Importance of cell proliferative state and potentially lethal damage repair on radiation effectiveness: implications for combined tumor treatments (review).

The dependence of parameters of the linear-quadratic (LQ) model on cell proliferation kinetics of tumors in relation to potentially lethal damage (PLD) and its repair is evaluated. The influence of sensitizing agents on these parameters during fractionated radiotherapy is assessed. Suggestions for scheduling of radiation combined of with sensitizing agents are derived. The parameters alpha and beta of the linear-quadratic model for dose dependence of cell reproductive inactivation, derived from experimental and clinical data, are evaluated to assess their dependence on cell proliferative state, on PLD repair and on the action of various sensitizing agents. PLD contributes to the linear as well as to the quadratic component of the LQ model. PLD is less effectively repaired in proliferating (P) cells than in clonogenic (G0) cells of the quiescent (Q) cell compartment. PLD is influenced by various agents applied during, as well as after irradiation. The parameters alpha and beta are affected differently by the proliferative state of cells, by some of the sensitizing agents, and by radiation quality. The relative fractions of P cells and Q cells can change during fractionated treatments. If recruitment is effective, the fraction of G0 cells decreases in the latter part of a treatment schedule. PLD from subsequent radiation doses is then repaired less and the effectiveness of radiation combined with sensitizing agents may be enhanced. The analyses using the LQ model show differences in PLD and its repair between P cells and G0 cells in tumors. If due to recruitment the compartment of clonogenic G0 cells diminishes during treatment, the combination of radiation with sensitizing agents and the application of high-LET radiation should be scheduled to take this factor into account. For poorly differentiated tumors with high labeling indices (LI), benefit from combined treatments is expected from early in the course of fractionated radiotherapy. Well differentiated tumors with low LI are suggested to benefit most from irradiation combined with sensitizing agents in the latter part of a treatment schedule. New methods are required to assess the clonogenic G0 cells in the Q cell compartment and to monitor recruitment of these cells into the P cell compartment.