Saturable Repair Models of Radiation Action in Mammalian Cells

Abstract

Most quantitative models of radiation action in mammalian cells make the implicit assumption that all relevant repair processes proceed in a dose-independent manner. Thus it is implicitly assumed that the repair processes (1) follow totally unsaturated kinetics, (2) are not themselves inactivated by the radiation, and (3) are not enhanced by the presence of radiation damage. Contradiction of any of these three assumptions could have important theoretical and practical implications. The possible relevance of (1) and (2) in mammalian cells is discussed by considering a selection of saturable repair (and related) models. Repair inactivation is improbable, but repair saturation provides a ready explanation of common radiobiological phenomena without the need for the existence of "sublethal" damage. Furthermore, such models can "explain" additional phenomena which appear as contradictions to some sublethal damage models. Recent experiments by Wheeler and Wierowski have demonstrated the existence of dose-dependent repair of DNA damage in mammalian cells.

Analyzing the Role of Biochemical Processes in Determining Response to Ionizing Radiations

“…Although these equations cannot be solved empirically, iterative processes have permitted us to determine relationships between the concentrations of enzyme molecules available at any given time and cell survival. For further information and a review of each model, see Calkins ( 197 1 ) and Goodhead (1985).…”

Effect of Dose Rate on Cell Killing and DNA Strand Break Repair in CHO Cells Exposed to Internal β-rays from Incorporated [3H]thymidine

“…For V79 cells the dose-response curve after X-irradiation was analysed using the repair model, showing that the initial rate of relevant damage was expected to be 0 . 64 per Gy (Goodhead 1985) . This rate is 1000-fold lower than generally found for the initial rate of strand breaks ranging from 300 to 1000 DNA strand breaks per Gy and per cell (see, for instance, Hagen 1973, Roots andSmith 1975) .…”

“…According to the repair model a shouldered survival curve is obtained due to `a movement of repair kinetics for the damage relevant for cell killing from an unsaturated state where the substrate concentration at low doses is much smaller than the concentration of repair enzyme, to a state where both are comparable, and on to a totally saturated state where the enzyme concentration alone is rate limiting' (Goodhead 1985) . In cells exposed at 4°C, strand break repair was measured after an accumulation of about 970 decays per cell .…”

“…One possible explanation for this generally observed phenomenon might be that repair of induced damage becomes less efficient with increasing dose or dose rate . This concept, which was first suggested by Powers (1962), was developed in greater detail later (Alper 1979, Goodhead 1982, 1985, Haynes 1966 and is generally termed the `repair model' . The main postulate of this model is the assumption that the decrease in repair efficiency is caused by either an exhausted, a saturated, or even an inactivated, repair system .…”

“…For low doses or dose rates, repair kinetics are supposed to be in an unsaturated state where the substrate concentration is much smaller than the concentration of repair enzymes . When dose or dose rate is increased both become comparable, and at even higher doses or dose rates the repair kinetics are in a saturated state where the enzyme concentration alone is rate-limiting (Goodhead 1985) . The transition of repair kinetics from an unsaturated to a saturate state causes an increase in the repair half-time .…”