Effect of the oxic cell sensitizer, beta-ara A on human fibroblasts in plateau and in exponential growth phases

Before an oxic cell sensitizer such as beta-ara A (a DNA-dependent DNA polymerase inhibitor) can be used in cancer treatment, it is essential to know both the influence of this type of drug on certain critical normal tissues and the role of proliferation kinetics in the radiosensitizing capacity. The biological system chosen for this in vitro study was the human fibroblast cell line HF19. Cells were studied in plateau phase and in the exponential growth phase. Cells were incubated with beta-ara A for 7 hr (1 hr before and 6 hr after irradiation). beta-ara A was extremely toxic to growing cells (concentrations ranging from 200 to 1000 microM), but no detectable effect was found on plateau-phase cells (up to 4000 microM). However, for a given drug concentration, the radiosensitizing effect (Sensitizing Enhancement Ratio SER) was very similar for growing and plateau phase cells (SER measured with Ds ratio was about 1.7 for a concentration of 500 microM). The enhancement ratio depended on the radiation dose; it was relatively higher for low doses. This can be explained by a differential effect of the drug on the alpha and beta components of the survival curve. Only the alpha component was increased