Abstract
The aim of this study was to explain why 5-ethyldeoxyuridine (EUdR) showed cytotoxic activity against Ehrlich ascites tumour (EAT) cells in vitro but not in vivo. In vitro studies showed that EUdR was phosphorylated to nucleotides which inhibit thymidylate synthetase and DNA polymerase. Toxicity in tissue culture appeared to be related to the inhibition of one or both of these enzymes; and could be prevented/reversed by thymidine (TdR). In vivo EAT cells also formed active EUdR nucleotides at levels which in vitro would have been associated with cytotoxicity but these levels were not maintained. EUdR has been shown to compete with TdR for catabolism by pyrimidine nucleoside phosphorylases from mouse liver and gut. In the ascitic fluid it was found that the level of EUdR fell rapidly while that of TdR and 5-ethyl-uracil increased. It is proposed that competition for catabolism in vivo resulted in the rise in TdR which then compromised the antitumour effect of EUdR.
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