A Theoretical Investigation of Cell Cycle Effects and 
Interspecies Radiosensitivies

Abstract (table of contents)

One limitation of radiobiological models currently used to quantify the cell killing effects of ionizing radiation is that they use ad hoc parameters to account for the aggregate effects of many biological and molecular processes. Such models do not provide any insight into the biological basis for cell cycle effects or for differences in cell killing among cell types. The usefulness of these models is thus severely limited. In this work, a new molecular-level model is proposed. This model accounts for the heterogeneous formation and repair of DNA damage among various types of chromatin, damage-induced cell-cycle blocking, temporal changes in the structure of a cell's chromatin, and cell desynchronization effects in groups of proliferating cells. One important aspect of the model is that all of the associated model parameters can, in principle, be estimated from ab initio calculations, measurements, or at least constrained to some meaningful range of values.

The proposed radiobiological model has been used to investigate the cell killing effects of ionizing radiation in groups of stationary-phase and proliferating Chinese Hamster cells. A series of sensitivity studies illustrating the cell killing effects associated with biological processes such as DNA damage repair, cell cycle blocking, and DNA replication have also been conducted. Finally, interspecies differences in cell killing associated with cell DNA content and the rate of cell proliferation have been investigated. The results of these studies indicate that the attempt to model the cell killing effects of ionizing radiation at a molecular level has been successful. Model results suggest that changes in the structure of a cell's chromatin during the cell cycle produce cyclic changes in the yield of damage produced in a cell. Cyclic changes in a cell's chromatin also produce cyclic changes in the rates of damage repair, fixation, and pairwise damage interaction. It is concluded that these phenomena are responsible for observed cell cycle effects. The results presented here also indicate that a portion of the DNA damage responsible for cell killing has a characteristic repair half-time between 9 and 10 hours and that damage repair is coupled to DNA replication.

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Comments

On pages 160-162, it says "Calculated and measured survival probabilities late in the S phase are in better agreement without the G2 phase block than with it (see Fig. 5.9)." It was concluded that either the Chinese Hamster cells used by Sinclair [Si69] did not have a G2 checkpoint control - or - the good agreement between measured and calculated survival probabilities in this portion of the survival curve is purely a fortuitous cancellation of model factors. Chaung et al. report [CH97] that the Chinese hamster V79 cells frequently used for studies on DNA damage and DNA repair have a mutated and nonfunctional p53 protein. Because evidence suggests that activated p53 proteins can temporarily delay cell cycle progression to allow time for DNA damage to be repaired [Ag95,Go97,Gr95,St95], the G2 phase checkpoint control in the V79 cells used by Sinclair [Si69] may have been dysfunctional.

Errata

• p. 10. table 2.1. the average nucleotide mass of the sugar-phosphate DNA sub-unit should be changed to 176.1 Da and 0.2924 x 10^-21 g.
• p. 147, caption for Fig 5.3. Change The solid lines indicate to The dashed lines indicate and change The dotted lines indicate to The solid lines indicate
• p. 153, caption for Fig. 5.4. Change 35.90 x 10^-6 to 37.75 x 10^-6.
• Appendix 3. Corrections to analytical solution of LPL model. See [Cu89] for details. NOTE: corrections (fortuitously) do not affect comparison of analytical and numerical solution comparisons in Appendix 3.

References

[Ag95] M.L. Agarwal, W.R. Taylor, and G.R. Stark, "p53 controls both the G2/M and the G1 cell cycle checkpoints and mediates reversible growth arrest in human fibroblasts," Proc. Natl. Acad. Sci. (USA), 92(18) p. 8493-8497 (1995).

[Ch97] W. Chaung, L.J. Mi, and R.J. Boorstein "The p53 status of Chinese hamster V79 cells frequently used for studies on DNA damage and DNA repair," Nucleic Acids Res., 25(5) p. 992-994 (1997).

[Cu89] S.B. Curtis, "Erratum [in the article "Lethal and Potentially Lethal Lesions Induced by Radiation – A Unified Repair Model]," Radiat. Res., 119, p. 584 (1989).

[Go97] K. Goi, M. Takagi, S. Iwata, D. Delia, M. Asada, R. Donghi, Y. Tsunematsu, S. Nakazawa, H. Yamamoto, J. Yokota, K. Tamura, Y. Saeki, J. Utsunomiya, T. Takahashi, R. Ueda, C. Ishioka, M. Eguchi, N. Kamata, and S. Mizutani, "DNA damage-associated dysregulation of the cell cycle apoptosis control in cells with germ-line p53 mutation," Cancer Res., 57(10), p. 1895-1902 (1997).

[Gr95] R. Aloni-Grinstein, D. Schwartz, and V. Rotter, "Accumulation of wild-type p53 protein upon gamma-irradiation induces a G2 arrest-dependent immunoglobulin kappa light chain gene expression," EMBO J., 14(7), p. 1392-1401 (1995).

[Si69] W.K. Sinclair, "Protection by Cysteamine Against Lethal X-ray Damage During the Cell Cycle of Chinese Hamster Cells," Radiat. Res., 39, p. 135- 154 (1969).

[St95] N. Stewart, G.G. Hicks, F. Paraskevas, and M. Mowat "Evidence for a second cell cycle block at G2/M by p53," Oncogene, 10(1), p. 109-115 (1995).