Differential effects of CLDR and PDR brachytherapy on cell cycle progression in a syngeneic rat prostate tumour model

PURPOSE: The study consisted of two treatment arms comparing the effects of CLDR (continuous low dose rate) and PDR (pulsed dose rate) brachytherapy on cell cycle progression in a radioresistant rat prostate tumour model. MATERIALS AND METHODS: Interstitial PDR and CLDR brachytherapy (both 192-Ir, 0.75 Gy/h) were administered to Dunning prostate R3327-AT1 carcinomas transplanted subcutaneously into the thigh of Copenhagen rats. Increasing doses of up to 20 as well as up to 40 Gy were applied. Cell cycle distributions of the aneuploid tumour cell subpopulations were determined at 4 h (3 Gy), 24 h (18 Gy), 48 h (20 and 36 Gy), as well as during the subsequent redistribution period (20 and 40 Gy) at 72, 96, and 120 h. Tumours either implemented with an empty tubing system (n=5) or under undisturbed growth (n=5) served as controls. Three animals were irradiated per time point and exposure condition. At least two flow cytometrical analyses were carried out per animal. RESULTS: The aneuploid cells possessed a constant DNA-Index of 1.9+/-0.06. In contrast to sham-treated controls, the aneuploid cell fraction with G2/M DNA content was significantly increased (p<0.05) after initiation of both, CLDR and PDR brachytherapy. However, CLDR resulted in an earlier accumulation of tumour cells in G2/M (24 h: 28% CLDR vs. 19% PDR, p<0.05) with a concomitant reduction of cells in G1, whereas PDR yielded delayed, but then more pronounced cell cycle changes, particularly expressed during the redistribution period after both 20 and 40 Gy. CONCLUSION: CLDR and PDR brachytherapy showed differential effects on cell cycle progression. The induction of a significantly earlier but also less persistent G2/M cell cycle arrest after CLDR compared to PDR brachytherapy implies that a substantially higher fraction of tumour cells are irradiated in G2/M after CLDR.