MODELING THE YIELD OF DOUBLE-STRAND BREAKS DUE TO FORMATION OF MULTIPLY DAMAGED SITES IN IRRADIATED PLASMID DNA

Although double-strand breaks ha ve long been recognized as an importa nt type of DNA lesion, it is well established that this broad class of damage does not correlate well with indicators of the effectiveness o f radiation at the cellular level. Assays of double-strand breaks do n ot distinguish the degree of complexity or clustering of singly damage d sites produced in a single energy deposition event, which is current ly hypothesized to be key to understanding cellular end points. As a s tep toward this understanding, double-strand breaks that are formed pr oportionally to dose in plasmid DNA are analyzed from the mechanistic aspect to evaluate the yield that arises from multiply damaged sites a s hypothesized by Ward (Frog. Nucleic Acid Res. Mel. Biol. 35, 95-125, 1988) and Goodhead (Int. J. Radiat. Biol. 65, 7-17, 1994) as opposed to the yield that arises from single hydroxyl radicals as hypothesized by Siddiqi and Bothe (Radiat. Res. 112, 449-463, 1987). For low-LET r adiation such as gamma rays, the importance of multiply damaged sites is shown to increase with the solution's hydroxyl radical scavenging c apacity. For moderately high-LET radiation such as 100 keV/mu m helium ions, a much different behavior is observed. In this case, a large fr action of double-strand breaks are formed as a result of multiply dama ged sites over a broad range of scavenging conditions. Results also in dicate that the RBE for common cellular end points correlates more clo sely with the RBE for multiply damaged sites than with the RBE for tot al double-strand breaks over a range of LET up to at least 100 keV/mu m. (C) 1996 by Radiation Research society