THE ANTIPROLIFERATIVE ACTIVITY OF DMDC IS MODULATED BY INHIBITION OF CYTIDINE DEAMINASE

We showed that the efficacy of the new 2'-deoxycytidine (2'-dCyd) anal ogue antimetabolite 2'-deoxy-2'-methylidenecytidine (DMDC) correlates well with tumor levels of cytidine (Cyd) deaminase in human cancer xen ograft models. DMDC was highly effective in tumors with higher levels of Cyd deaminase, whereas lower levels yielded only slight activity. I n contrast, gemcitabine (2',2'-difluorodeoxycytidine), which has actio n mechanisms similar to those of DMDC, is only slightly active in tumo rs with higher levels of the enzyme. In the present study, we investig ated the roles of Cyd deaminase in the antitumor activity of the two 2 '-dCyd antimetabolites in 13 human cancer cell lines, Tetrahydrouridin e, an inhibitor of Cyd deaminase, reduced the antiproliferative activi ty of DMDC (P = 0.0015). Furthermore, tumor cells transfected with the gene of human Cyd deaminase become more susceptible to DMDC both in v itro 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 tetrahydrouri dine (P = 0.0277), particularly in tumor cell Lines with higher levels of Cyd deaminase. This suggests that higher levels of Cyd deaminase m ay inactivate gemcitabine. Among nucleosides and deoxynucleosides test ed, only dCyd, a natural substrate of both Cyd deaminase and dCyd kina se, suppressed the antiproliferative activity of DMDC by up to 150-fol d. Because the V-max/K-m of DMDC for dCyd kinase was I-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 corr elated with levels of Cyd deaminase activity. It is therefore suggeste d that higher levels of Cyd deaminase reduce the intrinsic cellular co ncentrations of dCyd in tumors, resulting in efficient activation of D MDC to DMDCMP by dCyd kinase. These results indicate that the efficacy of DMDC may be predicted by measuring the activity of Cyd deaminase i n tumor tissues before treatment starts and that DMDC may be exploited in a new treatment modality: tumor enzyme-driven cancer chemotherapy.