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Blood, 15 November 2006, Vol. 108, No. 10, pp. 3477-3483. Prepublished online as a Blood First Edition Paper on July 20, 2006; DOI 10.1182/blood-2006-04-015743. This Article Full Text (PDF) All Versions of this Article: blood-2006-04-015743v1 108/10/3477    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 CrossRef Citing Articles via Google Scholar Google Scholar Articles by Levis, M. Articles by Small, D. Search for Related Content PubMed PubMed Citation Articles by Levis, M. Articles by Small, D. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted April 11, 2006 Accepted June 12, 2006 Plasma inhibitory activity (PIA): A pharmacodynamic assay reveals insights into the basis for cytotoxic response to FLT3 inhibitors Mark Levis*, Patrick Brown, B Douglas Smith, Adam Stine, Rosalyn Pham, Richard Stone, Daniel DeAngelo, Ilene Galinsky, Frank Giles, Elihu Estey, Hagop Kantarjian, Pamela Cohen, Yanfeng Wang, Johannes Roesel, Judith E. Karp, and Donald Small Kimmel Cancer Center at Johns Hopkins Johns Hopkins University University of Washington Dana Farber Cancer Institute, Harvard MD Anderson Cancer Center, Houston, TX Novartis Oncology Inc., East Hanover, NJ Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Johns Hopkins University School of Medicine * Corresponding author; email: levisma{at}jhmi.edu. We have developed a useful surrogate assay for monitoring the efficacy of FLT3 inhibition in patients treated with oral FLT3 inhibitors. The plasma inhibitory activity (PIA) for FLT3 correlates with clinical activity in patients treated with CEP-701 and PKC412. Using the PIA assay, along with in vitro phosphorylation and cytotoxicity assays in leukemia cells, we compared PKC412 and its metabolite, CGP52421, with CEP-701. While both drugs could effectively inhibit FLT3 in vitro, CEP-701 was more cytotoxic to primary samples at comparable levels of FLT3 inhibition. PKC412 appears to be more selective than CEP-701 and therefore less effective at inducing cytotoxicity in primary acute myeloid leukemia (AML) samples in vitro. However, the PKC412 metabolite CGP52421 is less selective than its parent compound PKC412, and is more cytotoxic against primary blast samples at comparable levels of FLT3 inhibition. The plasma inhibitory activity assay represents a useful correlative tool in the development of small molecule inhibitors. Our application of this assay has revealed that the metabolite CGP52421 may contribute a significant portion of the anti-leukemia activity observed in patients receiving oral PKC412. Additionally, our results suggest that non-selectivity may constitute an important component of the cytotoxic effect of FLT3 inhibitors in FLT3-mutant AML. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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