Previous studies on the
biological effects of the
2',3'-dideoxynucleosides (
ddNs) have shown that while ddAdo is lethal to E. coli,
ddThd has minimal effects on the growth of mammalian cell lines and that it inhibits
retrovirus infection of some cell lines but not others. Previous studies have also shown that the 5'-triphosphate of
ddThd,
ddTTP, selectively inhibits cellular
DNA polymerases beta and gamma and retroviral reverse
transcriptases. Cellular
DNA polymerase alpha is relatively resistant to
ddTTP. We have extended these findings to show that the 5'-triphosphates of the other 3
ddNs (
ddATP, ddCTP, and
ddGTP) affect cellular
DNA polymerases alpha, beta, and gamma in the same fashion as does
ddTTP. We also show that all four
ddNs in concentrations up to 100 microM have negligible effects on the growth of NIH Swiss 3T3 cells. These negligible effects may be due to inefficient intracellular phosphorylation of each
nucleoside to the
triphosphate. We have determined that, in several different cell lines,
ddThd is phosphorylated only at a very slow rate to
ddTTP, and in the one cell line tested (monkey CV-1 cells), ddAdo and ddGuo are also poorly phosphorylated. Both ddAdo and ddGuo, and probably
ddThd, are converted by
CV-1 cells to additional unknown compounds which may have
biological activity. The four
ddNs display effects of different magnitudes on certain
virus infections. Although 30 microM
ddThd inhibits
herpes simplex I
infection of
CV-1 cells by 50%, 30 microM ddAdo has no effect.
Infection of NIH Swiss 3T3 cells by 334C murine leukemia virus is inhibited 70-80% by ddAdo, ddCyd, and
ddThd at 50 microM, but inhibition by 50 microM ddGuo is 100%.