Inhibition of ribonucleotide reductase and L1210 cell growth by N-hydroxy-N'-aminoguanidine derivatives.
A series of N-hydroxy-N'-aminoguanidine derivatives was studied for their effects on L1210 cell growth and ribonucleotide reductase activity. With the twelve compounds studied, there was a good correlation between the inhibition of L1210 cell growth and the inhibition of ribonucleotide reductase activity. The most potent compound required concentrations of only 1.4 and 2 microM for 50% inhibition of L1210 cell growth and ribonucleotide reductase activity respectively. These guanidine analogs specifically inhibited the conversion of [14C]cytidine and deoxycytidine nucleotides in the nucleotide pool and the incorporation of [14C]cytidine into DNA without altering the incorporation of [14C]cytidine into RNA. Ribonucleotide reductase activity in drug-treated cells was reduced markedly. Iron-chelating agents did not either increase or decrease the inhibition caused by the N-hydroxy-N'-aminoguanidine derivatives. No evidence was obtained that these derivatives selectively inactivated one of the subunits of ribonucleotide reductase. These compounds appear to inhibit ribonucleotide reductase by a mechanism different from hydroxyurea or the thiosemicarbazone derivatives.
D000818:Animals; D002250:Carbon Radioisotopes; D003562:Cytidine / Q000378:metabolism; D006146:Guanidines / Q000494:pharmacology*; D007502:Iron Chelating Agents / Q000494:pharmacology; D007939:Leukemia L1210 / Q000201:enzymology / Q000473:pathology*; D051379:Mice; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors*
D002250:Carbon Radioisotopes; D006146:Guanidines; D007502:Iron Chelating Agents; D003562:Cytidine; D012264:Ribonucleotide Reductases