ID 110755
Author
Matsumoto, Yoshihito Department of Neurological Surgery, Kagawa University School of Medicine
Tamiya, Takashi Department of Neurological Surgery, Kagawa University School of Medicine
Nagao, Seigo Department of Neurological Surgery, Kagawa University School of Medicine
Keywords
topoisomerase II
mutation
drug resistance
multidrug resistance
chemotherapy
MRP
Content Type
Journal Article
Description
For understanding of the resistance to topoisomerase II inhibitors, 50 sublines were isolated as single clones from parental glioma cell lines by exposure to VP-16 or m-AMSA. The quantitative aspects of topoisomerase IIα,multi drug resistant gene (MDR)-1,breast cancer resistance protein (BCRP), and multidrug resistant associated protein (MRP)1-5were studied by Northern blotting in 50 resistant cell lines. By understanding the function of MRP2, we picked up three drug resistant sublines (T98G-m1, T98G-m2, and gli36-VP1) that overexpressed MRP2, but did not overexpress MDR-1 orMRP1-5 except 2. Moreover, in the results of northern blot analysis of mRNA for topoisomerase IIα identical results are observed in parental cell lines and their resistant cell lines, suggesting that alterations in topoisomerase II do not account for the resistance in these cells. To determine whether the cellular sensitivity to anticancer agents was closely associated with the cellular levels of MRP2, we established cell lines with the same levels of MRP2 as their parental cells by introducing the MRP2 antisense expression plasmid into resistant cells. Etoposide (VP-16) accumulation and efflux studies were carried out in the parental cell lines and their drug resistant cell lines. Decreases in the H3-VP-16 accumulation and increases in the efflux were observed in these drug resistant cell lines. In the cytotoxicity assay, these drug resistant cell lines were resistant to multiple topoisomerase II inhibitors with little cross resistance to vincristine, and display efflux of VP-16. We found that the resistant cells transfected with MRP2 antisense cDNA displayed increased cellular levels of VP-16 and enhanced sensitivities to topoisomerase II inhibitors. In this study on the T98G-m1, T98G-m2, and gli36-VP1 cell lines, we showed a high correlation between MRP2 mRNA and VP-16 efflux, suggesting that MRP2 could be a new transporter for topoisomerase II inhibitors.
Journal Title
The journal of medical investigation : JMI
ISSN
13431420
NCID
AA11166929
Volume
52
Issue
1-2
Start Page
41
End Page
48
Sort Key
41
Published Date
2005-02
DOI (Published Version)
URL ( Publisher's Version )
FullText File
language
eng
TextVersion
Publisher