Derangement of DNA synthesis in erythroleukaemia. Normal deoxyuridine suppression and impaired thymidine incorporation in bone marrow culture.
Deoxyuridine (dU) suppression test (i.e. ability of exogenous dU to suppress the incorporation of subsequently added 3H-thymidine into DNA) and the incorporation of 3H-thymidine (3H-TdR) alone without dU were studied in bone marrow cultures from 10 patients with erythroleukaemia, 10 patients with vitamin B12/folate-deficient megaloblastic anaemia and 10 haematologically normal subjects. Despite morphological resemblance between megaloblastosis in erythroleukaemia and nutritional megaloblastosis, the dU suppression values in erythroleukaemia were within normal range in contrast to abnormal dU suppression in vitamin B12/folate-deficient megaloblastic bone marrows. The incorporation of 3H-thymidine alone was significantly lower in erythroleukaemia than in normal or vitamin B12/folate-deficient megaloblastic bone marrows. Autoradiographic studies showed that 3H-TdR labelling indices as well as mean grain count (MGC) of basophilic and polychromatic erythroblasts were significantly lower in erythroleukaemia than in normal or vitamin B12/folate-deficient bone marrows. The reduced incorporation of 3H-TdR in erythroleukaemia erythroblasts was probably not due to deficiency of the salvage pathway enzyme, thymidine kinase, since MTX (10(-5) M) which blocks the de novo pathway of thymine-DNA synthesis, enhanced the incorporation of 3H-TdR into erythroblasts in erythroleukaemia as well as in normal bone marrows. A high intracellular pool of thymidine-triphosphate (dTTP) due to defective DNA synthesis may allosterically inhibit thymidine kinase and 3H-TdR incorporation.
D000293:Adolescent; D000328:Adult; D000749:Anemia, Megaloblastic / Q000378:metabolism; D001853:Bone Marrow / Q000378:metabolism*; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis*; D003857:Deoxyuridine / Q000494:pharmacology; D005260:Female; D005494:Folic Acid Deficiency / Q000378:metabolism; D006801:Humans; D004915:Leukemia, Erythroblastic, Acute / Q000378:metabolism*; D008297:Male; D008727:Methotrexate / Q000494:pharmacology; D008875:Middle Aged; D013936:Thymidine / Q000378:metabolism; D014806:Vitamin B 12 Deficiency / Q000378:metabolism
D004247:DNA; D013936:Thymidine; D003857:Deoxyuridine; D008727:Methotrexate