Affiliation:
1. From the Department of Interdisciplinary Oncology and Experimental Therapeutics Program, Biostatistics Core Facility, H. Lee Moffitt Cancer Center & Research Institute at the University of South Florida, Tampa, FL.
Abstract
Abstract
Melphalan, a DNA cross-linker, 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 cross-link (ICL) repair via the Fanconi anemia (FA)/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 with 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. (Blood. 2005;106:698-705)
Publisher
American Society of Hematology
Subject
Cell Biology,Hematology,Immunology,Biochemistry
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