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Title: Phosphate-group of DNA as a potential target for RSU-1069, a nitroimidazole-aziridine radiosensitizer

Abstract

Strand breakage of plasmid DNA by parent and radiation-reduced RSU-1069 (2.0-8.0 mmol dm-3) has been measured in air over 4 hr at 310K. Reduced RSU-1069 was shown to be approximately 4 times as efficient as the parent compound at causing strand breakage. The aziridine moiety of both parent and reduced RSU-1069 is required for strand break production and, furthermore, is capable of alkylating inorganic phosphate (k = 1.0 X 10(-3) dm3 mol-1 s-1) and a series of nucleotides (k = 0.8 - 2.1 X 10(-3) dm3 mol-1 s-1) at pH 7.0. From the determined rate constants and the nature of the adducts observed, it was shown that phosphate is a target on nucleotides, although additional sites probably exist particularly, on dGMP and dAMP. The mechanism of action of RSU-1069 is discussed in terms of its ability to act as a cytotoxic agent, radiosensitizer and bioreductive drug.

Authors:
; ; ;
Publication Date:
Research Org.:
Medical Research Council, Chilton, England
OSTI Identifier:
5072265
Resource Type:
Journal Article
Journal Name:
Int. J. Radiat. Oncol., Biol. Phys.; (United States)
Additional Journal Information:
Journal Volume: 7
Country of Publication:
United States
Language:
English
Subject:
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.; DNA; STRAND BREAKS; IMIDAZOLES; RADIOSENSITIVITY EFFECTS; TOXICITY; ALKYLATING AGENTS; DNA ADDUCTS; MISONIDAZOLE; PLASMIDS; ADDUCTS; ANTINEOPLASTIC DRUGS; AZOLES; CELL CONSTITUENTS; DRUGS; HETEROCYCLIC COMPOUNDS; NUCLEIC ACIDS; ORGANIC COMPOUNDS; ORGANIC NITROGEN COMPOUNDS; RADIOSENSITIZERS; 560111* - Radiation Effects on Biochemicals- In Vitro- (-1987); 560301 - Chemicals Metabolism & Toxicology- Cells- (-1987)

Citation Formats

Silver, A R, O'Neill, P, Jenkins, T C, and McNeil, S S. Phosphate-group of DNA as a potential target for RSU-1069, a nitroimidazole-aziridine radiosensitizer. United States: N. p., 1986. Web. doi:10.1016/0360-3016(86)90258-0.
Silver, A R, O'Neill, P, Jenkins, T C, & McNeil, S S. Phosphate-group of DNA as a potential target for RSU-1069, a nitroimidazole-aziridine radiosensitizer. United States. doi:10.1016/0360-3016(86)90258-0.
Silver, A R, O'Neill, P, Jenkins, T C, and McNeil, S S. Tue . "Phosphate-group of DNA as a potential target for RSU-1069, a nitroimidazole-aziridine radiosensitizer". United States. doi:10.1016/0360-3016(86)90258-0.
@article{osti_5072265,
title = {Phosphate-group of DNA as a potential target for RSU-1069, a nitroimidazole-aziridine radiosensitizer},
author = {Silver, A R and O'Neill, P and Jenkins, T C and McNeil, S S},
abstractNote = {Strand breakage of plasmid DNA by parent and radiation-reduced RSU-1069 (2.0-8.0 mmol dm-3) has been measured in air over 4 hr at 310K. Reduced RSU-1069 was shown to be approximately 4 times as efficient as the parent compound at causing strand breakage. The aziridine moiety of both parent and reduced RSU-1069 is required for strand break production and, furthermore, is capable of alkylating inorganic phosphate (k = 1.0 X 10(-3) dm3 mol-1 s-1) and a series of nucleotides (k = 0.8 - 2.1 X 10(-3) dm3 mol-1 s-1) at pH 7.0. From the determined rate constants and the nature of the adducts observed, it was shown that phosphate is a target on nucleotides, although additional sites probably exist particularly, on dGMP and dAMP. The mechanism of action of RSU-1069 is discussed in terms of its ability to act as a cytotoxic agent, radiosensitizer and bioreductive drug.},
doi = {10.1016/0360-3016(86)90258-0},
journal = {Int. J. Radiat. Oncol., Biol. Phys.; (United States)},
number = ,
volume = 7,
place = {United States},
year = {1986},
month = {7}
}