Abstract
Background and PurposeNovel radiotherapy techniques increasingly use very large dose fractions. It has been argued that the biological effect of large dose fractions may differ from that of conventional fraction sizes. The purpose was to study the biological effect of large single doses.Material and MethodsClonogenic cell survival of MCF7 and MDA-MB-231 cells was determined after direct X-ray irradiation, irradiation of feeder cells, or transfer of conditioned medium (CM). Cell-cycle distributions and the apoptotic sub-G1 fraction were measured by flow cytometry. Cytokines in CM were quantified by a cytokine antibody array. γH2AX foci were detected by immunofluorescence microscopy.ResultsThe surviving fraction of MCF7 cells irradiated in vitro with 12 Gy showed an 8.5-fold decrease (95% c.i.: 4.4–16.3; P<0.0001) when the density of irradiated cells was increased from 10 to 50×103 cells per flask. Part of this effect was due to a dose-dependent transferrable factor as shown in CM experiments in the dose range 5–15 Gy. While no effect on apoptosis and cell cycle distribution was observed, and no differentially expressed cytokine could be identified, the transferable factor induced prolonged expression of γH2AX DNA repair foci at 1–12 h.ConclusionsA dose-dependent non-targeted effect on clonogenic cell survival was found in the dose range 5–15 Gy. The dependence of SF on cell numbers at high doses would represent a “cohort effect” in vivo. These results support the hypothesis that non-targeted effects may contribute to the efficacy of very large dose fractions in radiotherapy.
Highlights
With the rise of novel radiotherapy techniques such as stereotactic radiosurgery (SRS) [1,2], stereotactic body radiation therapy (SBRT) [3], high-dose-rate (HDR) brachytherapy boost [4], and intra-operative radiotherapy (IORT) [5,6], irradiation with a single or very few, very large dose fractions is becoming more frequently used
A dose-dependent non-targeted effect on clonogenic cell survival was found in the dose range 5–15 Gy
In order to improve the accuracy of surviving fraction (SF) values at 12 Gy (SF12), two different cell numbers per flask were seeded
Summary
With the rise of novel radiotherapy techniques such as stereotactic radiosurgery (SRS) [1,2], stereotactic body radiation therapy (SBRT) [3], high-dose-rate (HDR) brachytherapy boost [4], and intra-operative radiotherapy (IORT) [5,6], irradiation with a single or very few, very large dose fractions is becoming more frequently used. It has been argued that the biological effect of large doses (.,10 Gy) may be different from that predicted from the response to multiple fractions of 1.8–3 Gy commonly used in radiotherapy. A recent review on intercellular signalling in human exposure scenarios restricts the definition of genuine BEs to effects on unirradiated cells within a volume irradiated with very low doses; effects outside the irradiated volume are termed ‘‘abscopal effects’’, and effects on irradiated cells caused by other irradiated cells within the target volume are termed ‘‘cohort effects’’ [17]. Doses larger than 10 Gy, relevant for very large fraction sizes, have rarely been studied. Novel radiotherapy techniques increasingly use very large dose fractions. It has been argued that the biological effect of large dose fractions may differ from that of conventional fraction sizes. The purpose was to study the biological effect of large single doses
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