Cytosine arabinoside deamination in human leukaemic myeloblasts and resistance to cytosine arabinoside therapy.
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.
D000328:Adult; D001085:Arabinofuranosylcytosine Triphosphate / Q000096:biosynthesis; D001086:Arabinofuranosyluracil / Q000096:biosynthesis; D001853:Bone Marrow / Q000378:metabolism; D002478:Cells, Cultured; D003561:Cytarabine / Q000378:metabolism* / Q000627:therapeutic use; D004273:DNA, Neoplasm / Q000096:biosynthesis; D003641:Deamination; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000378:metabolism*; D013767:Tetrahydrouridine / Q000494:pharmacology
D004273:DNA, Neoplasm; D003561:Cytarabine; D001085:Arabinofuranosylcytosine Triphosphate; D013767:Tetrahydrouridine; D001086:Arabinofuranosyluracil