Nucleoside analogs are efficacious
cancer chemotherapeutics due to their incorporation into
tumor cell
DNA. However, they exhibit vastly different antitumor efficacies, suggesting that incorporation produces divergent effects on DNA replication. Here we have evaluated the consequences of incorporation on DNA replication and its fidelity for three structurally related
deoxyguanosine analogs:
ganciclovir (GCV), currently in clinical trials in a suicide gene therapy approach for
cancer, D-
carbocyclic 2'-deoxyguanosine (CdG) and
penciclovir (PCV). GCV and CdG elicited similar cytotoxicity at low concentrations, whereas PCV was 10-100-fold less cytotoxic in human
tumor cells. DNA replication fidelity was evaluated using a supF plasmid-based mutation assay. Only GCV induced a dose-dependent increase in mutation frequency, predominantly GC-->TA transversions, which contributed to cytotoxicity and implicated the
ether oxygen in mutagenicity. Activation of mismatch repair with
hydroxyurea decreased mutations but failed to repair the GC-->TA transversions. GCV slowed S-phase progression and CdG also induced a G2/M block, but both drugs allowed completion of one cell cycle after
drug treatment followed by cell death in the second cell cycle. In contrast, PCV induced a lengthy early S-phase block due to profound suppression of
DNA synthesis, with cell death in the first cell cycle after
drug treatment. These data suggest that GCV and CdG elicit superior cytotoxicity due to their effects in template
DNA, whereas strong inhibition of nascent strand synthesis by PCV may protect against cytotoxicity.
Nucleoside analogs based on the
carbohydrate structures of GCV and CdG is a promising area for
antitumor drug development.