Distinct effects of dual substitution on inductive and differentiative activities of C8-substituted guanine ribonucleosides.

The current studies compare the inductive and differentiative properties of 8-mercaptoguanosine with those of 7-methyl-8-oxoguanosine. 7-Methyl-8-oxoguanosine (7m8oGuo) is a new member of the family of C8-substituted guanine ribonucleosides, the first such biologically active compound described that differs from guanosine other than by the specific substituent at the 8 position. Like 8MGuo, 7m8oGuo stimulates proliferation selectively in B lymphocytes. However, 7m8oGuo possesses greater activity than 8MGuo as a mitogen and greater potency as an adjuvant for humoral immune responses. Thus, as a B-lymphocyte mitogen, 7m8oGuo induces quantitatively greater [3H]TdR uptake than does 8MGuo, but with the same concentration optimum. As an adjuvant for in vitro antibody responses, however, 7m8oGuo achieves the same degree of immunoenhancement as 8MGuo but at approximately 10-fold lower concentrations, that is, the dose-response profile has been shifted to the left. Moreover, whereas the mitogenic responses to 8MGuo and 7m8oGuo exhibit parallel kinetic profiles, the adjuvant activity of 7m8oGuo arises earlier and persists later than does that of 8MGuo. These results are interpreted in terms of two distinct intracellular pathways: one mediating mitogenesis and the other adjuvanticity.