Mechanism of action of 5-nitro-2'-deoxyuridine.
Results are described that demonstrate that the mechanism of action of the potent cytotoxic agent 5-nitro-2'-deoxyuridine (NO2-dUrd) involves thymidine (dThd) kinase catalyzed formation of 5-nitro-2'-deoxyuridylate (NO2dUMP) and subsequent potent inhibition of thymidylate (dTMP) synthetase by this compound. The evidence for this is as follows: (a) cells lacking dThd kinase are not inhibited by high concentrations of NO2dUrd; (b) the drug has no effect on dThd or uridine (Urd) incorporation into nucleic acids but prevents incorporation of deoxyuridine (dUrd); (c) growth inhibition is reversed by dThd but not by dUrd; (d) NO2dUrd causes changes in deoxynucleoside triphosphate pool sizes which are characteristic of specific inhibition of dTMP synthetase; (e) cells treated with [3H]NO2dUrd possess macromolecular bound [3H]NO2dUMP, which has properties characteristic of the NO2dUMP-dTMP synthetase complex. Treatment of L1210 leukemic mice at 400 mg/kg daily for 6 days gave only a 33% increase in life span, probably because of its rapid degradation to the inactive nitrouracil.
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D003857:Deoxyuridine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D007939:Leukemia L1210 / Q000188:drug therapy; D051379:Mice; D012313:RNA / Q000378:metabolism; D013997:Time Factors
D000970:Antineoplastic Agents; C016012:5-nitro-2'-deoxyuridine; D012313:RNA; D000255:Adenosine Triphosphate; D004247:DNA; D003857:Deoxyuridine