Ribavirin induced differentiation of murine erythroleukemia cells

The synthetic nucleoside, ribavirin (1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide), a broad spectrum antiviral agent currently being tested in clinical studies with AIDS patients; and mycophenolic acid, a non-nucleoside inhibitor of inosinate (IMP) dehydrogenase, are effective inducers of terminal differentiation of Friend virus transformed murine erythroleukemia cells. The inhibition of cell division and the induced maturation produced by these agents appears to be a consequence of inhibition of IMP dehydrogenase, since growth inhibition is reversed and differentiation is prevented by the simultaneous exposure of cells treated with the agents to exogenous guanine or guanosine, which circumvents the effects of blockage of IMP dehydrogenase. However, while the effects mycophenolic acid, a pure IMP dehydrogenase inhibitor with no other biochemical effects, were completely reversed by guanine salvage supplies, cells exposed to ribavirin responded in a different manner. At levels of guanine salvage supplies below 50 microM, growth inhibition and cell differentiation were partially reversed. At salvage supply concentrations greater than 50 microM, while differentiation was completely blocked, the toxicity of ribavirin was increased and cell division was greatly diminished. These results indicate additional biochemical effects for ribavirin unrelated to the inhibition of IMP dehydrogenase, which may be related to its antiviral properties.