Thymidylate synthase (TS) and thymidine kinases (TKs) mediate production of dTMP for DNA synthesis and repair. The activity of both pathways increases intracellular dTMP and can potentially contribute to tumor cell resistance to TS-targeting agents. Di Cresce et al. tested the hypothesis that TKs mediate resistance to the capacity of TS small interfering RNA (siRNA) to sensitize tumor cells to TS-targeting agents. Using siRNA against cytosolic TK (TK1) and mitochondrial TK (TK2), it was demonstrated that knockdown of TK2 enhanced the ability of TS siRNA to sensitize tumor cells to the TS-targeting agent 5-fluorodeoxyuridine (5FUdR), and knockdown of TK1 sensitized pemetrexed. These data suggest nonoverlapping functions of TK1 and TK2, perhaps based on cellular localization. Modulation of TK activity affects only sensitivity to TS-targeting agents, because no increase in sensitivity to cisplatin was observed. A novel observation was that TS siRNA, in combination with 5FUdR, increased TK1 protein, and in combination with pemetrexed, increased TK2 protein. These effects support the hypothesis that TKs could mediate enhanced cell survival (resistance) when TS activity is reduced and suggest that TK1 and TK2 are potential targets to enhance tumor sensitivity to TS-targeting drugs.
See article at J Pharmacol Exp Ther 2011, 338:952–963.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics