SEARCH:   Advanced

Blood, 1 September 2008, Vol. 112, No. 5, pp. 2020-2023. Prepublished online as a Blood First Edition Paper on June 10, 2008; DOI 10.1182/blood-2008-02-137141. This Article Full Text (PDF) Supplemental Table All Versions of this Article: blood-2008-02-137141v1 112/5/2020    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 Teachey, D. T Articles by Grupp, S. A Search for Related Content PubMed PubMed Citation Articles by Teachey, D. T Articles by Grupp, S. A Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted February 7, 2008 Accepted May 28, 2008 mTOR inhibitors are synergistic with methotrexate: an effective combination to treat acute lymphoblastic leukemia (ALL) David T Teachey*, Cecilia Sheen, Junior Hall, Theresa Ryan, Valerie I. Brown, Jonathan Fish, Gregor SD Reid, Alix E Seif, Robin Norris, Yueh J Chang, Martin Carroll, and Stephan A Grupp Divison of Oncology, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsyvlania School of Medicine, Philadelphia, PA, United States Divison of Hematology and Oncology, University of Pennsylvania School of Medicine, Philadelphia, PA, United States Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, University of Pennsyvlania School of Medicine, Philadelphia, PA, United States * Corresponding author; email: teacheyd{at}email.chop.edu. We have previously demonstrated that mTOR inhibitors (MTIs) are active in preclinical models of ALL. MTIs may increase degradation of cyclin D1, a protein involved in dihydrofolate reductase (DHFR) synthesis. Because resistance to methotrexate may correlate with high DHFR expression, we hypothesized MTIs may increase sensitivity of ALL to methotrexate through decreasing DHFR by increasing turn-over of cyclin D1. We tested this hypothesis using multiple ALL cell lines and NOD/SCID mice xenografted with human ALL. We found MTIs and methotrexate were synergistic in combination in vitro and in vivo. Mice treated with both drugs went into a complete and durable remission whereas single agent treatment caused an initial partial response that ultimately progressed. ALL cells treated with MTIs had markedly decreased expression of DHFR and cyclin D1, providing a novel mechanistic explanation for a combined effect. We found methotrexate and MTIs are an effective and potentially synergistic combination in ALL. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: R. Crazzolara, A. Cisterne, M. Thien, J. Hewson, R. Baraz, K. F. Bradstock, and L. J. Bendall Potentiating effects of RAD001 (Everolimus) on vincristine therapy in childhood acute lymphoblastic leukemia Blood, April 2, 2009; 113(14): 3297 - 3306. [Abstract] [Full Text] [PDF]

	Copyright © 2008 by American Society of Hematology         Online ISSN: 1528-0020