title: Radiosensitization and production of DNA double-strand breaks in U87MG brain tumor cells induced by tetraiodothyroacetic acid (tetrac).
abstract: We describe the steady-state levels and molecular and cellular repair of DNA double-strand breaks (DSBs) in tetraiodothyroacetic acid (tetrac)-treated human U87MG glioblastoma cells after x-irradiation in vitro. This study was conducted to provide a basis for our previous observation of radiosensitization and inhibition of cellular recovery after irradiation of tetrac-exposed GL261 murine brain tumor cells. We used the neutral comet assay to assess DSBs, and found that the steady-state DSB levels as indicated by the mean tail moment after a 1 h application of 2 nM tetrac at 37 °C was increased from a value of 6.1 in control cells to 12.4 in tetrac treated cells at 0 radiation dose. However, at all radiation doses, the induction curves of DSBs were parallel, suggesting that no interaction of tetrac with the initial physical-chemical actions of ionizing radiation occurred. Flow cytometric measurements indicated that this increase was not due to alterations in the relative percentages of U87MG cells throughout the cell cycle. In split-dose DNA repair studies we found that tetrac decreased the repair rate of U87 cells by a factor of 72.5%. This suggests that the radiosensitization from graded single doses of x-rays occurs as a consequence of tetrac inhibition of the post-irradiation repair process. These results link the previously noted changes in cellular endpoints to a molecular endpoint. That is, tetrac produces increased numbers of DSBs in the unirradiated steady-state coupled with a decreased repair rate of DSBs in fractionated radiation experiments.
authors.affiliation: Department of Radiation Oncology, The Cleveland Clinic Foundation, Cleveland, OH, USA. hercbergs@gmail.com
authors.forename: Aleck H
authors.initials: AH
authors.lastname: Hercbergs
authors.forename: Hung-Yun
authors.initials: HY
authors.lastname: Lin
authors.forename: Faith B
authors.initials: FB
authors.lastname: Davis
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Davis
authors.forename: John T
authors.initials: JT
authors.lastname: Leith
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D020552:Comet Assay; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D006801:Humans; D051379:Mice; D011839:Radiation, Ionizing; D011838:Radiation-Sensitizing Agents; D013974:Thyroxine / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D011838:Radiation-Sensitizing Agents; C011126:tetraiodothyroacetic acid; D013974:Thyroxine