Biochemical mechanism of drug resistance—VII: Inhibition of orotic acid metabolism by 5-azacytidine in leukemic mice sensitive and resistant to 5-azacytidine

Application of 5-azacytidine to leukemic AKR mice results in an inhibition of the utilization of orotic acid in the liver. In 5-azacytidine-sensitive animals, the inhibition is greater than in the resistant ones. Similarly, the excretion of orotic acid and orotidine in the urine is higher after application of 5-azacytidine in the sensitive animals. Cell-free extracts from leukemic cells, both sensitive and resistant to 5-azacytidine, showed a decreased activity of orotidylic acid decarboxylase after application of 5-azacytidine in vivo. The differences in the metabolism of orotate are related to the decreased ability of 5-azacytidine-resistant leukemic cells to convert 5-azacytidine to 5-azacytidine 5'-phosphate.