title: Sequentially-induced responses define tumour cell radiosensitivity.
abstract: OBJECTIVE
  Our aim was to define dose-dependent and genotype-dependent components of radiosensitivity by resolving patterns of radiation-induced clonal inactivation into specific responses.
  
  
  METHODS
  In a set of 10 tumour cells with varying expression of radiosensitivity and genotype, we identified doses at which all tumour cells change in their rate of clonogenic inactivation. We tested intervening dose-segments as to whether inactivation was constant, expressing inactivation as a log-linear function of dose. We compared these segments to components proposed in the Hit-target (HT) model and the Linear-quadratic (LQ) model. Temporal changes in redistribution in cell-cycle prevalence and apoptosis were examined as essential components of cellular radiosensitivity.
  
  
  RESULTS
  We identified four distinct responses induced sequentially in all cells independent of genotype. Rates of inactivation within each response varied with expression of genotype and identified: (i) A hypersensitive component H (0.0-0.10 Gy); (ii) a resistant component R (0.1-0.2 Gy); (iii) an induced repair response alpha* (0.2 Gy and higher); and (iv) a more sensitive component omega* (3.0 Gy and higher). The H, alpha* and omega* components were fitted well by log-linear patterns, the R response did not.
  
  
  CONCLUSIONS
  Four distinct, sequentially-induced responses comprise cellular radiosensitivity. H and R responses are associated with low dose hyper-radiosensitivity and early apoptosis, while the alpha* and omega* responses share characteristics of the HT and LQ models and are associated with post-repair apoptosis. Radiation induces these four responses at the same doses in all cells, but the rate of inactivation over each response depends on genotype.
authors.affiliation: Radiation Research Laboratories, Department of Radiation Medicine, Loma Linda University & Medical Center, Loma Linda, CA 92354, USA. jrwilliams_france@yahoo.com
authors.forename: Jerry R
authors.initials: JR
authors.lastname: Williams
authors.forename: Yonggang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Haoming
authors.initials: H
authors.lastname: Zhou
authors.forename: Daila S
authors.initials: DS
authors.lastname: Gridley
authors.forename: Cameron J
authors.initials: CJ
authors.lastname: Koch
authors.forename: James M
authors.initials: JM
authors.lastname: Slater
authors.forename: John F
authors.initials: JF
authors.lastname: Dicello
authors.forename: John B
authors.initials: JB
authors.lastname: Little
mesh_terms: D017209:Apoptosis / Q000528:radiation effects; D064007:Ataxia Telangiectasia Mutated Proteins; D002453:Cell Cycle / Q000528:radiation effects; D018797:Cell Cycle Proteins / Q000235:genetics; D002869:Chromosome Aberrations; D015179:Colorectal Neoplasms / Q000235:genetics / Q000532:radiotherapy*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D004307:Dose-Response Relationship, Radiation; D016158:Genes, p53; D005838:Genotype; D005909:Glioblastoma / Q000235:genetics / Q000532:radiotherapy*; D006801:Humans; D008962:Models, Theoretical; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011836:Radiation Tolerance / Q000235:genetics*; D012062:Relative Biological Effectiveness; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases