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Blood, 1 December 2007, Vol. 110, No. 12, pp. 4037-4046. Prepublished online as a Blood First Edition Paper on August 27, 2007; DOI 10.1182/blood-2007-02-076075. This Article Full Text (PDF) Supplemental Methods and Figures All Versions of this Article: blood-2007-02-076075v1 110/12/4037    most recent 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 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 Daniel, D. Articles by Ashkenazi, A. Search for Related Content PubMed PubMed Citation Articles by Daniel, D. Articles by Ashkenazi, A. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted February 27, 2007 Accepted August 17, 2007 Cooperation of the pro-apoptotic receptor agonist rhApo2L/TRAIL with the CD20 antibody rituximab against non-Hodgkin's lymphoma xenografts Dylan Daniel, Becky Yang, David A. Lawrence, Klara Totpal, Inessa Balter, Wyne P. Lee, Alvin Gogineni, Mary J. Cole, Sharon Fong Yee, Sarajane Ross, and Avi Ashkenazi* Department of Molecular Oncology, Genentech, Inc., South San Francisco, CA, United States Department of Translational Oncology, Genentech, Inc., South San Francisco, CA, United States Department of Immunology, Genentech, Inc., South San Francisco, CA, United States Biomedical Imaging Group, Genentech, Inc., South San Francisco, CA, United States * Corresponding author; email: aa{at}gene.com. Recombinant human rhApo2L/TRAIL selectively stimulates apoptosis in various cancer cells through its receptors DR4 and DR5, and is currently in clinical trials. Preclinical studies have established antitumor activity of rhApo2L/TRAIL in models of epithelial cancers; however, efficacy in non-Hodgkin's lymphoma (NHL) models is not well studied. Of 7 NHL cell lines tested in vitro, rhApo2L/TRAIL stimulated apoptosis in BJAB, Ramos RA1, and DoHH-2 cells. Rituximab, a CD20 antibody used to treat certain types of NHL, augmented rhApo2L/TRAIL-induced caspase activation in Ramos RA1 and DoHH2 but not BJAB or SC-1 cells, through modulation of intrinsic rather than extrinsic apoptosis signaling. In vivo, rhApo2L/TRAIL and rituximab cooperated to attenuate or reverse growth of tumor xenografts of all four of these cell lines. Depletion of NK cells or serum complement substantially reduced combined efficacy against Ramos RA1 tumors, suggesting involvement of antibody-dependent cell- and complement-mediated cytotoxicity. Both agents exhibited greater activity against disseminated than subcutaneous BJAB xenografts, and worked together to inhibit or abolish disseminated tumors and increase survival. Moreover, rhApo2L/TRAIL helped circumvent acquired rituximab resistance of a Ramos variant. These findings provide a strong rationale for clinical investigation of rhApo2L/TRAIL in combination with rituximab as a novel strategy for NHL therapy. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. Ashkenazi, P. Holland, and S. G. Eckhardt Ligand-Based Targeting of Apoptosis in Cancer: The Potential of Recombinant Human Apoptosis Ligand 2/Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (rhApo2L/TRAIL) J. Clin. Oncol., July 20, 2008; 26(21): 3621 - 3630. [Abstract] [Full Text] [PDF]

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