Preliminary evidence for a dose-rate-dependent threshold for low dose suppression of radiation-induced neoplastic transformation in vitro

J.L. Redpath, X-Y. Lao, R. Kapadia, E. Giedzinski, C. Limoli and E. Elmore Department of Radiation Oncology, University of California Irvine, Irvine, CA.

Purpose: To see if adaptation against neoplastic transformation could be induced by exposure to very low dose-rate (VLDR) low-LET radiation.

Experimental Procedures: HeLa x skin fibroblast human hybrid cells were irradiated with ~30 kVp photons from an array of I-125 seeds. The initial dose-rate was 4 mGy/day. The cell cultures were split after 10 days to avoid overcrowding. Half of the culture was processed for the presence of ROS. The other half was returned to the irradiator. At 20 days the culture was again split with half being used for a transformation assay and the other half being returned to the irradiator. This procedure was continued for a 3 mo. period by which time the dose-rate had declined to 1 mGy/day (acc. dose ~250 mGy). This allowed for 4 separate assays. Transformation frequencies were compared to those of parallel unirradiated controls. At the end of 3 mo. VLDR treated cells were exposed to a high dose-rate 3 Gy challenge dose of Cs-137 gamma rays and this was compared with the effect of 3 Gy on parallel unirradiated cells.

Results: Cells exposed to VLDR radiation exhibited a trend towards a reduction in neoplastic transformation frequency compared to the unirradiated controls. This reduction seemed to diminish with time indicating that the dose-rate, rather than accumulated dose, may be the more important factor in eliciting an adaptive response. This pattern was paralleled by a reduction of ROS present in the irradiated cultures compared to controls. The VLDR treated cells were less sensitive to a high challenge dose suggesting the induction of an adaptive response. Since there was a suggestion of a dose-rate threshold for induction of suppression, a second experiment was started with a fresh batch of cells at an initial dose-rate of < 0.8 mGy/day. These cells were allowed to accumulate ~27 mGy over a period of 45 days. In this experiment there was no evidence of an adaptive response as indicated by a lack of suppression of transformation in the VLDR only treated cells.

Conclusions: VLDRs in the range 1 to 4 mGy/day induced an adaptive response against neoplastic transformation in vitro. This adaptive response was apparently lost at dose-rates below ~1 mGy/day suggesting a dose-rate-dependent threshold.

Acknowledgments: Supported by the U.S.D.O.E. Low Dose Program Grant No.’s DE-FG02-03ER63548 and DE-FG02-05ER64083.

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