Selective resistance of L1210 cell lines to inhibitors directed at the subunits of ribonucleotide reductase

Abstract

L1210 cell lines were generated which were resistant to specific ribonucleotide reductase inhibitors. Hydroxyurea-resistant L1210 cells (HU-7) were cross-resistant to IMPY but sensitive to deoxyadenosine and deoxyguanosine. Deoxyadenosine-resistant L1210 cells (Y-8) were cross-resistant to 2-fluorodeoxyadenosine and showed only a small increase in resistance to hydroxyurea or IMPY. L1210 cells which were generated in the presence of deoxyadenosine/EHNA/IMPY/Desferal were markedly resistant to deoxyadenosine, deoxyguanosine and 2-fluorodeoxyadenosine with moderate increases in resistance to IMPY. The HU-7, Y-8 and ED2 cell lines were sensitive to the inhibitory effects of MAIQ and HAG-IQ. The HU-7 L1210 cell line had elevated levels of ribonucleotide reductase activity and this activity showed normal inhibition by hydroxyurea, IMPY, dATP, dGTP and dTTP. The Y-8 L1210 cell line did not have elevated levels of ribonucleotide reductase activity, but had altered allosteric properties relative to dATP. The ED2 L1210 cell line had elevated levels of ribonucleotide reductase activity and had altered allosteric properties relative to dATP. These data show that resistance to ribonucleotide reductase inhibitors is specifically generated in response to the particular drug. The biochemical basis can be related to either increased levels of ribonucleotide reductase activity or loss of feedback control by dATP or both.