Reduced DNA topoisomerase II in VP-16 resistant mouse breast cancer cell line.
VP-16 resistant cells, FvprB350 (50B-3), were isolated from mouse breast cancer cell line FM3A. 50B-3 cells showed 84-fold higher resistance than their parent cells. Reduced drug uptake was not found in resistant cells. Quantitative analysis of drug-stimulated DNA cleavage activity using 3'32P end-labeled pBR322 restriction fragments showed that VP-16 stimulated DNA-topoisomerase II cleavable complex forming activity in crude nuclear extract from 50B-3 cells was approximately one-fifth as compared with that of FM3A wild-type cells. Dot-blot analysis of RNA extracted from the two cell lines showed that mRNA levels of topoisomerase II in 50B-3 cells drastically decreased and catalytic activity was also 1/2-1/3 as compared with that of parent cells. 50B-3 cells showed cross resistance to VM-26, m-AMSA, adriamycin. These findings suggest that reduced topoisomerase II activity (cellular levels) and cleavable complex forming activity may be significant factors in the marked drug resistance.
Department of Hematology, Hiroshima University Hospital, Japan.
J H
JH
Hong
K
K
Okada
T
T
Kusano
Y
Y
Komazawa
M
M
Kobayashi
A
A
Mizutani
N
N
Kamada
A
A
Kuramoto
D000818:Animals; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D017405:Herpes Simplex Virus Protein Vmw65 / Q000494:pharmacology*; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology*; D051379:Mice; D013997:Time Factors; D014407:Tumor Cells, Cultured
D017405:Herpes Simplex Virus Protein Vmw65; D004264:DNA Topoisomerases, Type I