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

Journal Article · Fri Apr 01 00:00:00 EST 1994 · Radiation Research; (United States)

DOI:https://doi.org/10.2307/3578845· OSTI ID:6758717

Grdina, D J ^[1]; Constantinou, A ^[2]; Shigematsu, N; Murley, J S ^[3]

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1. Argonne National Lab., IL (United States) Univ. of Chicago, IL (United States)
2. Univ. of Illinois, Chicago, IL (United States)
3. Argonne National Lab., IL (United States)

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 II[alpha] 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 not reduce Topo II[alpha] activity by an average of 50%. The magnitude of Topo II[alpha] 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 g[sub 2]/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. 54 refs., 5 figs., 2 tabs.

• DOE Contract Number: W-31109-ENG-38
• OSTI ID: 6758717
• Journal Information: Radiation Research; (United States), Vol. 138:1; ISSN 0033-7587
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
CHO CELLS
BIOLOGICAL REPAIR
RADIATION INDUCED MUTANTS
RADIOPROTECTIVE SUBSTANCES
RESPONSE MODIFYING FACTORS
THIOLS
BIOCHEMICAL REACTION KINETICS
CELL CYCLE
CHEMOTHERAPY
DNA REPLICATION
ENZYME ACTIVITY
ANIMAL CELLS
BIOLOGICAL RECOVERY
DRUGS
KINETICS
MUTANTS
NUCLEIC ACID REPLICATION
ORGANIC COMPOUNDS
ORGANIC SULFUR COMPOUNDS
REACTION KINETICS
REPAIR
THERAPY
550200* - Biochemistry
560160 - Radionuclide Effects
Kinetics
& Toxicology