Evidence for Two Forms of Substructure in the Cell Survival Curve: Mechanisms and Clinical Consequences

Recent laboratory studies have clearly demonstrated the presence of two types of fine structure in the radiation survival response of cultured mammalian cells: a) one type of substructure, observed at doses of a few Gy, is the result of the differential killing of subpopulations of cells of different, cell-cycle-related radiosensitivity; this substructure is strongly dependent on the cell-cycle distribution and is absent in tightly synchronized cell populations; b) the other type of substructure, found at lower doses (1 Gy), is expressed as a very sensitive (hypersensitive) response at very low doses followed by increased resistance as the dose increases until, by approximately 1 Gy, the response usually follows a standard linear-quadratic (LQ) function; it thus has the characteristics of a radiation-induced radioresistance and is assumed to reflect an inducible repair process. Although the linear-quadratic (LQ) model is widely used to describe the dose-effect response both in the laboratory and in the clinic, over the past 20 years there have been several reports of an anomalous departure from the simple LQ formalism, particularly at low doses. A review of these reports suggests that the observed anomalies are not so much a failure of the LQ formalism as a manifestation of the effects of the response substructure: mixed populations, a) and hypersensitivity, b) described above.