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.
Hong
J H
JH
Department of Hematology, Hiroshima University Hospital, Japan.
Okada
K
K
Kusano
T
T
Komazawa
Y
Y
Kobayashi
M
M
Mizutani
A
A
Kamada
N
N
Kuramoto
A
A
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