We showed that the efficacy of the new 2'-deoxycytidine (2'-dCyd) analogue
antimetabolite 2'-deoxy-2'-methylidenecytidine (DMDC) correlates well with
tumor levels of
cytidine (Cyd) deaminase in human
cancer xenograft models. DMDC was highly effective in
tumors with higher levels of Cyd deaminase, whereas lower levels yielded only slight activity. In contrast,
gemcitabine (2',2'-difluorodeoxycytidine), which has action mechanisms similar to those of DMDC, is only slightly active in
tumors with higher levels of the
enzyme. In the present study, we investigated the roles of Cyd deaminase in the antitumor activity of the two 2'-dCyd
antimetabolites in 13 human
cancer cell lines.
Tetrahydrouridine, an inhibitor of Cyd deaminase, reduced the antiproliferative activity of DMDC (P = 0.0015). Furthermore,
tumor cells transfected with the gene of human Cyd deaminase become more susceptible to DMDC both in vitro and in vivo. These results indicate that Cyd deaminase is indeed essential for the activity of DMDC. In contrast, the antiproliferative activity of
gemcitabine was increased to some extent by
tetrahydrouridine (P = 0.0277), particularly in tumor cell lines with higher levels of Cyd deaminase. This suggests that higher levels of Cyd deaminase may inactivate
gemcitabine. Among
nucleosides and deoxynucleosides tested, only dCyd, a natural substrate of both Cyd deaminase and dCyd
kinase, suppressed the antiproliferative activity of DMDC by up to 150-fold. Because the Vmax/Km of DMDC for dCyd
kinase was 8-fold lower than that for dCyd, the activation of DMDC to DMDC monophosphate (DMDCMP) by dCyd
kinase might be competitively inhibited by dCyd. In addition, the dCyd concentrations in human
cancer xenografts were inversely correlated with levels of Cyd deaminase activity. It is therefore suggested that higher levels of Cyd deaminase reduce the intrinsic cellular concentrations of dCyd in
tumors, resulting in efficient activation of DMDC to DMDCMP by dCyd
kinase. These results indicate that the efficacy of DMDC may be predicted by measuring the activity of Cyd deaminase in
tumor tissues before treatment starts and that DMDC may be exploited in a new treatment modality:
tumor enzyme-driven
cancer chemotherapy.