Protracted exposure radiosensitization of experimental human malignant glioma

Clinical modulation of radiosensitivity via combined fractionated high dose rate and continuous ultra-low dose rate irradiation (ULDR) holds promise for the radiosensitization of human malignant gliomas. We measured both the in vitro and in vivo responses of a human malignant glioma cell line to combined continuous ULDR and high dose rate treatments. For in vitro ULDR treatments, U251 human malignant glioma cells were cultured in media containing tritiated water to yield a continuous dose rate of 0.03 Gy/hr. After exposures of 24, 48, or 72 hr, cells were acutely (1.1 Gy/min) irradiated, replated, and scored for colony formation. In vivo, U251 flank xenografts in nude mice had 125-iodine (125-I) seed brachytherapy at a dose rate of 0.05 Gy/hr. For whole-body continuous ULDR (0.03 Gy/hr), a 137-Cs source was mounted a fixed distance above the cages of animals bearing xenografts. After 3 days' continuous exposure, xenografts were acutely irradiated (2 Gy x 8 vs. 5 Gy x 2 daily fractions), and the regrowth delay in tumors was measured. In vitro, exposure to ULDR (0.03 Gy/hr) alone caused only modest killing and reduced the surviving fraction by approximately 0.2 logs after 72 hr exposure. The highest (10 Gy) dose of acute irradiation alone reduced survival by 1 log. However, U251 cell killing increased to 2.5 logs after combined HDR and ULDR treatments. Linear-quadratic modeling showed comparatively greater increase in the beta than the alpha coefficients of the linear-quadratic model for cell killing. In vivo, the 125-I seed brachytherapy treatments delayed tumor growth but resulted in no regression. The HDR treatments (5 Gy x 2 or 2 Gy x 8 daily fractions) caused growth delays (in days) of 17+/-2 or 16+/-2 (P=NS) days, respectively. The combined seed and 5 Gy x 2 or 2 Gy x 8 daily fractions regimen resulted in striking prolongation of regrowth delay (52.3+/-8.7 vs. 59.5+/-7.7 days) (P < 0.001 vs. HDR treatments alone). External ULDR alone caused no regression and minimal growth delay. Combined continuous external ULDR and the 5 Gy x 2 vs. 2 Gy x 8 daily fraction regimens resulted in prolongation of growth delay (33+/-0.9 (P=0.01 vs. 5 Gy x 2 daily fractions alone) vs. 35+/-0.7 (P=0.049 vs. 2 Gy x 8 daily fractions alone). We conclude that continuous ULDR increases the effect of HDR treatments of experimental malignant glioma. This increased effect may prove clinically important in the treatment of human malignant brain tumors.