Hypophosphorylation of Topoisomerase IIα in Etoposide (VP‐16)‐resistant Human Carcinoma Cell Lines Associated with Carboxy‐terminal Truncation

Gene expression analysis for predicting gemcitabine sensitivity in pancreatic cancer patients

“…The activity or quantity of this enzyme was lower in cell lines resistant to topoisomerase II‐inhibiting drugs. In those lines, topoisomerase gene mutations were found which were presumed to be the bases for the drug resistance 15 , 16 .…”

Characterization of human NSCLC cell line with innate etoposide‐resistance mediated by cytoplasmic localization of topoisomerase II alpha

“…In all of these cells, the TOP2A gene has been affected through various mechanisms, including exonic extension through a splice site, alternative splicing, insertions or deletions, which result in large deletions in the COOH‐terminal region of topo II alpha, and consequently, the loss of a functional NLS resident in this region. ( 13–25 ) This report describes the characterization of the human NSCLC line named INER‐37, which shows an innate resistance to etoposide. In this cell line, etoposide resistance was directly associated with the expression of topo II alpha, resident mainly in the cytoplasmic region.…”

“…( 9–12 ) More recently, a third cluster of mutations and deletions has been described in the COOH‐terminal region of the enzyme, all of which result in the aberrant localization of topo II alpha in the cytoplasm. ( 13–25 ) The presence of a cytoplasmic enzyme provides a plausible explanation for the resistance of topo II poisons, as it would result in the formation of fewer topo II/DNA complexes that could be stabilized by topo II‐targeting drugs and, hence, reduce drug sensibility.…”

“…The first description of topo II poison resistance and topo II alpha cytoplasmic localization was found in the small‐cell lung cancer (SCLC) cell line H69/VP with resistance to etoposide, ( 13,14 ) and later to several other topo II poison‐resistant cell lines representative from different tissues. ( 15–25 ) In all these cell lines, deletions in the TOP2A gene around the nucleotide 4267 conduce to an alternative splicing that is translated into a truncated 160 kDa topo II alpha with cytoplasmic localization. A remarkable finding of these studies is that the truncation affected at least one of the two bipartite nuclear localization signals (NLS) present in the COOH‐terminal region of topo II alpha.…”