Mechanisms for T-cell selective cytotoxicity of arabinosylguanine

Blood. 2003 Sep 1;102(5):1842-8. doi: 10.1182/blood-2003-01-0317. Epub 2003 May 15.

Abstract

Nelarabine, prodrug of arabinosylguanine (ara-G), has demonstrated T-lymphoblastic antileukemic activity in cell lines and in the clinic. To investigate the mechanism for lineage-specific toxicity, the effects of ara-G were compared in CEM (T-lymphoblast), Raji (B-lymphoblast), and ML-1 (myeloid) cell lines. CEM cells were the most sensitive to ara-G-induced apoptosis and accumulated the highest levels of ara-G triphosphate (ara-GTP). However, compared with myeloid and B-lineage cell lines, CEM cells incorporated fewer ara-G molecules-which were at internucleotide positions in all 3 cell lines- into DNA. Ara-G induced an S-phase arrest in both Raji and ML-1, while in CEM the S-phase cells decreased with a concomitant increase in the sub-G1 population. Within 3 hours of ara-G treatment, the levels of soluble Fas ligand (sFasL) in the medium increased significantly in CEM cultures. In parallel, an induction of FasL gene expression was observed by real-time reverse transcriptase-polymerase chain reaction (RT-PCR). Pretreatment of CEM cells with a Fas antagonistic antibody inhibited ara-G-mediated cell death. These results demonstrate that high ara-GTP accumulation in T cells results in an S phase-dependent apoptosis induced by ara-G incorporation into DNA, which may lead to a T cell-specific signal for the induction and liberation of sFasL. Subsequently, the sFasL induces an apoptotic response in neighboring non-S-phase cells. In contrast, myeloid and B cells accumulated lower levels of ara-GTP and arrested in S phase, blocking any apoptotic signaling.

Publication types

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

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Arabinonucleosides / pharmacokinetics*
  • Cell Division / drug effects
  • Fas Ligand Protein
  • Gene Expression / drug effects
  • Guanosine Monophosphate / metabolism
  • Guanosine Triphosphate / metabolism
  • Humans
  • Jurkat Cells
  • Kinetics
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism
  • Nucleic Acid Synthesis Inhibitors / pharmacology
  • T-Lymphocytes / cytology
  • T-Lymphocytes / drug effects*
  • T-Lymphocytes / metabolism
  • Up-Regulation / drug effects
  • fas Receptor / genetics
  • fas Receptor / metabolism

Substances

  • Antineoplastic Agents
  • Arabinonucleosides
  • FASLG protein, human
  • Fas Ligand Protein
  • Membrane Glycoproteins
  • Nucleic Acid Synthesis Inhibitors
  • fas Receptor
  • 9-arabinofuranosylguanine
  • Guanosine Monophosphate
  • Guanosine Triphosphate