title: Characterization of in vitro radiosensitization in mammalian cells using biomathematical modelling: implications for hypofractionated radiotherapy with a combined modality approach.
abstract: OBJECTIVE
  It is unclear whether radiosensitization is beneficial when radiotherapy is administered at a high dose per fraction. The aim of this study was to assess the impact of radiation dose on the effectiveness of a broad range of radiosensitizers.
  
  
  METHODS
  We analyzed 653 pairs of clonogenic survival curves in 285 published articles, in which modifications of radiosensitivity were studied using the colony-forming assay. The modifications of radiosensitivity were arbitrarily classified into 20 classes. The survival curves were fitted to two biomathematical models: the linear-quadratic model and the repair-misrepair (RMR) model.
  
  
  RESULTS
  We found that radiosensitization was predominantly characterized by an increase of the α value (α-sensitization) without an increase of the β value (β-sensitization). A subset analysis revealed that all 20 classes showed significant α-sensitization. In contrast, only oxygen/hypoxic sensitizers (oxygen) and poly(adenosine diphosphate-ribose) polymerase inhibition (PARPi) exhibited β-sensitization. An analysis using the RMR model revealed two major sources of radiosensitization: an increased residual DNA lesion through repair inhibition and a shift from linear repairs to quadratic misrepairs, leading to enhanced lethal chromosomal aberrations.
  
  
  CONCLUSIONS
  Oxygen and PARPi were found to show β-sensitization, which was favourable for eliciting a comparable degree of sensitization in the higher dose range. Reduced fidelity of the repair was suggested to be a possible mechanism of β-sensitization. Further study targeting β-sensitization is needed to develop a novel combined modality therapy with high-dose-per-fraction radiotherapy.
  
  
  CONCLUSIONS
  Radiosensitization can be classified into two groups, α- and β-sensitizations. These two phenomena may stem from distinct underlying mechanisms.
authors.affiliation: Department of Radiation Oncology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Seo
authors.affiliation: Department of Radiation Oncology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Tamari
authors.affiliation: Department of Radiation Oncology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Yoshioka
authors.affiliation: Department of Radiation Oncology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Isohashi
authors.affiliation: Department of Radiation Oncology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Suzuki
authors.affiliation: Department of Radiation Oncology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Hayashi
authors.affiliation: Department of Radiation Oncology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Takahashi
authors.affiliation: Department of Radiation Oncology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: SungJae
authors.initials: S
authors.lastname: Baek
authors.affiliation: Department of Radiation Oncology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Otani
authors.affiliation: Department of Radiation Oncology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Ogawa
mesh_terms: D000818:Animals; D002468:Cell Physiological Phenomena / Q000187:drug effects* / Q000528:radiation effects*; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D003131:Combined Modality Therapy / Q000379:methods; D003198:Computer Simulation; D004249:DNA Damage / Q000187:drug effects / Q000502:physiology; D004307:Dose-Response Relationship, Radiation; D006801:Humans; D008954:Models, Biological; D000069473:Radiation Dose Hypofractionation; D011836:Radiation Tolerance / Q000187:drug effects* / Q000502:physiology* / Q000528:radiation effects; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage*
chemical_list: D011838:Radiation-Sensitizing Agents