Preclinical activity of LBH589 alone or in combination with chemotherapy in a xenogeneic mouse model of human acute lymphoblastic leukemia.
Summary of "Preclinical activity of LBH589 alone or in combination with chemotherapy in a xenogeneic mouse model of human acute lymphoblastic leukemia."
Histone deacetylases (HDACs) have been identified as therapeutic targets due to their regulatory function in chromatin structure and organization. Here we analyzed the therapeutic effect of LBH589, a class I-II HDAC inhibitor, in acute lymphoblastic leukemia (ALL). In vitro, LBH589 induced dose-dependent antiproliferative and apoptotic effects, which were associated with increased H3 and H4 histone acetylation. Intravenous (i.v.) administration of LBH589 in immunodeficient BALB/c-RAG2(-/-)γc(-/-) mice in which human-derived T and B-ALL cell lines were injected induced a significant reduction in tumor growth. Using primary ALL cells, a xenograft model of human leukemia in BALB/c-RAG2(-/-)γc(-/-) mice was established, allowing continuous passages of transplanted cells to several mouse generations. Treatment of mice engrafted with T or B-ALL cells with LBH589 induced an in vivo increase in the acetylation of H3 and H4, which was accompanied with prolonged survival of LBH589-treated mice in comparison with those receiving Vincristine and Dexametasone. Notably, the therapeutic efficacy of LBH589 was significantly enhanced in combination with Vincristine and Dexametasone. Our results demonstrate the therapeutic activity of LBH589 in combination with standard chemotherapy in pre-clinical models of ALL and suggest that this combination may be of clinical value in the treatment of patients with ALL.Leukemia accepted article preview online, 6 February 2012; doi:10.1038/leu.2012.31.
Affiliation
Oncology Division, Foundation for Applied Medical Research, University of Navarra, Pamplona, Spain.
Journal Details
This article was published in the following journal.
Name: Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K
ISSN: 1476-5551
Pages:
Links
- PubMed Source: http://www.ncbi.nlm.nih.gov/pubmed/22307227
- DOI: http://dx.doi.org/10.1038/leu.2012.31
Medical and Biotech [MESH] Definitions
Drug Evaluation, Preclinical
Preclinical testing of drugs in experimental animals or in vitro for their biological and toxic effects and potential clinical applications.
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