PARENT SESSION
3:45 PM to 5:15 PM
Tuesday, April 23, 2002
Mini-Symposium 12
Cell Cycle and Apoptosis
Room: Nevada 4-5
, Co-Chair: Muschel, Ruth1; Haimovitz-Friedman, Adriana21University of Pennsylvania, Philadelphia, PA2Memorial Sloan-Kettering Cancer Center, New York, NY
(MS12-4) Mechanism of DNA radiosensitization by bromouridine.
Cecchini, Sylvain*,1, Girouard, Sonia1, Hunting, Darel1, Huels, Michael1, Sanche, Leon1, 1 Faculté de médecine, Département de Radiobiologie et Médecine nucléaire, Sherbrooke, Canada
ABSTRACT-
The radiosensitization properties of 5-bromouracil (5-BrU) have been known for forty years; however, the underlying mechanism involved in strand breakage at sites of 5-BrU incorporation is still not well understood. Irradiation of cells in which some DNA thymines (TdR) have been replaced by BrU increases the frequency of both single and double strand breaks and chromosomal alterations. The clinical potential of relatively non-toxic halogenated thymine analogues, such as 5-bromouridine (5-brUdR), 5-iodoiodine (5-IUdR) and 5-chlorouridine (5-ClUdR) in radiotherapy has long been recognized but their effects are limited to cells undergoing DNA replication and the restuls from clinical trials, while promising, have not been as good as hoped for based on the results in cultured cells and animal models. The mechanism leading to strand breakage at sites of BrU incorporation is not completely elucidated but low energy electrons interact with both thymine and bromouracil and can induce resonant dissociative attachment. We have studied the effect of BrU substitution for thymine on g-ray induced strand breakage in both single and double-stranded oligonucleotides. Our results clearly show that BrU does not sensitize double stranded DNA to g-ray-induced strand breakage but greatly sensitizes single stranded DNA. In addition, we have found that when the BrU is present in a single stranded bubble of a double stranded oligonucleotide, both the bromine substituted strand as well as several unpaired sites on the unsubstituted strand are sensitized to strand breakage by gamma-rays. Thus, one would predict that only actively transcribed genes and replication forks would be sensitized by BrU incorporation. Our results may have profound implications for the clinical use of BrUdR as a radiosensitizer. This work was funded by the National Cancer Institute of Canada.
KEYWORDS: DNA damage, radiosensitizer, gamma rays, Bromouracil