tetrahydrouridine and Leukemia--Myeloid--Acute

1. The conversion of cytosine arabinoside into its active metabolite cytosine arabinoside triphosphate, and catabolism by deamination to uracil arabinoside, was measured in intact marrow myeloblasts from patients with acute myeloid leukaemia. The ratio of uracil arabinoside/cytosine arabinoside triphosphate ranged from 0.32 to 19.11. 2. The effect of tetrahydrouridine, and inhibitor of cytosine arabinoside deamination, on cytosine arabinoside triphosphate production was studied. The greatest increase of cytosine arabinoside triphosphate production caused by addition of tetrahydrouridine was 27%. 3. The increase in cytosine arabinoside triphosphate production wad not related to the ratio of uracil arabinoside/cytosine arabinoside triphosphate or to the deaminase activity per 10(6) cells. It wa proportional to the percentage change of cytosine arabinoside in the incubation medium. 4. The sensitivity of DNA synthesis to inhibition by cytosine arabinoside was measured in myeloblasts from 11 patients. Addition of tetrahydrouridine did not increase the sensitivity of the marrow to cytosine arabinoside. 5. Cytosine arabinoside deamination is unlikely to be an important mechanism of resistance in myeloblasts in vivo, although it may produce apparent resistance in vitro.

Topics: Adult; Arabinofuranosylcytosine Triphosphate; Arabinofuranosyluracil; Bone Marrow; Cells, Cultured; Cytarabine; Deamination; DNA, Neoplasm; Dose-Response Relationship, Drug; Drug Resistance; Humans; Leukemia, Myeloid, Acute; Tetrahydrouridine

Topics: Bone Marrow; Cells, Cultured; Cytarabine; Deamination; Humans; Leukemia, Myeloid, Acute; Tetrahydrouridine

The effect of 1 mu M deoxycytidine (dC) on Ara-C conversion to Ara-CTP and on inhibition of DNA synthesis by Ara-C was measured in intact leukaemic myeloblasts. dC decreased Ara-CTP production in blasts with high Ara-C phosphorylation, but not those with low activity. The Ki for dC was similar to values found with partially purified deoxycytidine kinase. The change in Ara-CTP concentration was associated with a proportional reduction in inhibition of DNA synthesis. dC decreased the effects of Ara-C by inhibition of Ara-CTP production, rather than by production of dCTP and competition with Ara-CTP. Since low Ara-CTP production in patients' blasts is a predictor of poor therapeutic response to Ara-C, the use of dC with Ara-C may improve the therapeutic index in this group of patients.

Topics: Arabinofuranosylcytosine Triphosphate; Arabinonucleotides; Deoxycytidine; DNA, Neoplasm; Humans; Kinetics; Leukemia, Myeloid, Acute; Phosphorylation; Tetrahydrouridine

Topics: Bone Marrow; Cells, Cultured; Cytarabine; Humans; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Leukocytes; Phosphotransferases; Tetrahydrouridine; Uridine

Topics: Adult; Cytarabine; Delayed-Action Preparations; Drug Resistance; Humans; In Vitro Techniques; Infusions, Parenteral; Leukemia, Myeloid, Acute; Tetrahydrouridine

Topics: Bone Marrow; Bone Marrow Cells; Cytarabine; Cytidine Deaminase; Deoxycytidine; Drug Resistance; Erythrocytes; Granulocytes; Humans; Kinetics; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Nucleoside Deaminases; Phosphotransferases; Tetrahydrouridine