HIGH SUSCEPTIBILITY OF HUMAN CANCER XENOGRAFTS WITH HIGHER LEVELS OF CYTIDINE DEAMINASE TO A 2'-DEOXYCYTIDINE ANTIMETABOLITE, 2'-DEOXY-2'-METHYLIDENECYTIDINE

2'-Deoxy-2'-methylidenecytidine (DMDC) is a new 2'-deoxycytidine (dCyd ) antimetabolite. The present study compared its antitumor activities with those of 2',2'-difluorodeoxycytidine (gemcitabine) in 15 human ca ncer xenograft models, DMDC was highly resistant to cytidine (Cyd) dea minase, which deaminates the dCyd analogues to inactive molecules, whe reas gemcitabine was susceptible to the enzyme. Given p.o., high antit umor activity with therapeutic index of more than 10 was found with DM DC in 7 of 15 xenograft lines, In contrast, gemcitabine given i.v. or p.o. was highly effective in 4 of 15 human cancer xenograft lines. The antitumor spectrum of these compounds was quite different, although t heir molecular targets are reported to be similar, DMDC was highly eff ective in tumors with higher levels of Cyd deaminase activity, whereas it showed only slight activity in those with lower levels of Cyd deam inase. In contrast, gemcitabine appeared to be less effective in tumor s with high levels of Cyd deaminase. We also investigated the correlat ion with the susceptibility to the two dCyd antimetabolites and dCyd k inase activity in tumors, but none was observed, Cyd deaminase activit y was found to be high in tumor tissues from various types of human ca ncers thus far tested, such as colorectal cancer and non-small cell lu ng cancer, Such cancer types or individual patients who have tumors wi th high activity of the enzyme may be targets for DMDC therapy.