Radiation Effects on Cell Cycle Dynamics

Abstract

A number of inconsistencies appear when attempts are made to correlate some of the experimental radiobiologic data with clinical problems. Not the least of these is the firm clinical opinion that fractionation of radiation treatments is of value. The response of mammalian cells to ionizing radiation is characterized by a logarithmic decrease in their surviving fraction with increasing radiation dose. Extrapolation of this survival curve data to 1010 cells yields a predicted tumor curative dose in the clinically therapeutic range (1, 2). This, however, would be for a single exposure. The curved shape of the initial portion of the survival curve would suggest that multiple exposures in the 200 rad range would rarely produce a cure with a total tumor dose of 5,000 to 7,000 rad (3). For our purposes, radiation sensitivity is defined in relation to loss of reproductive integrity; that is, the loss of the ability of cells to undergo multiple subsequent mitotic divisions. A number of recent papers have demonstrated considerable variation in the radiation sensitivity around the cell cycle (4–6, 9). While opinions differ as to the most sensitive period, there is no doubt that such periods exist. It is shown in Figure 1 that the variation in sensitivity may be as great as fourfold from one portion of the cell cycle to another. It would appear that “G1” is insensitive and that “G2” is relatively sensitive with differences of opinion concerning the relative sensitivity of the “S” period. The sensitivity of a randomly dividing population is the sum of the sensitivities of each period. The survival curves of such populations represent such a summation of the proportion of cells in each period. Terasima and Tohnach (6) have constructed a curve with these variations in sensitivity which is indistinguishable from the published experimental survival curves for many cell lines. One need not postulate a homogeneous population to have a linear portion of the survival curve. In any treatment involving more than one dose, we are dealing with random distribution within the cell cycle for the first exposure only. Each succeeding exposure is to a modified cell population which has been altered in number and physiologic state. In any such circumstance, there will be an optimum interval between doses to achieve a maximum effect with a minimal total dose. Elkind (7) and Till (8) have shown that, following an exposure of ionizing radiation, the radiosensitivity of the surviving fraction of tissue culture cells changes profoundly with time in the post-irradiation period. An attempt is made to represent this diagrammatically in Figure 2. In such systems of several different cell lines, this change consists of a period of several hours during which there is a decreasing sensitivity, followed by a period of two to three hours when there is an increase and then a succeeding period of decreasing sensitivity.