Cytotoxicity of 5-fluoro-5'-O-nitro-2'-deoxyuridine, a new fluorinated pyrimidine derivative, in L1210 cultures

D Roberts, P Franklin, G Odom, C Peck and TL Chwang

5-Fluoro-5'-O-nitro-2'-deoxyuridine (FdUMN), a neutral isostere of 5- fluoro-2'-deoxyuridine 5'-monophosphate, inhibited the growth of L1210 cultures. The inhibition of L1210 cultures by FdUMN was prevented by thymidine, but not by 2'-deoxyuridine. Like 5-fluoro-2'-deoxyuridine (FdUrd), FdUMN inhibited the incorporation of 2'-deoxyuridine into DNA, but the onset of this inhibition was not immediate, as was seen with FdUrd. FdUMN did not inhibit the activity of purified thymidylate synthetase from Lactobacillus casei and was a poor inhibitor of thymidylate synthetase activity in homogenates of L1210 ascites cells. However, after incubation with homogenates of these cells and subsequent addition of ATP, FdUMN inhibited this enzyme effectively. These results indicate that intracellular activation of FdUMN is required for its inhibition of thymidylate synthetase.

Volume 22, Issue 3, pp. 760-765, 11/01/1982
Copyright © 1982 by American Society for Pharmacology and Experimental Therapeutics