SEARCH:   Advanced

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Smith, B. D. Articles by Karp, J. E. Search for Related Content PubMed Articles by Smith, B. D. Articles by Karp, J. E. Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 1 September 2003, Vol. 102, No. 5, pp. 1565 Ara-G Fas L–itates T-cell death Irreversible DNA damage is the hallmark of traditional cytotoxic chemotherapy. Antimetabolites exert their impact through interrupting the DNA replication and repair processes that are required for normal cellular function. Unfortunately, these processes are necessary for both normal and malignant cells and have resulted in fairly narrow therapeutic indexes for many agents. Efforts to find selectivity have focused on differences between normal and malignant cell populations in terms of rates of proliferation, regulation of apoptosis and cell cycle, and ability to repair DNA damage. However, the redundancy of these critical growth and survival pathways in all cell types continues to thwart our abilities to discriminate and target the malignant clone. Rodriguez and colleagues (page 1842) offer an important model to better understand the mechanisms of arabinosylguanine (ara-G)–induced lymphocyte cell death, specifically the death of T cells, and they have shed important light on the mechanisms that contribute to the drug's selectivity. Provocatively, ara-G works by at least 2 complementary mechanisms. One is the classical inhibition of DNA synthesis for all nucleoside analogs. Ara-G also exploits a unique feature of T-cell biology, the autoregulation (in part through Fas/FasL-induced apoptosis) that is fundamental to the development of a normal, functioning immune system. However, the authors' insight creates important new questions needed in order to further exploit and broaden the applicability of these findings: (1) Does ara-G trigger expression and/or liberation of multiple proapoptotic factors by additional mechanisms? (2) Do other nucleoside analogs trigger similar bystander effects? How? Is this also restricted to T cells or other lineages as well? (3) How can the selectivity of T-cell death through ara-G be translated clinically? T-cell malignancies and inherited disorders remain a small fraction of malignancies, even within their respective rare disease categories. Our bias is that broader application of this finding may be found as a treatment approach for other T-cell regulation disorders such as autoimmunity and graft-versus-host disease. We also suggest that ara-G's full potential will be realized through the development of rational combinations and sequences of drugs that exploit discrete pathways in selective and complementary fashions. B. Douglas Smith, and Judith E. Karp Sidney Kimmel Cancer Center at Johns Hopkins University CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Smith, B. D. Articles by Karp, J. E. Search for Related Content PubMed Articles by Smith, B. D. Articles by Karp, J. E. Social Bookmarking                   What's this?

	Copyright © 2003 by American Society of Hematology         Online ISSN: 1528-0020