Enhancement of the effect of X-irradiation against cultured human glioblastoma cells by pretreatment with ACNU]

Human glioblastoma A-7 (GB A-7) cells can apparently recover from potentially lethal X-irradiation. The authors, using a colony-forming assay, studied the influence of pretreatment with 1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU) on the effectiveness of X-irradiation against GB A-7 cells grown in monolayers and as multicellular spheroids. Pre-exposure to ACNU inhibited the recovery of irradiated GB A-7 cells. In monolayer cells, the combination treatment was most effective when ACNU was applied 2 to 8 hours prior to irradiation, and the larger the X-ray dose, the more potent the effect. ACNU pretreatment was more effective against large spheroids (enhancement ratio 1.86) than against small ones (1.34). Large spheroids showed necrosis, whereas small ones did not. Isobolographic analysis disclosed that the effect of combining X-irradiation and ACNU is within an additive envelope at the surviving fraction of 10(-2), while supra-additive at the surviving fraction of 10(-3). These results suggest that the potency of X-irradiation is augmented by ACNU pretreatment through an interactive mechanism. Further, suppression of recovery from X-ray induced potentially lethal damage was influenced by the presence of necrosis.