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Prepublished online as a Blood First Edition Paper on May 15, 2003; DOI 10.1182/blood-2003-01-0317. This Article Full Text Full Text (PDF) All Versions of this Article: 2003-01-0317v1 102/5/1842    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Rodriguez, C. O. Articles by Gandhi, V. Search for Related Content PubMed PubMed Citation Articles by Rodriguez, C. O., Jr Articles by Gandhi, V. Related Collections Immunobiology Neoplasia Apoptosis Cell Cycle Gene Expression Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 1 September 2003, Vol. 102, No. 5, pp. 1842-1848 NEOPLASIA Mechanisms for T-cell selective cytotoxicity of arabinosylguanine Carlos O. Rodriguez, Jr, Christine M. Stellrecht, and Varsha Gandhi From the Departments of Experimental Therapeutics and Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston. 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. H. Cohen, J. R. Johnson, T. Massie, R. Sridhara, W. D. McGuinn Jr., S. Abraham, B. P. Booth, M. A. Goheer, D. Morse, X. H. Chen, et al. Approval summary: nelarabine for the treatment of T-cell lymphoblastic leukemia/lymphoma. Clin. Cancer Res., September 15, 2006; 12(18): 5329 - 5335. [Abstract] [Full Text] [PDF] J. Kurtzberg, T.J. Ernst, M.J. Keating, V. Gandhi, J.P. Hodge, D.F. Kisor, J.J. Lager, C. Stephens, J. Levin, T. Krenitsky, et al. Phase I Study of 506U78 Administered on a Consecutive 5-Day Schedule in Children and Adults With Refractory Hematologic Malignancies J. Clin. Oncol., May 20, 2005; 23(15): 3396 - 3403. [Abstract] [Full Text] [PDF] C. M. Stellrecht, C. O. Rodriguez Jr., M. Ayres, and V. Gandhi RNA-Directed Actions of 8-Chloro-Adenosine in Multiple Myeloma Cells Cancer Res., November 15, 2003; 63(22): 7968 - 7974. [Abstract] [Full Text] [PDF]

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