Hypothesis. Elkind recovery and “sub-lethal damage”: a misleading association?

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Abstract
While some failures in radiation sterilization of tumors may be attributable to the existence of foci of hypoxic cells, another possibility is that Elkind recovery, during the fractionation intervals in a conventional radiotherapy regime, may confer more sparing on tumor cells than the clonogenic cells in normal tissues at risk. It is of clinical as well as fundamental interest that more should be learned about the cellular events during the period of Elkind recovery. That phenomenon is intimately bound up with the occurrence of shoulders in many survival curves for eukaryotic cells. It is commonly accepted that these result from the cells'' requirement for an accumulation of damaging events before they lose proliferative capacity: 2 or more hits for the inactivation of each target, or the inactivation of 2 or more targets, the survival of any 1 of which would suffice to leave the cell viable. In that context complete Elkind recovery represents the repair of every sublethal lesion in all surviving cells. Comparatively little attention was paid to a fundamentally different view of survival curve shoulders, according to which they represent a dose range within which some potentially lethal lesions are repaired. But the cells'' repair capacity decreases with increasing dose, until the survival curve approaches a final slope determined by the number of unrepaired lesions inflicted per unit dose. Surviving cells will recover their repair capacity, during a radiation free interval, and that is how Elkind recovery would be defined. Many experimental observations are well accommodated by the latter repair model. Sinclair (1972) suggested that repair might be mediated by a specific factor, Q factor, and the hypothesis would gain plausibility if Q factor could leave the nucleus and even cross the plasma membrane. The phenomenon known as repair of potentially lethal damage imposes the requirement that there is also another class of lesion the repair of which is independent of dose. The design of experiments aimed at elucidating the phenomenon of Elkind recovery must depend on the basic assumptions made to account for survival curve shoulders. Since the phenomenon is central to the mechanism by which radiation kills cells, and also has clinical implications, it would seem important that one or other of these mutually exclusive explanations should be validated.