Heterogeneous X-ray survival characteristics of lymphocytes in prolymphocytic leukaemia: mathematical analysis distinguishing delayed cell death and true radioresistance.

The survival of non-dividing (G0) leukaemic lymphocytes in culture is generally too short for their radiosensitivity to be quantitatively assessed, since lethally X-irradiated cells may show a long delay before manifestations of cell death ("interphase death") are seen. Counts of surviving cells will therefore include both lethally-hit cells (apparent survivors), and real survivors which have not been lethally hit. Death rates of irradiated leukaemic and normal cells show great variation between individuals, so that comparisons of radiosensitivity between different cell populations based on surviving cell counts at a single time-point are invalid. In this study the supposed radioresistance of prolymphocytic leukaemia lymphocytes was examined in 6 patients with B-cell disease. Survival curves were plotted from serial observations made over several days after graded X-irradiation (0-1000 cGy). We attempted to interpret these radiation responses in terms of their dose dependence (intrinsic radiosensitivity) and time dependence (cell death rate) characteristics using the best-fitting of four mathematical models, all based on classical "single-hit" target theory. The apparent radioresistance shown in 4 cases could be explained by very slow death rates (T1/2 values 55-205 h) of cells proving otherwise radiosensitive (D37 values 38-123 cGy). Genuine radioresistance was found in only 1 case (actual D37 value above 2000 cGy). By ignoring delayed cell death in clinical assessments, pathological lymphocytes could be mistakenly categorised as resistant to elimination by radiotherapy.