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

While some failures in radiation sterilization of tumours 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 régime, may confer more sparing on tumour cells than on the clonogenic cells in the normal tissues at risk. It is therefore of clinical as well as of 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: two or more “hits” for the inactivation of each target, or the inactivation of two or more targets, the survival of any one of which would suffice to leave the cell viable. In that context, complete Elkind recovery represents the repair of every “sub-lethal lesion” in all surviving cells. Comparatively little attention has been 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. However, surviving cells will recover their repair capacity, during a radiation-free interval, and that is how Elkind recovery would be denned. Many experimental observations are well accommodated by that 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. However, 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, to a large extent, 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.