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Blood, 20 August 2009, Vol. 114, No. 8, pp. 1563-1575. Prepublished online as a Blood First Edition Paper on June 18, 2009; DOI 10.1182/blood-2009-02-207654. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2009-02-207654v1 114/8/1563    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 CrossRef Google Scholar Articles by Alonso, R. Articles by Colomer, D. PubMed PubMed Citation Articles by Alonso, R. Articles by Colomer, D. Related Collections Lymphoid Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  LYMPHOID NEOPLASIA Forodesine has high antitumor activity in chronic lymphocytic leukemia and activates p53-independent mitochondrial apoptosis by induction of p73 and BIM Roberto Alonso1, Mónica López-Guerra1, Ramanda Upshaw2, Shanta Bantia2, Caroline Smal3, Françoise Bontemps3, Chantal Manz4, Thomas Mehrling4, Neus Villamor1, Elias Campo1, Emili Montserrat5, and Dolors Colomer1 1 Hematopathology Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain; 2 BioCryst Pharmaceuticals Inc, Birmingham, AL; 3 Laboratory of Physiological Chemistry, de Duve Institute–Université Catholique de Louvain, Brussels, Belgium; 4 Mundipharma International Limited, Cambridge, United Kingdom; and 5 Department of Hematology, Hospital Clínic, IDIBAPS, University of Barcelona, Barcelona, Spain Chronic lymphocytic leukemia (CLL) is an incurable disease derived from the monoclonal expansion of CD5+ B lymphocytes. High expression levels of ZAP-70 or CD38 and deletions of 17p13 (TP53) and 11q22-q23 (ATM) are associated with poorer overall survival and shorter time to disease progression. DNA damage and p53 play a pivotal role in apoptosis induction in response to conventional chemotherapy, because deletions of ATM or p53 identify CLL patients with resistance to treatment. Forodesine is a transition-state inhibitor of the purine nucleoside phosphorylase with antileukemic activity. We show that forodesine is highly cytotoxic as single agent or in combination with bendamustine and rituximab in primary leukemic cells from CLL patients regardless of CD38/ZAP-70 expression and p53 or ATM deletion. Forodesine activates the mitochondrial apoptotic pathway by decreasing the levels of antiapoptotic MCL-1 protein and induction of proapoptotic BIM protein. Forodesine induces transcriptional up-regulation of p73, a p53-related protein able to overcome the resistance to apoptosis of CLL cells lacking functional p53. Remarkably, no differences in these apoptotic markers were observed based on p53 or ATM status. In conclusion, forodesine induces apoptosis of CLL cells bypassing the DNA-damage/ATM/p53 pathway and might represent a novel chemotherapeutic approach that deserves clinical investigation. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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