[Cellular resistance to DNA-topoisomerase II inhibitors].
Chinese hamster lung cells resistant to 9-OH-ellipticine (DC-3F/9-OH-E) present a complex phenotype. These cells, which are about 150-fold resistant to 9-OH-E, display a cross-resistance to other topo-II inhibitors, such as m-AMSA or VP-16, which stabilize the cleavable complex. In addition, these cells display also a cross-resistance to suramin, which is also a topo-II inhibitor, but does not stabilize the cleavable complex. Finally, DC-3F/9-OH-E present a multidrug-resistant phenotype (MDR) which confers a cross-resistance to natural products such as actinomycin D, taxol or vincristine, due to a decrease of cellular accumulation of these drugs. Analysis of expression of the genes encoding topo-II alpha and beta, and the evaluation of both enzyme forms by immunoblotting, revealed that DC-3F cells contained about 20-fold less of the beta form than of the alpha form. The alpha form was decreased by about 4-5-fold in DC-3F/9-OH-E, whereas the beta form became undetectable. Purification and characterization of topo-II activities in sensitive and resistant cells is presently in progress. Analysis of the expression of pgp1, 2, 3 genes, involved in the MDR phenotype in hamster, by Northern blotting or by immunoblotting, has shown that the MDR phenotype in DC-3F/9-OH-E cells is due to the overexpression of pgp1 gene. In these cells, pgp3 expression is positively regulated by myc oncogene expression. Overexpression of the myc gene is followed by an overexpression of the pgp3 gene and is associated to a reversal of the MDR phenotype.
Jacquemin-Sablon
A
A
CNRS URA147-INSERM U140, unité de biochimie et enzymologie, institut Gustave-Roussy, Villejuif, France.
Bojanowski
K
K
Casabianca-Pignède
M R
MR
Crémier
S
S
Delaporte
C
C
Khelifa
T
T
Markovits
J
J
René
B
B
Saucier
J M
JM
Larsen
A K
AK
D000818:Animals; D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology; D002455:Cell Division; D002460:Cell Line; D006224:Cricetinae; D004250:DNA Topoisomerases, Type II / Q000235:genetics; D004351:Drug Resistance / Q000235:genetics*; D018432:Drug Resistance, Multiple / Q000235:genetics; D004611:Ellipticines / Q000037:antagonists & inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D008168:Lung / Q000166:cytology / Q000201:enzymology*; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D004611:Ellipticines; D059005:Topoisomerase II Inhibitors; C008009:9-hydroxyellipticine; D004250:DNA Topoisomerases, Type II
Résistance cellulaire aux inhibiteurs de l'ADN topo-isomérase II.