A study of cross-resistance pattern and expression of molecular markers of multidrug resistance in a human small-cell lung-cancer cell line selected with doxorubicin.
A doxorubicin-resistant variant of the human small-cell lung-cancer cell line N592 was selected by in vitro continuous exposure to increasing drug concentrations. The aim of this study was to examine the cross-resistance pattern, cellular pharmacokinetics of doxorubicin and expression of molecular factors of resistance. The sub-line N592/DX exhibited a multidrug-resistance phenotype, which was somewhat atypical, since it included cisplatin. Development of doxorubicin resistance could not be attributed to differential doxorubicin uptake or retention. Verapamil partially reverted doxorubicin resistance without affecting cellular pharmacokinetics. These findings are consistent with undetectable levels of mdr-1-gene expression in these cells. A molecular analysis of other putative mechanisms of multidrug resistance indicated no alterations in GSH levels or GSH-related enzymes, but a marginal reduction of topoisomerase II alpha expression in the resistant sub-line. This reduction, which was associated with an increase in topoisomerase I, does not explain the high degree of resistance. This study supports the view that alternative, unidentified mechanisms, which may be of clinical relevance, must be involved in the development of multidrug resistance of small-cell lung cancer.
Supino
R
R
Division of Experimental Oncology B, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy.
Binaschi
M
M
Capranico
G
G
Gambetta
R A
RA
Prosperi
E
E
Sala
E
E
Zunino
F
F
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001692:Biological Transport; D018288:Carcinoma, Small Cell / Q000503:physiopathology*; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000235:genetics / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D004351:Drug Resistance; D015870:Gene Expression; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000503:physiopathology*; D008562:Membrane Glycoproteins / Q000235:genetics; D011493:Protein Kinase C / Q000378:metabolism; D014407:Tumor Cells, Cultured; D005723:gamma-Glutamyltransferase / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D008562:Membrane Glycoproteins; D004317:Doxorubicin; D005723:gamma-Glutamyltransferase; D011493:Protein Kinase C; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II; D005978:Glutathione