Mechanism of deoxycytidine rescue of thymidine toxicity in human T-leukemic lymphocytes

Abstract

Cultured malignant human lymphocytes are highly sensitive to growth inhibition by thymidine (50% inhibitory dose congruent to 10(-5) M). Growth inhibition reflects sustained elevation of the deoxythymidine 5'-triphosphate pool associated with secondary elevation of the deoxyguanosine 5'-triphosphate pool and reduction in the deoxycytidine 5'-triphosphate (dCTP) pool. Deoxycytidine was capable of partially reversing thymidine growth inhibition at a concentration of 0.5 microM, and growth recovery was virtually complete at 8 microM. The dCTP pool remained depressed until growth inhibition reversal by deoxycytidine was complete, and at a higher concentration of deoxycytidine the dCTP rose above control levels, but the deoxythymidine 5'-triphosphate and deoxyguanosine 5'-triphosphate pools remained elevated. These results support the view that thymidine growth inhibition induces a critical deficiency of dCTP via allosteric inhibition of ribonucleotide reductase rather than inhibiting DNA replication directly by elevated deoxythymidine 5'-triphosphate or deoxyguanosine 5'-triphosphate pools.