Single-strand-specific radiosensitization of DNA by bromodeoxyuridine.
The effects of bromodeoxyuridine (BrdUrd) substitution for thymidine on gamma-ray-induced strand breakage were determined in single- and double-stranded oligonucleotides and double-stranded oligonucleotides containing a mismatched bubble region. BrdUrd does not sensitize complementary double-stranded DNA to gamma-ray-induced strand breakage, but it greatly sensitizes single-stranded DNA. However, when the BrdUrd is present in a single-stranded bubble of a double-stranded oligonucleotide, the non-base-paired nucleotides adjacent to the BrdUrd as well as several unpaired sites on the opposite unsubstituted strand are strongly sensitized. The radiosensitization properties of BrdUrd result primarily from the electrophilic nature of the bromine, making it a good leaving group and leading to the irreversible formation of the uridine-yl radical (dUrd(.)) or the uridine-yl anion (dUrd(-)) upon addition of an electron. The radiolytic loss of the bromine atom is greatly suppressed in double-stranded compared to single-stranded DNA. Thus we propose that the radiosensitization effects of bromouracil in vivo will likely be limited to single-strand regions such as found in transcription bubbles, replication forks, DNA bulges and the loop region of telomeres. Our results may have profound implications for the clinical use of bromodeoxyuridine (BrdUrd) as a radiosensitizer as well as for the development of targeted radiosensitizers.
Cecchini
S
S
Group in the Radiation Sciences, Department of Nuclear Medicine and Radiobiology, Université de Sherbrooke, Sherbrooke, Quebec, Canada J1H 5N4.
Girouard
S
S
Huels
M A
MA
Sanche
L
L
Hunting
D J
DJ
D001973:Bromodeoxyuridine / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D004249:DNA Damage; D004277:DNA, Single-Stranded / Q000528:radiation effects*; D005720:Gamma Rays; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*
D004277:DNA, Single-Stranded; D011838:Radiation-Sensitizing Agents; D001973:Bromodeoxyuridine