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Blood, 15 August 2004, Vol. 104, No. 4, pp. 1145-1150. Prepublished online as a Blood First Edition Paper on May 4, 2004; DOI 10.1182/blood-2004-01-0388. This Article Full Text (PDF) All Versions of this Article: 2004-01-0388v1 104/4/1145    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 Levis, M. Articles by Small, D. Search for Related Content PubMed PubMed Citation Articles by Levis, M. Articles by Small, D. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted January 30, 2004 Accepted April 11, 2004 In vitro studies of a FLT3 inhibitor combined with chemotherapy: sequence of administration is important in order to achieve synergistic cytotoxic effects Mark Levis*, Rosalyn Pham, B D Smith, and Donald Small Department of Oncology, The Kimmel Cancer Center at Johns Hopkins, Baltimore, MD, USA * Corresponding author; email: levisma{at}jhmi.edu. Acute myeloid leukemia (AML) patients harboring internal tandem duplication mutations of the FLT3 receptor (FLT3/ITD mutations) have a poor prognosis compared to patients lacking such mutations. Incorporation of FLT3 inhibitors into existing chemotherapeutic regimens has the potential to improve clinical outcomes in this high-risk group of patients. CEP-701, an indolocarbazole-derived selective FLT3 inhibitor, potently induces apoptosis in FLT3/ITD-expressing cell lines and primary leukemic blasts. We conducted a series of in vitro cytotoxicity experiments combining CEP-701 with chemotherapy using the FLT3/ITD-expressing cell lines MV4-11 and BaF3/ITD as well as a primary blast sample from an AML patient harboring a FLT3/ITD mutation. CEP-701 induced cytotoxicity in synergistic fashion with cytarabine, daunorubicin, mitoxantrone, or etoposide if used simultaneously or immediately following exposure to the chemotherapeutic agent. In contrast, the combination of pre-treatment with CEP-701 followed by chemotherapy was generally antagonistic, particularly with the more cell-cycle-dependent agents such as cytarabine. This effect appears to be due to CEP-701 causing cell cycle arrest. We conclude that in FLT3/ITD-expressing leukemia cells, CEP-701 is synergistic with standard AML chemotherapeutic agents, but only if used simultaneously or immediately following the chemotherapy. These results should be considered when designing trials combining chemotherapy with each of the FLT3 inhibitors currently in clinical development. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: FLT3 target practice Richard M. Stone Blood 2004 104: 915-916. [Full Text] [PDF] This article has been cited by other articles: Y. Shiotsu, H. Kiyoi, Y. Ishikawa, R. Tanizaki, M. Shimizu, H. Umehara, K. Ishii, Y. Mori, K. Ozeki, Y. Minami, et al. KW-2449, a novel multikinase inhibitor, suppresses the growth of leukemia cells with FLT3 mutations or T315I-mutated BCR/ABL translocation Blood, August 20, 2009; 114(8): 1607 - 1617. [Abstract] [Full Text] [PDF] S. Meshinchi and F. R. 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