Deoxycytidine kinase and deoxycytidine deaminase activities in human tumour xenografts

Abstract

Deoxycytidine kinase (dCK) and deaminase (dCDA) are both key enzymes in the activation and inactivation, respectively, of several deoxycytidine antimetabolites. We determined the total dCK and dCDA activities using standard assays, in 28 human solid tumours grown as xenografts in nude mice, and four corresponding cell lines. dCK activities in colon tumours varied from 11 to 12 nmol/h/mg protein, in ovarian tumours from 3 to 10 nmol/h/mg protein, in soft tissue sarcomas from 2 to 7 nmol/h/mg protein and in squamous cell carcinomas of the head and neck about 45-fold, between 0.4 and 18 nmol/h/mg protein. The dCDA activities showed a larger variation, from 243 to 483, 14 to 1231, 3 to 7 and 1 to 222 nmol/h/mg protein, respectively. The ratios of dCK vs. dCDA activities in these tumours varied from 0.025 to 0.046, 0.004 to 0.240, 0.581 to 1.123 and from 0.012 to 4.227, respectively. In four cell lines (A2780, OVCAR-3, WiDr and UM-SCC-14C), sources for some of the abovementioned tumours, a different pattern in dCK and dCDA was observed than in the corresponding tumours. The variation in dCDA activities was in a smaller range (20-fold) than in the tumours (40-fold). In all cell lines dCK activity was higher than dCDA activity, in contrast to the corresponding tumours, in which the reverse pattern was observed. Previously, some of the tumours were tested for sensitivity to the deoxycytidine analogues 5-aza-deoxycytidine and 2′,2′-difluorodeoxycytidine. In the sensitive tumours, both the highest and lowest dCK activity was observed, indicating that dCK activity in solid tumours is high enough to activate deoxycytidine analogues.