Increased level of ribonucleotide reductase and associated resistance to aphidicolin in mouse FM3A cell mutants selected for simultaneous resistance to 9-beta-D-arabinofuranosyladenine and 1-beta-D-arabinofuranosylcytosine.

Mutants simultaneously resistant to 9-beta-D-arabinofuranosyladenine and 1-beta-D-arabinofuranosylcytosine were isolated by single-step selection from mutagenized mouse FM3A cells with a frequency of about 10(-5). Most of the mutants showed cross-resistance to aphidicolin and excess thymidine. In some of these mutants, the level of ribonucleotide reductase was 2 approximately 5 times that of the parent with concomitantly greater resistance to hydroxyurea than that of the parent, and their reductase showed normal sensitivity in vitro to the allosteric negative effector dATP. Consequently, the intracellular pools of dATP and dCTP were expanded in the mutants. These mutants thus differ from the aphidicolin-resistant mutants isolated previously, which have an altered reductase desensitized to dATP with a concomitant increase in the dATP pool. Therefore, either increase in the level of ribonucleotide reductase or its structural change leading to desensitization to dATP seems to confer resistance to the nucleoside analogs and to aphidicolin.