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ID 38131
file
creator
Hong, Jae Hoon
subject
DNA topoisomernse II
VP-16
Drug resistance
NDC
Medical sciences
abstract
K6-1 and 50B-3 cell lines, resistant to VP-16, a DNA topoisomerase II inhibitor, were established from two different types of cells respectively: human T-cell derived acute lymphoblastic leukemia cell line RPMI8402 and mouse mammary tumor cell line FM3A. IC50 values of K6-1 and 50B-3 cells to VP-I6, evaluated by the colony forming ability on methyl cellulose medium, were 11- and 84-fold higher than their sensitive parental cell lines, respectively. Membrane permeability of the drug was not responsible for the resistance in K6-l and 50B-3 cells. Quantitative analysis of drug-induced DNA cleavage (so called cleavable complex formation) was performed using 32P end-labeled pBR322 restriction fragments. The formation of the topoisomerase II-DNA cleavable complex stimulated by VP-16 in 50B-3 cells was approximately 1/5 compared with that of FM3A wild-type cells. Dot blot analysis of RNA extracted from these cell lines showed that the levels of mRNA for DNA topoisomerase II in 50B-3 cells were markedly decreased and that catalytic activity was reduced to 1/2-113 compared with that of parent cells. There was a slight reduction of DNA topoisomerase II mRNA in K6-1 cells. However, DNA topoisomerase II activities were similar in wild-type and K6-1 cells. In addition, 50B-3 cells showed cross resistance to VM-26, m-AMSA and adriamycin, whereas K6-1 cells exhibited increased resistance only to VM-26. These resistant cell lines did not show collateral sensitivity to CPT-11, a DNA topoisomerase I inhibitor. Southern blot analysis of genomic DNA did not show any change in the restriction pattern of the DNA topoisomerase II gene between the parental and their resistant lines. These findings suggest that the reduced levels in DNA topoisomerase II contribute to the drug resistance of 50B-3 cells.
description
Earlier versions of this work were presented at the 47th Annual Meeting of the Japanese Cancer Association (1988, Tokyo) and at the 51th Annual Meeting of the Japanese Hematological Society (1989, Gunma).
journal title
Hiroshima Journal of Medical Sciences
volume
Volume 38
issue
Issue 4
start page
197
end page
207
date of issued
1989-12
publisher
Hiroshima University Medical Press
issn
0018-2052
ncid
pubmed id
language
eng
nii type
Departmental Bulletin Paper
HU type
Departmental Bulletin Papers
DCMI type
text
format
application/pdf
text version
publisher
department
Research Institute for Radiation Biology and Medicine
Graduate School of Biomedical Science
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