Toxicity of DNA-incorporated iodine-125: quantifying the direct and indirect effects.
To understand the biophysical mechanism(s) underlying the induction of cell death by the decay of the Auger electron emitter iodine-125 in DNA, Chinese hamster V79 lung fibroblasts were labeled with 5-[(125)I]iodo-2'-deoxyuridine ((125)IdU) for two doubling times and frozen and stored at -135 degrees C in the presence of 0.26-3.0 M dimethyl sulfoxide (DMSO), which acts simultaneously as a cryoprotector and a hydroxyl radical scavenger. After the accumulation of (125)I decays, the cells were defrosted and their survival was determined. Within the range of the number of decays examined (up to 470 disintegrations per cell), the survival curves are exponential. The dependence of the D(37) on DMSO concentration is triphasic and seems to reach a plateau at approximately 1.3 M. By extrapolating to infinite DMSO concentration, we estimate the D(37) for maximal hydroxyl radical scavenging to be 411 +/- 36 disintegrations per cell. To determine the D(37) in the absence of DMSO, we extrapolate the D(37) curve to zero concentration, and a D(37) of 54 +/- 5 disintegrations per cell is obtained. The maximal dose modification factor, calculated as the ratio of the D(37) at infinite DMSO concentration (i.e. direct effects only) to the D(37) at zero DMSO concentration (i.e. direct and indirect effects), is 7.6 +/- 1.0. By inference, approximately 90% of the radiotoxic effects of DNA-incorporated (125)I are due to indirect mechanisms.
Walicka
M A
MA
Harvard Medical School, Boston, Massachusetts 02115, USA.
Ding
Y
Y
Adelstein
S J
SJ
Kassiss
A I
AI
D000818:Animals; D006224:Cricetinae; D003412:Cricetulus; D003451:Cryoprotective Agents / Q000494:pharmacology; D004247:DNA / Q000528:radiation effects*; D004249:DNA Damage; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D005347:Fibroblasts / Q000737:chemistry / Q000187:drug effects / Q000528:radiation effects*; D016166:Free Radical Scavengers / Q000494:pharmacology; D005615:Freezing; D017665:Hydroxyl Radical / Q000378:metabolism; D007457:Iodine Radioisotopes / Q000032:analysis / Q000633:toxicity*; D018384:Oxidative Stress
D003451:Cryoprotective Agents; D016166:Free Radical Scavengers; D007457:Iodine Radioisotopes; D017665:Hydroxyl Radical; D004247:DNA; D004121:Dimethyl Sulfoxide