Degradation of 1-β-D-arabinofuranosylcytosine 5'-triphosphate in human leukemic myeloblasts and lymphoblasts

• Published in: Cancer research (Chicago, Ill.) Vol. 47; no. 12; pp. 3130 - 3135
• Main Authors: JAMIESON, G. P, FINCH, L. R, SNOOK, M, WILEY, J. S
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.06.1987
• Subjects: Antineoplastic agents; Arabinofuranosylcytosine Triphosphate - metabolism; Arabinonucleotides - metabolism; Biological and medical sciences; Cytarabine - therapeutic use; DCMP Deaminase - metabolism; General aspects; Guanosine - analogs & derivatives; Guanosine - pharmacology; Half-Life; Humans; Kinetics; Leukemia, Lymphoid - metabolism; Leukemia, Myeloid, Acute - metabolism; Lymphocytes - metabolism; Medical sciences; Pharmacology. Drug treatments; Phosphorylation; Thioinosine - analogs & derivatives; Thioinosine - pharmacology; Thionucleosides - pharmacology; Antineoplastic agent; Human; Metabolite; Metabolic activation; Lymphoblast; Acute lymphocytic leukemia; In vitro; Activity metabolism relation
• ISSN: 0008-5472; 1538-7445

The intracellular half-life for retention of the active triphosphate metabolite 1-beta-D-arabinofuranosylcytosine 5'-triphosphate (araCTP) of 1-beta-D-arabinofuranosylcytosine was measured in vitro in blast cells from patients with acute myeloblastic leukemia, acute lymphoblastic leukemia, and T-cell lymphoblastic lymphoma. araCTP accumulation from 1 microM 1-beta-D-arabinofuranosylcytosine in leukemic blast cells was closely correlated with the nucleoside transport capacity as measured by equilibrium binding of [3H]nitrobenzylthioinosine. The half-life of araCTP retention was related to araCTP accumulation only when the level of araCTP was expressed as a percentage of total intracellular 1-beta-D-arabinofuranosylcytosine metabolites. Accumulation of 1-beta-D-arabinofuranosyluracil 5'-monophosphate was inversely related to the half-life of araCTP retention and directly related to dCMP deaminase activity in cell free extracts. No conversion of 1-beta-D-arabinofuranosyluracil to 1-beta-D-arabinofuranosyluracil 5'-monophosphate was detectable in intact cells. The end product of araCTP degradation was 1-beta-D-arabinofuranosyluracil and it is proposed that conversion of 1-beta-D-arabinofuranosylcytosine 5'-monophosphate to 1-beta-D-arabinofuranosyluracil 5'-monophosphate is a step in the degradative pathway of araCTP. However, it is the cells' nucleoside transport capacity which primarily determines the level of intracellular araCTP accumulation.