Premium
Molecular cytogenetic characterization of doxorubicin‐resistant neuroblastoma cell lines: Evidence that acquired multidrug resistance results from a unique large amplification of the 7q21 region
Author(s) -
Flahaut Marjorie,
MühlethalerMottet Annick,
Martinet Danielle,
Fattet Sarah,
Bourloud Katia Balmas,
Auderset Katya,
Meier Roland,
Schmutz Nathalie Besuchet,
Delattre Olivier,
Joseph JeanMarc,
Gross Nicole
Publication year - 2006
Publication title -
genes, chromosomes and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.754
H-Index - 119
eISSN - 1098-2264
pISSN - 1045-2257
DOI - 10.1002/gcc.20312
Subject(s) - biology , multiple drug resistance , neuroblastoma , cancer research , amplicon , comparative genomic hybridization , drug resistance , efflux , p glycoprotein , gene , doxorubicin , locus (genetics) , genetics , cell culture , genome , chemotherapy , polymerase chain reaction
Neuroblastoma is a heterogeneous neural crest–derived embryonic childhood neoplasm that is the second most common solid tumor found in children. Despite recent advances in combined therapy, the overall survival of patients with high‐stage disease has not improved in the last decades. Treatment failure is in part attributed to multidrug resistance. To address the mechanisms involved in the development of multidrug resistance, we have generated two doxorubicin‐resistant neuroblastoma cell lines (IGRN‐91R and LAN‐1R). These cells were shown to overexpress the MDR1 gene coding for the P‐glycoprotein and were resistant to other MDR1‐ and non‐MDR1‐substrate drugs. Indeed, the MDR1 inhibitor verapamil only partially restored sensitivity to drugs, confirming that P‐glycoprotein‐mediated drug efflux was not responsible for 100% resistance. High‐resolution and array‐based comparative genomic hybridization analyses revealed the presence of an amplicon in the 7q21 region as the unique genomic alteration common to both doxorubicin‐resistant cell lines. In addition to the MDR1 locus, this large amplified region is likely to harbor additional genes potentially involved in the development of drug resistance. This study represents the first molecular cytogenetic and genomic approach to identifying genomic regions involved in the multidrug‐resistant phenotype of neuroblastoma. These results could lead to the identification of relevant target genes for the development of new therapeutic modalities. © 2006 Wiley‐Liss, Inc.