Inhibition of topoisomerase IIα activity in CHO K1 cells by 2- [(aminopropyl)amino]ethanethiol (WR-1065)
Date
1994Source
Radiation researchVolume
138Pages
44-52Google Scholar check
Keyword(s):
Metadata
Show full item recordAbstract
The aminothiol 2-[(aminopropyl)amino]ethanethiol (WR-1065) is the active thiol of the clinically studied radioprotective agent S-2-(3- aminopropylamino)ethylphosphorothioic acid (WR-2721). WR-1065 is an effective radiation protector when it is administered 30 min prior to exposure of Chinese hamster ovary K1 cells to radiation (i.e., a dose modification factor of 1.4) at a concentration of 4 mM. Under these exposure conditions, topoisomerase (Topo) I and IIα activities and associated protein contents were measured in cells of the K1 cell line using the DNA relaxation assay, the P4 unknotting assay and immunoblotting, respectively. WR-1065 was ineffective in modifying Topo I activity, but it did reduce Topo IIα activity by an average of 50%. The magnitude of Topo IIα protein content, however, was not affected by these exposure conditions. The effects on the cell cycle were monitored by the method of flow cytometry. Exposure of cells to 4 mM WR-1065 for up to 6 h resulted in a build-up of cells in the G2/M- phase compartment. However, under these conditions and in contrast to Topo II inhibitors used in chemotherapy, WR-1065 is an effective radioprotective agent capable of protecting against both radiation-induced cell lethality and mutagenesis. One of several mechanisms of action attributed to aminothiol compounds such as WR-1065 has been their ability to affect endogenous enzymatic reactions involved in DNA synthesis and repair and progression of cells through the phases of the cell cycle. These results are consistent with such a proposed mechanism and demonstrate in particular a modifying effect by WR-1065 on Topo II, which is involved in DNA synthesis.
Collections
Cite as
Related items
Showing items related by title, author, creator and subject.
-
Article
Selection of cancer chemopreventive agents based on inhibition of topoisomerase II activity
Cho, K. H.; Pezzuto, J. M.; Bolton, J. L.; Steele, V. E.; Kelloff, G. J.; Lee, S. K.; Constantinou, Andreas I. (2000)The present study was undertaken to determine if in vitro inhibition of one or both of the two most dominant mammalian DNA topoisomerases (topos) is common among chemopreventive agents. To determine if an agent was a topo ...
-
Article
Flavonoids as DNA topoisomerase antagonists and poisons: Structure-activity relationships
Constantinou, Andreas I.; Mehta, R.; Runyan, C.; Rao, K.; Vaughan, A.; Moon, R. (1995)Selected flavonoids were tested for their ability to inhibit the catalytic activity of DNA topoisomerase (topo) I and II. Myricetin, quercetin, fisetin, and morin were found to inhibit both enzymes, while phloretin, ...
-
Article
Commitment to erythroid differentiation in mouse erythroleukemia cells is controlled by alterations in topoisomerase IIα phosphorylation
Constantinou, Andreas I.; Vaughan, A. T. M.; Yamasaki, H.; Kamath, N. (1996)To explore the program of cell differentiation in Friend murine erythroleukemia (MEL) cells, we used three clonal variants: phorbol 12- myristate 13-acetate (PMA)-hypersensitive TS-19-101, PMA-resistant TR19-9, and ...