Radiation chemical studies of sensitization by 5-bromouridine-5'-monophosphate (5-BrUMP).
This study was undertaken to investigate the mechanism of chemical radiosensitization by halogenated bases incorporated into DNA. Radiation-induced base and sugar-phosphate backbone damage to 5-bromouridine-5'-monophosphate (5-BrUMP) was monitored using a flow system connected in series with a recording spectrophotometer, a bromide (Br-)-specific ion analyzer and a Technicon auto-sampler. The system was used to assay loss of UV-absorbing 5,6 double-bond, release of Br- and inorganic phosphate (Pi) release using an automated colorimetric method, as a function of gamma-ray dose. Results obtained with radical scavengers indicate that, unlike non-halogenated nucleotides where the hydroxyl radical (.OH) is the principal damaging species, 5-BrUMP is damaged by the hydrated electron (e-aq), hydrogen atom (H.) and .OH, producing a high yield of base damage and Br- and Pi release in anoxia. Another novel feature of 5-BrUMP radiolysis is that oxygen, by converting e-aq and H. to the unreactive superoxide radical anion (O2-), has a protective effect on both base and phosphate ester damage. Under .OH-scavenging conditions, where the radiation yield of reductive debromination is 3.8, there is some Pi release, suggesting the possibility of intramolecular hydrogen atom transfer from the sugar ring to the 5-uracilyl radical and subsequent sugar-phosphate bond cleavage. This hypothesis is supported by the action of oxygen and thiols in modifying the e-aq-mediated sugar-phosphate damage.
Greenstock
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Radiation Biology Branch, AECL Research, Chalk River Laboratories, Ontario, Canada.
Whitehouse
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D004579:Electron Transport / Q000187:drug effects; D016166:Free Radical Scavengers; D010100:Oxygen / Q000494:pharmacology; D010710:Phosphates / Q000378:metabolism; D011063:Poly A-U / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D013056:Spectrophotometry, Ultraviolet; D014542:Uridine Monophosphate / Q000031:analogs & derivatives* / Q000494:pharmacology
D016166:Free Radical Scavengers; D010710:Phosphates; D011838:Radiation-Sensitizing Agents; C074604:5-bromouridine-5'-monophosphate; D011063:Poly A-U; C018640:poly (dA-BrdU); D014542:Uridine Monophosphate; D010100:Oxygen