In vitro test of the cytotoxic equivalence between pulsed dose rate and continuous low dose rate

Abstract

AbstractPulsed low dose rate (PDR) irradiation is being investigated as an alternative to continuous low dose rate (CLDR) irradiation for the treatment of certain malignancies. Mathematical modeling by Brenner and Hall suggests that the two irradiation regimens will be equivalent under certain conditions. We are testing these predictions directly by using the mouse/SCC VII in vitro‐in vivo tumor model. This study involved in vitro irradiations that would not be expected to severely stress the assumptions of the mathematical model. The cytotoxicity of CLDR was compared to that for PDR regimens consisting of hourly radiation pulses of 5, 10, or 20 minutes and a 20‐minute radiation pulse every 2 hours. A total dose of 15.7 Gy of 60Co γ‐rays was delivered over the same total time for all irradiations. Confluent cultures were irradiated in low serum at room temperature to minimize the effects of cell proliferation and cell cycling. Flow cytometric analysis demonstrated that an average of ≧80% of cells were in G0/G1 phase, with ≦5% incorporating bromodeoxyuridine. Also, mitotic indices averaged <0.2%. There were no significant differences between the mean values for these cell cycle measures between CLDR and PDR or between PDR regimens. All PDR regimens showed increased cell kill relative to the CLDR, but in no case were the increases statistically significant. The increase in cell kill was by factors of 1.14–2.00, with the greatest increase in cell kill in the PDR regimen using 5‐minute pulses once per hour. The increase in cell kill, even if it was real, would not appear to be sufficient to violate the criteria for being “clinically indistinguishable,” as suggested by Brenner and Hall. Although these results generally support the modeling of Brenner and Hall, this experimental model does show increased cell killing in the PDR regimens, and this in vitro model does not stress the assumptions of the Brenner‐Hall model as severely as in vivo models would. © 1995 Wiley‐Liss, Inc.