Role of thymidine kinase and thymidylate synthetase in the cytostatic, antimetabolic, and antitumor effects of the carbocyclic analogue of 5-nitro-2'-deoxyuridine. A comparison with 5-nitro-2'-deoxyuridine.

Abstract

The carbocyclic analogue of 5-nitro-2'-deoxyuridine (NO2dUrd), in which the sugar moiety is replaced by a cyclopentane ring and which was designated C-NO2dUrd, has been evaluated for its cytostatic, antimetabolic, and antitumor properties. The following findings are noted. C-NO2dUrd is about 500- to 2000-fold less inhibitory to tumor cell proliferation in vitro than NO2dUrd. Phosphorolysis of C-NO2dUrd by rabbit liver extracts was not observed under conditions where NO2dUrd was readily converted to 5-nitrouracil (NO2Ura). Also, C-NO2dUrd is converted to its 5'-monophosphate (C-NO2dUMP) by dThd kinase nearly as efficiently as the true nucleoside NO2dUrd. This metabolic conversion is necessary for the inhibitory effect of C-NO2dUrd on tumor cell proliferation in cell culture. The principal target enzyme for the cytostatic action of C-NO2dUrd is 2'-deoxythymidylate (dTMP) synthetase. C-NO2dUMP, the active metabolite of C-NO2dUrd, has a much lower affinity for dTMP synthetase than does NO2dUMP. This is the first demonstration of the interaction of a carbocyclic pyrimidine nucleotide analogue with dTMP synthetase. Neither NO2dUrd nor C-NO2dUrd exerts any significant antitumor activity in mice bearing L1210 or P388 leukemia; for NO2dUrd, this failure may be related to a rapid degradation to its inactive metabolite, NO2Ura; for C-NO2dUrd, it is most likely due to a decreased affinity of C-NO2dUMP for its target enzyme, dTMP synthetase.

• Authors: J Balzarini, E De Clercq, P Herdewijn, M J Robins
• Journal: Molecular pharmacology (Mol Pharmacol) Vol. 27 Issue 5 Pg. 578-83 (May 1985) ISSN: 0026-895X [Print] United States
• PMID: 3990680 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antimetabolites
• Antineoplastic Agents
• N(1)-cyclopentyl-5-nitropyrimidine-2,4-dione
• 5-nitro-2'-deoxyuridine
• Uracil
• Methyltransferases
• Thymidylate Synthase
• Thymidine Phosphorylase
• Thymidine Kinase
• Deoxyuridine

Topics

• Animals
• Antimetabolites (pharmacology)
• Antineoplastic Agents (pharmacology)
• Cell Division (drug effects)
• Cells, Cultured
• Deoxyuridine (analogs & derivatives, pharmacology)
• Humans
• Methyltransferases (antagonists & inhibitors)
• Mice
• Rats
• Thymidine Kinase (antagonists & inhibitors)
• Thymidine Phosphorylase (antagonists & inhibitors)
• Thymidylate Synthase (antagonists & inhibitors)
• Uracil (analogs & derivatives, pharmacology)