Mechanism of deoxycytidine rescue of thymidine toxicity in human T-leukemic lymphocytes.
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.
D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004261:DNA Replication / Q000187:drug effects; D003841:Deoxycytidine / Q000494:pharmacology*; D003854:Deoxyribonucleotides / Q000378:metabolism; D006801:Humans; D007938:Leukemia / Q000473:pathology*; D008214:Lymphocytes / Q000187:drug effects*; D012264:Ribonucleotide Reductases / Q000378:metabolism; D013936:Thymidine / Q000037:antagonists & inhibitors* / Q000633:toxicity
D003854:Deoxyribonucleotides; D003841:Deoxycytidine; D012264:Ribonucleotide Reductases; D013936:Thymidine