Role of Deoxycytidine Kinase (dCK), Thymidine Kinase 2 (TK2), and Deoxycytidine Deaminase (dCDA) in the Antitumor Activity of Gemcitabine (dFdC)

Abstract

Deoxycytidine kinase (dCK) and deaminase (dCDA) are as activating and inactivating enzymes, respectively, in the metabolism of several chemotherapeutically important deoxynucleoside analogues [1]. 2′2′-Difluorodeoxycytidine (dFdC; gemcitabine) has considerable antitumor activity against solid tumors, such as against the chemoresistant non-small cell lung cancer (NSCLC) and pancreatic cancer [2]. dCK catalyses the rate-limiting phosphorylation of CdR and its analogues to their corresponding monophos-phates [1,3]. To avoid an overestimation of the dCK activity by thymidine kinase 2 (TK2), which can also efficiently phosphorylate CdR [3], dCK activity was measured in the presence of thymidine (TdR) to inhibit TK2 [4]. dCDA inactivates cytidine (CR), CdR and its analogues to their deaminated products [5,6]. Previously we could not establish a relationship between antitumor activity and the dCK and dCDA activities [6], while in a cell line study more precise measurements of dCK showed a relation between sensitivity to dFdC and efficiency of dCK [7]. We now reevaluated the role of dCK, TK2 and dCDA in the antitumor effect of dFdC against different solid tumors.