Response to ICRF-159 in cell lines resistant to cleavable complex-forming topoisomerase II inhibitors.
We have studied the relationship between expression of genes implicated in mediating resistance to cleavable complex-forming topoisomerase II (topo II) inhibitors and cellular sensitivity to ICRF-159, a 'catalytic' inhibitor of topo II. Overexpression of the membrane transporters, P-glycoprotein and multidrug resistance-related protein (MRP), or down-regulation of topo IIalpha and/or -beta, did not confer ICRF-159 resistance. Indeed, marked topo IIalpha down-regulation appeared to be associated with collateral sensitivity to ICRF-159. Our results indicate that the resistance mechanisms that pertain to cleavable complex-forming topo II inhibitors and ICRF-159 are distinct. The evidence presented here suggests that topo IIalpha, not topo IIbeta, is more likely to be the major in vivo target for ICRF-159.
Davies
S L
SL
Imperial Cancer Research Fund Laboratories, University of Oxford, UK.
Bergh
J
J
Harris
A L
AL
Hickson
I D
ID
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D004250:DNA Topoisomerases, Type II / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D006801:Humans; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D011929:Razoxane / Q000494:pharmacology*; D013736:Testicular Neoplasms / Q000378:metabolism / Q000473:pathology; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000201:enzymology
D000970:Antineoplastic Agents; D012333:RNA, Messenger; D059005:Topoisomerase II Inhibitors; D011929:Razoxane; D004250:DNA Topoisomerases, Type II