Cecchini S, Girouard S, Huels M A, Sanche L, Hunting D J
Group in the Radiation Sciences, Department of Nuclear Medicine and Radiobiology, Université de Sherbrooke, Sherbrooke, Quebec, Canada J1H 5N4.
Radiat Res. 2004 Dec;162(6):604-15. doi: 10.1667/rr3267.
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.
在单链和双链寡核苷酸以及含有错配泡区的双链寡核苷酸中，测定了用溴脱氧尿苷（BrdUrd）替代胸苷对γ射线诱导的链断裂的影响。BrdUrd不会使互补双链DNA对γ射线诱导的链断裂敏感，但它会极大地使单链DNA敏感。然而，当BrdUrd存在于双链寡核苷酸的单链泡中时，与BrdUrd相邻的非碱基配对核苷酸以及未取代的相反链上的几个未配对位点会被强烈敏化。BrdUrd的放射增敏特性主要源于溴的亲电性质，使其成为一个良好的离去基团，并在添加一个电子后导致尿苷基自由基（dUrd(.)）或尿苷基阴离子（dUrd(-)）的不可逆形成。与单链DNA相比，双链中溴原子的辐射分解损失被极大地抑制。因此，我们提出体内溴尿嘧啶的放射增敏作用可能仅限于单链区域，如转录泡、复制叉、DNA凸起和端粒的环区域中发现的那些区域。我们的结果可能对溴脱氧尿苷（BrdUrd）作为放射增敏剂的临床应用以及靶向放射增敏剂的开发具有深远意义。
