当前位置： SCI文献检索 > TOXICOLOGY LETTERS期刊下所有文献 > Correlation between the DNA-binding affinity of topoisomerase inhibiting drugs and their capacity to induce hematopoetic cell differentiation.

Correlation between the DNA-binding affinity of topoisomerase inhibiting drugs and their capacity to induce hematopoetic cell differentiation.

Abstract：

:There is accumulating evidence that both type I and type II DNA-topoisomerases play a key role in cellular differentiation. Human HL-60 leukemia cells can be induced to monocytic or granulocytic differentiation with various compounds; amongst them camptothecin, a topoisomerase I inhibitor and VP-16, VM-26 and mitoxantrone, all potent topoisomerase II inhibitors. During HL-60 cell differentiation topoisomerase I activity increases and topoisomerase II activity decreases. The two isoenzymes topoisomerase II alpha and topoisomerase II beta seem to have different physiological functions in highly proliferating cells, G0 cells and differentiated cells as their expression is regulated differently. In concentrations sublethal to undifferentiated cells, m-AMSA, also a potent topoisomerase II inhibitor, is able to prevent DMSO-induced granulocytic HL-60 cell differentiation. In drug-sensitive cells derived from several sources (mouse erythroleukemia, human gastric carcinoma, human leukemia), we found a functional heterogeneity of topoisomerase activity which is altered specifically during cellular differentiation. The isoactivities can be separated by their different pH and salt requirements and they exhibit different sensitivity to topoisomerase II inhibiting drugs. Functional heterogeneity of topoisomerases seems to be a prerequisite to high drug sensitivity of the cells, since drug-resistant sublines in our experiments do not exhibit this heterogeneity. We propose that the topoisomerase II inhibiting drugs which are able to induce differentiation, namely the epipodophyllotoxines VP-16 and VM-26, inhibit subfractions of the topoisomerase II pool which are necessary to maintain the undifferentiated status of the cells. These drugs induce differentiation in concentrations 10-100-fold below the lethal dose, the concentration must be sufficient to inhibit topoisomerase II but well below the concentration to induce the cleavable complex. This might be the reason that anthracyclines with a high DNA binding affinity have low differentiation-inducing capacity.

journal_name

Toxicol Lett

journal_title

Toxicology letters

authors

Gieseler F,Boege F,Clark M,Meyer P

doi

10.1016/0378-4274(93)90066-7

subject

Has Abstract

pub_date

1993-04-01 00:00:00

pages

331-40

issue

1-3

eissn

0378-4274

issn

1879-3169

pii

0378-4274(93)90066-7

journal_volume

pub_type

杂志文章

在线工具

Correlation between the DNA-binding affinity of topoisomerase inhibiting drugs and their capacity to induce hematopoetic cell differentiation.