HIGH CELL DENSITY-DEPENDENT RESISTANCE AND P-GLYCOPROTEIN-MEDIATED MULTIDRUG RESISTANCE IN MITOXANTRONE-SELECTED CHINESE-HAMSTER CELLS

被引:10
作者
MULLER, C [1 ]
LAVAL, F [1 ]
SOUES, S [1 ]
BIRCK, C [1 ]
CHARCOSSET, JY [1 ]
机构
[1] CNRS,PHARMACOL & TOXICOL FONDAMENTALES LAB,205 ROUTE NARBONNE,F-31077 TOULOUSE,FRANCE
关键词
D O I
10.1016/0006-2952(92)90166-G
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Mitoxantrone (MIT) resistance has been studied in a colony selected from the CHO AA8 parental line in one step under a low degree of selective pressure (9 nM). The cells of the clonal isolate AA8/MIT C1(0) were sensitive to 9 nM MIT at low cell density but able to grow at high density. Parental AA8 cells were not able to grow under the latter condition. Decreased MIT accumulation (-20%) was observed at this step (step 0) in the absence of overexpression of mdr RNA coding for the drug efflux pump P-glycoprotein. Furthermore, AA8/MIT C1(0) did not exhibit cross resistance to vincristine, Adriamycin and etoposide at low cell density. During subsequent controlled growth for 2 months at high cell density in the presence of 9 nM drug, an additional selection occurred leading to a 4-fold MIT-resistant subline AA8/MIT C1(+). This subline was characterized at this step (step I) and after an additional 4 months of culture in the presence of 9 nM MIT (step II). Analysis of mdr gene expression and gene copy number showed an increase in mdr RNA and a pattern of mdr gene amplification which changed between step I and II. AA8/MIT C1(+)II exhibited a classical multidrug resistance phenotype with decreased accumulation of [C-14]MIT and cross-resistance to vincristine, Adriamycin and etoposide. The ability to form the cleavable complex in the presence of etoposide in DNA topoisomerase II-containing nuclear extracts was identical in AA8/MIT C1(+)II and AA8 cell lines. These results demonstrate a new sequence of events in MIT resistance: low level of drug resistance at high cell density followed by mdr gene amplification.
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页码:2091 / 2102
页数:12
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