Jk. Kwee et al., Cell proliferation induced by 8-oxoguanosine and 8-methylguanosine, two adducts produced by free radical attack on ribonucleosides and RNA, CHEM-BIO IN, 116(1-2), 1998, pp. 61-77
The ability of C8-substituted guanine (Gua) ribonucleosides to induce B cel
l proliferation has been well documented in the literature. These compounds
are analogues of adducts formed from free radical attack on ribonucleoside
s and RNA. Here we examined the proliferative properties of two of these ra
dical adducts, 8-methylguanosine (8-MeG) and 8-oxo-7,8-dihydroguanosine (8-
OxoG) and compared them with those of the well studied B cell mitogen, 8-br
omoguanosine (8-BrG). 8-MeG and 8-OxoG were synthesized in the considerable
yields of 28, and 55%, respectively, and were characterized by UV, NMR and
CG-MS. Their effects upon [H-3]thymidine uptake into DNA by Swiss mouse sp
lenocytes, mouse embryo 3T3 fibroblasts (A31) and mouse B16F10 melanoma wer
e examined. Both guanosine (G) radical adducts were shown to increase [H-3]
thymidine uptake by mouse splenocytes but displayed selectivity in respect
to continuous cell lines. 8-MeG acted upon 3T3 fibroblasts whereas 8-OxoG a
cted upon B16F10 melanoma. The non-physiological analogue 8-BrG acted upon
all tested cells. Parallel experiments of cell counting, cytotoxicity, and
cell sorting indicated that DNA synthesis induced by the C8-substituted G's
reflected cell growth. It is proposed that the compounds act intracellular
ly because their proliferative effects were blocked in the presence of a nu
cleoside transport inhibitor but were not inhibited by an antagonist of the
A2 purine receptor. The present results, taken together with data from the
literature, suggest that in the case of 3T3 fibroblasts and mouse splenocy
tes the proliferative effects of the compounds are not dependent on metabol
ism through purine salvage pathways. In the case of melanoma, however, the
compounds are likely to become part of the purine nucleoside pool. The demo
nstration that adducts produced by free radical attack on ribonucleosides a
nd RNA are able to induce cell proliferation opens new perspectives for the
understanding of free radical mediated carcinogenesis. (C) 1998 Published
by Elsevier Science Ireland Ltd. All rights reserved.