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Blood, 15 July 2005, Vol. 106, No. 2, pp. 698-705. Prepublished online as a Blood First Edition Paper on March 31, 2005; DOI 10.1182/blood-2004-11-4286. This Article Full Text (PDF) All Versions of this Article: 2004-11-4286v1 106/2/698    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 Chen, Q. Articles by Dalton, W. S Search for Related Content PubMed PubMed Citation Articles by Chen, Q. Articles by Dalton, W. S Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted November 9, 2004 Accepted March 27, 2005 The FANC/BRCA pathway is involved in melphalan induced DNA interstrand crosslink repair and accounts for melphalan resistance in multiple myeloma cells Qing Chen, Pieter C Van der Sluis, David Boulware, Lori A Hazlehurst, and William S Dalton* Department of Interdisciplinary Oncology and Experimental Therapeutics Program, H. Lee Moffitt Cancer Center & Research Institute at the University of South Florida, Tampa, FL, USA Department of Interdisciplinary Oncology and Experimental Therapeutics Program, H. Lee Moffitt Cancer Center & Research Institute at the University of South Florida, Tampa, FL, USA; Biostatistics Core Facility, H. Lee Moffitt Cancer Center & Research Institute at the University of South Florida, Tampa, FL, USA * Corresponding author; email: Dalton{at}moffitt.usf.edu. Melphalan, a DNA crosslinker, is one of the most widely used and effective drugs in the treatment of multiple myeloma (MM). In this report, we demonstrate that enhanced interstrand crosslink (ICL) repair via the FANC/BRCA pathway contributes to acquired drug resistance in melphalan-resistant myeloma cell lines, and disruption of this pathway reverses drug resistance. Using the alkaline comet assay (single cell gel electrophoresis), we observed that melphalan-resistant cells have reduced ICL formation and enhanced ICL repair compared to melphalan-sensitive cells. Cell cycle studies demonstrated that enhanced ICL repair released cells from melphalan-induced cell cycle delay. Using siRNA to knock down FANCF in 8226/LR5 and U266/LR6 drug-resistant cells demonstrated a direct relationship between ICL repair capacity and drug sensitivity. Overexpression of FANCF in 8226/S and U266/S drug sensitive cells partially reproduced the drug resistant phenotype. These data show that enhanced DNA repair via the Fanconi anemia/BRCA pathway is involved in acquired melphalan resistance. Our findings provide for a new target to enhance response to DNA cross-linking agents in cancer treatment. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. G. Turner, D. C. Marchion, J. L. Dawson, M. F. Emmons, L. A. Hazlehurst, P. Washausen, and D. M. Sullivan Human Multiple Myeloma Cells Are Sensitized to Topoisomerase II Inhibitors by CRM1 Inhibition Cancer Res., September 1, 2009; 69(17): 6899 - 6905. [Abstract] [Full Text] [PDF] M. B. Meads, L. A. Hazlehurst, and W. S. Dalton The Bone Marrow Microenvironment as a Tumor Sanctuary and Contributor to Drug Resistance Clin. Cancer Res., May 1, 2008; 14(9): 2519 - 2526. [Abstract] [Full Text] [PDF] Q. Chen, W. Xie, D. J. Kuhn, P. M. Voorhees, A. Lopez-Girona, D. Mendy, L. G. Corral, V. P. Krenitsky, W. Xu, L. Moutouh-de Parseval, et al. Targeting the p27 E3 ligase SCFSkp2 results in p27- and Skp2-mediated cell-cycle arrest and activation of autophagy Blood, May 1, 2008; 111(9): 4690 - 4699. [Abstract] [Full Text] [PDF] M. A. Dimopoulos, V. L. Souliotis, A. Anagnostopoulos, C. Bamia, A. Pouli, I. Baltadakis, E. Terpos, S. A. Kyrtopoulos, and P. P. Sfikakis Melphalan-induced DNA damage in vitro as a predictor for clinical outcome in multiple myeloma Haematologica, November 1, 2007; 92(11): 1505 - 1512. [Abstract] [Full Text] [PDF] T. Lwin, L. A. Hazlehurst, S. Dessureault, R. Lai, W. Bai, E. Sotomayor, L. C. Moscinski, W. S. Dalton, and J. Tao Cell adhesion induces p27Kip1-associated cell-cycle arrest through down-regulation of the SCFSkp2 ubiquitin ligase pathway in mantle-cell and other non-Hodgkin B-cell lymphomas Blood, September 1, 2007; 110(5): 1631 - 1638. [Abstract] [Full Text] [PDF] T. Oda, T. Hayano, H. Miyaso, N. Takahashi, and T. Yamashita Hsp90 regulates the Fanconi anemia DNA damage response pathway Blood, June 1, 2007; 109(11): 5016 - 5026. [Abstract] [Full Text] [PDF] G. Tricot, F. Zhan, Y. Huang, B. Barlogie, and J. Shaughnessy DNA Repair Genes Are Upregulated in Multiple Myeloma (MM) Patients Relapsing after Tandem Transplantation. Blood (ASH Annual Meeting Abstracts), November 16, 2006; 108(11): 3392 - 3392. [Abstract] [Full Text] [PDF] W. Dalton and K. C. Anderson Synopsis of a Roundtable on Validating Novel Therapeutics for Multiple Myeloma. Clin. Cancer Res., November 15, 2006; 12(22): 6603 - 6610. [Abstract] [Full Text] [PDF] L. Catley, E. Weisberg, T. Kiziltepe, Y.-T. Tai, T. Hideshima, P. Neri, P. Tassone, P. Atadja, D. Chauhan, N. C. Munshi, et al. Aggresome induction by proteasome inhibitor bortezomib and {alpha}-tubulin hyperacetylation by tubulin deacetylase (TDAC) inhibitor LBH589 are synergistic in myeloma cells Blood, November 15, 2006; 108(10): 3441 - 3449. [Abstract] [Full Text] [PDF] T. Taniguchi and A. D. D'Andrea Molecular pathogenesis of Fanconi anemia: recent progress Blood, June 1, 2006; 107(11): 4223 - 4233. [Abstract] [Full Text] [PDF] L. A. Hazlehurst, R. F. Argilagos, M. Emmons, D. Boulware, C. A. Beam, D. M. Sullivan, and W. S. Dalton Cell Adhesion to Fibronectin (CAM-DR) Influences Acquired Mitoxantrone Resistance in U937 Cells Cancer Res., February 15, 2006; 66(4): 2338 - 2345. [Abstract] [Full Text] [PDF]

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