Derivatives of
N-hydroxy-N'-aminoguanidine were recently shown to be efficient inhibitors of mammalian
ribonucleotide reductase and
cancer cell growth. We investigated the effects of the 1-isoquinolylmethylene and the 2-quinolylmethylene derivatives of
N-hydroxy-N'-aminoguanidine on intracellular targets, cell viability, and cell cycle of L1210 mouse
leukemia cells. A 2-h exposure of L1210 cells to either
drug in the low micromolar concentration range led to inhibition of intracellular
ribonucleotide reductase activity and
DNA synthesis. After a 24-h incubation in the presence of these drugs,
RNA synthesis was also markedly diminished. The clonogenicity of L1210 cells was inhibited
after treatment with the drugs for 24 and 48 h, the I50 values being comparable to the
drug concentrations required for 50% inhibition of
DNA synthesis and cell proliferation. The
isoquinoline compound was always more inhibitory to
reductase activity,
nucleic acid synthesis, and clonogenicity than the
quinoline compound. As shown by flow cytometry, the
N-hydroxy-N'-aminoguanidine isoquinoline derivative at 0.5-10 microM led to an elevation of G0/G1 cells and a decrease of G2/M and S cells.
At 10 microM of the
drug this shift remained unchanged over 48 h. L1210 cells treated with 0.5, 1, and 2 microM of the
drug overcame the block after 4 to 12 h of exposure and progressed through S- and G2/M-phase in a synchronized manner.