Metabolism of nitrobenzylthioinosine in leukemic cells

ABSTRACT

Nitrobenzylthioinosine [NBRT] an equilibrative nucleoside transporter inhibitor, was anabolized to its nucleotides following incubation with human erythrocytes, fresh and cultured leukemic cells. Concentration of NBMPR and its nucleotides in acute myelogenus leukemic [AML] cells were significantly higher than those in chronic lymphocytic [CLL] and chronic myelogenous [CML] leukemic cells. However, no significant correlation was found between concentration of cellular NBMPR and its nucleotides. In contrast to lymphocytes, human erythrocytes anabolized NBMPR only to NBMPR-monophosphate but no di- or triphosphate NBMPR was found following incubation of NBMPR with human erythrocytes. Phosphorylation of NBMPR in lymphocytes was almost completely inhibited in the presence of 10 micro M of adenosine kinase inhibitor, 5-iodotubercidin, indicating that anabolism of NBMPR was cayalyzed by adenosine kinase. NBMPR was stable up to 86% in plasma following in vitro incubation with whole blood obtained from leukemic patients. 6-thioinosine was the only significant metabolite of NBMPR in plasma [8% of total radioactive dose]. NBMPR was stable following overnight incubation with human purine nucleoside phosphorylase. No incorporation of NBMPR and/or its metabolites in nucleic acids was observed following overnight incubation of [3H]- NBMPR with fresh leukemic lymphocytes