Specific Cytotoxicity of Arabinosylguanine Toward Cultured T Lymphoblasts

J Clin Invest. 1984 Sep;74(3):951-5. doi: 10.1172/JCI111514.

Abstract

Purine nucleoside phosphorylase (PNP) deficiency in humans is associated with a severe T cell immunodeficiency. To understand further and exploit this T cell lymphospecificity, we have compared the cytotoxicities and metabolism of deoxyguanosine, the cytotoxic substrate of PNP and of arabinosylguanine, a deoxyguanosine analogue that is resistant to PNP cleavage, in T cell (8402) and B cell (8392) lines in continuous culture established from the same patient. In comparative growth rate experiments the T cells were 2.3-fold and 400-fold more sensitive to growth inhibition by deoxyguanosine and arabinosylguanine, respectively, than were the B cells. Only the T cells, but not the B cells, could phosphorylate in situ deoxyguanosine or arabinosylguanine to the corresponding triphosphate. Both the phosphorylation and cytotoxicity of arabinosylguanine in the T cell line could be prevented by deoxycytidine, which suggests that deoxycytidine-deoxyguanosine kinase initiated the intracellular metabolism and cytotoxicity of this nucleoside analogue. The sensitivity and selectivity of arabinosylguanine toward the T lymphoblastoid cells suggests a rational approach to the design of chemotherapeutic agents that are directed toward T cell malignancies and other T cell disorders.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Arabinonucleosides / toxicity*
  • B-Lymphocytes / cytology
  • B-Lymphocytes / drug effects
  • Cell Division / drug effects
  • Cell Line
  • Cell Survival / drug effects
  • Deoxyguanosine / metabolism
  • Deoxyguanosine / pharmacology
  • Humans
  • Kinetics
  • Leukemia, Lymphoid / pathology
  • T-Lymphocytes / cytology*
  • T-Lymphocytes / drug effects

Substances

  • Arabinonucleosides
  • 9-arabinofuranosylguanine
  • Deoxyguanosine