DOE Low Dose Radiation Research Program Workshop I Abstracts November 10-12, 1999, Washington, D.C.

4. Mechanisms of Enhanced Cell Killing at Low Doses: Implications for Radiation Risk

Michael C. Joiner, Peter J. Johnston, Brian Marples, Simon D. Scott, and George D. Wilson
Gray Laboratory Cancer Research Trust, P.O. Box 100, Mount Vernon Hospital, Northwood, Middlesex HA6 2JR, United Kingdom
joiner@graylab.ac.uk

Summary: To understand why individual cells show very high sensitivity to the lethal effects of low radiation doses, and whether this protects the whole cell population by destroying mutated cells before they can propagate and cause cancer.

Abstract: We have determined previously that radiation sensitivity can be dose-dependent so that small acute exposures (and possibly exposures at very low dose rates) are more lethal per unit dose than larger exposures above a threshold (typically 5-40 cGy) where radioresistance increases. We have termed these dual phenomena low-dose hypersensitivity (HRS) and increased radioresistance (IRR) as the dose increases. HRS/IRR had been recorded in cell-survival studies with yeast, bacteria, protozoa, algae, higher plant cells and insect cells. However, we were first to demonstrate this phenomenon in mammalian cells and over the past decade, we have accumulated data indicating that HRS/IRR is widespread in both immortalized and non-immortalized human cells in vitro, and in animal normal-tissue models in vivo. More recently, research has revealed this phenomenon in the epidermis of patients under-going radiotherapy for prostate cancer. We therefore believe that HRS may be the consti-tutive response of all normal cell systems to low-dose radiation exposures, which contrasts with the belief held for many years.

Our overall aim in this project is to gather understanding of the mechanisms underlying HRS/IRR. Little is currently known. However, there is now some direct evidence that this dose-dependent radiosensitivity phenomenon reflects changes in the amount, rate or type of DNA repair, rather than indirect mechanisms such as modulation of cell-cycle progression, growth characteristics or apoptosis. There is also indirect evidence that cell survival-related HRS/IRR in response to single doses might be a manifestation of the same underlying mechanism that determines the well-known adaptive response in the two-dose case, thus HRS can be removed by prior irradiation with both high- and low-LET radiations as well as a variety of other stress-inducing agents such as hydrogen peroxide and chemotherapeutic agents. Changed expression of some genes, only in response to low and not high doses, may occur within a few hours of irradiation and this might be rapid enough to explain this.

Our goals in this project are therefore:

1. Identify which aspects of DNA repair (amount, rate and type) determine HRS/IRR,

2. Investigate the known link we have discovered between the extent of HRS/IRR and position in the cell cycle, focusing on changes in DNA structure and conformation which may modulate DNA repair,

3. Use the results from studies in (1) and (2) to distinguish, if necessary, between HRS/IRR and the adaptive response. The aim is to finally determine if these are separate or interlinked phenomena.

4. Use the results from studies in (1), (2) and (3) to propose a mechanism to explain HRS/IRR.

Net cancer risk is a balance between cell transformation and cell kill. Our hypersensitive low-dose cell-survival responses suggest that cell lethality could more than compensate for transformation at low-LET radiation doses up to about 10 cGy. This would lead to a non-linear, threshold, dose-risk relationship implying that the cancer risk from small radiation doses (<10 cGy) could be overestimated in specific cases. This out (<10 cGy) could be overestimated in specific cases. This outcome would have major cost-reduction implications for the EM program.