Inhibition of topoisomerase II{alpha} activity in CHO K1 cells by 2-[(aminopropyl)amino]ethanethiol (WR-1065)

Technical Report · Tue Jun 01 04:00:00 EDT 1993

DOI:https://doi.org/10.2172/10184603· OSTI ID:10184603

Grdina, D J ^[1]; Constantinou, A ^[2]; Shigematsu, N; Murley, J S ^[1]

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1. Argonne National Lab., IL (United States)
2. Illinois Univ., Chicago, IL (United States). Specialized Cancer Center

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 and antimutagenic agent when it is administered 30 min prior to radiation exposure to Chinese hamster ovary Kl cells at a concentration of 4 mM. Under these exposure conditions, topoisomerase (topo) I and II activities and associated protein contents were measured in 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 IIa activity by an average of 50 percent. The magnitude of topo IIa protein content, however, was not affected by these exposure conditions. Cell cycle effects were monitored by the method of flow cytometry. Exposure of cells to 4 mM WR-1065 for a period of up to 6 h resulted in a buildup of cells in the G2 compartment. However, in contrast to topo II inhibitors used in chemotherapy, WR-1065 is an effective radioprotector agent capable of protecting against both radiation-induced cell lethality and mutagenesis. One of several mechanisms of radiation protection attributed to aminothiol compounds such as WR-1065 has been their ability to affect endogenous enzymatic reactions involved in DNA synthesis, repair, and cell cycle progression. These results are consistent with such a proposed mechanism and demonstrate in particular a modifying effect by 2-[(aminopropyl)amino]ethanethiol on type II topoisomerase, which is involved in DNA synthesis.

• Research Organization: Argonne National Lab., IL (United States)
• Sponsoring Organization: USDOE, Washington, DC (United States); National Cancer Inst., Bethesda, MD (United States)
• DOE Contract Number: W-31109-ENG-38
• OSTI ID: 10184603
• Report Number(s): ANL/CMB/PP--80219; ON: DE93040882; CNN: Grant CA 37435
• Country of Publication: United States
• Language: English

Related Subjects

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560120
59 BASIC BIOLOGICAL SCIENCES
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
BIOCHEMICAL REACTION KINETICS
BIOCHEMISTRY
BIOLOGICAL EFFECTS
BIOLOGICAL RADIATION EFFECTS
CHO CELLS
ENZYME ACTIVITY
ENZYME INHIBITORS
ISOMERASES
MYOSIN
RADIATION EFFECTS ON BIOCHEMICALS, CELLS, AND TISSUE CULTURE
RADIOPROTECTIVE SUBSTANCES
THIONATES
X RADIATION