Leptomycin B-induced fixation of X-ray-related potentially lethal damage.

Effects of an antifungal antibiotic, Leptomycin B (LMB), on X-ray cell killing were studied using cultured mammalian cells (BHK21). LMB at concentrations from 0.05 to 2 ng/ml inhibited cell proliferation but enhanced cell killing without significant cytotoxic effect when added to cell cultures pre- and postirradiation. The degree of enhanced cell killing decreased as the interval between irradiation and LMB treatment was prolonged. Enhancement of cell killing was probably due to fixation of potentially lethal damage (PLD) to LMB. Radioresistant S-phase cells were more sensitive to LMB-induced PLD fixation than G1-phase cells. Furthermore, a preliminary study showed that LMB not only inhibited the repair of PLD which was induced by conditioned medium but also inhibited splitdose repair of sublethal damage. Although the target molecule of LMB has not been identified, we suggest that LMB inhibits repair processes by altering the structure of the nuclear scaffold, which is supposed to be a radiosensitive site.