R.D. Stewart, J.K. Shultis and B.A. Montelone, A Kinetic Biological Model for Quiescent Cells, Report PNNL-13258, Pacific Northwest National Laboratory, Richland, WA, May 2000.

Theory and experiment suggest that the initial yield of radiation-induced DNA damage, as well as the subsequent rate of damage repair, is influenced by chromatin structure. To model chromatin structure effects better, a multiple-lesion, multiple-state model is formulated. In essence, this model is a unification and extension of the earlier repair-misrepair (RMR) and lethal and potentially lethal (LPL) models. The proposed model accounts for differences in the initial lesion yield among chromatin types. Because the model also allows the use of a different lesion repair probability (rate) for each chromatin state and type of lesion, the formalism of the model is sufficiently general to account for non-exponential or multi-exponential lesion removal transients, which are sometimes observed experimentally. Limitations of the original RMR and LPL models are illustrated and discussed by reducing the general multiple-lesion, multiple-state formalism to a simpler state-averaged model.

Contents

  ABSTRACT                                                                  ii
  INTRODUCTION                                                             1-1
  WHAT IS A LESION?                                                        2-1
      The Basic Unit of DNA Damage                                         2-1
      Prescription to Identify a Lesion                                    2-2
  GENERAL FORMULATION OF THE BALANCE EQUATIONS                             3-1
      Balance Equation for Repairable Lesions                              3-3
      Balance Equation for Mutations                                       3-5
      Balance Equation for Fatal Lesions                                   3-6
  MODEL FOR THE PRODUCTION OF LESIONS                                      4-1
      Production of Repairable Lesions by Ionizing Radiation               4-1
      Production of Fatal Lesions by Ionizing Radiation                    4-3
  MODEL FOR LESION REPAIR                                                  5-1
  MODELS FOR THE TRANSFORMATION OF LESIONS                                 6-1
      Lesion Misrepair (or Linear Misrepair)                               6-2
      Lesion Fixation                                                      6-3
      Pairwise Lesion Interaction                                          6-4
  MODEL SUMMARY AND DISCUSSION                                             7-1
      Repairable Lesions                                                   7-1
      Mutations                                                            7-2
      Fatal Lesions                                                        7-3
      Linear Energy Transfer (LET) Effects                                 7-4
  CONCLUSIONS                                                              8-1
  REFERENCES                                                               9-1

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