in patients with acquired immunodeficiency syndrome. It is now reported that 100 μM if2-[2-[(2-amino-l,6-dihydro-6-oxo-9H-purin-9-yl)methyl]-phenyl]ethenyl-phosphonic acid (MDL 74,428), a very potent inhibitor of PNP blocks the intracellular phosphorolysis of ddI in cultured human red blood cells, in T leukemic CEM lymphoblasts and prolongs ddl plasma effective concentration in mice at a dose of 250 mg/kg body weight given i.p. In MDL 74,428-treated CEM cells, despite marked reduction of ddI catabolism, neither further accumulation of ddATP, the active antiviral metabolite of ddI, nor potentiation of the activity of ddI against HIV cytopathogenicity is observed. MDL 74,428 does not also affect the inhibitory effect of ddI combined with ribavirin on the transformation in vitro of C3H/3T3 cells by Moloney murine sarcoma virus (MSV). In mice, on the contrary, MDL 74,428 (200 mg/kg body weight, i.p.) is effective at potentiating the effect of ribavirin used either alone, or combined with ddI on MSV-induced tumour formation and associated mortality. However, in the absence of ribavirin, co-administration of MDL 74,428 with ddI affords, no chemotherapeutic advantage.