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Prepublished online as a Blood First Edition Paper on May 15, 2003; DOI 10.1182/blood-2003-01-0317.
Submitted January 31, 2003
Accepted April 21, 2003
Mechanisms for T-cell selective cytotoxicity of arabinosylguanine
Carlos O Rodriguez, Christine M Stellrecht, and Varsha Gandhi*
Experimental Therapeutics, M.D. Anderson Cancer Center, Houston, TX, USA
* Corresponding author; email: vgandhi{at}mdanderson.org.
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 was the most sensitive to ara-G-induced apoptosis and accumulated the highest levels of ara-G triphosphate (ara-GTP). However, they incorporated less ara-G molecules into DNA; which were at internucleotide positions in all three lines. 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 h of ara-G treatment, the levels of soluble (s)FasL in the medium increased significantly in CEM cultures. In parallel, an induction of FasL gene expression was observed by real-time RT-PCR. Pretreatment of CEM 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.
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