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Changes in epidermal radiosensitivity with time associated with increased colony numbers

¹ Department of Radiation Oncology, Subdivision of Clinical Radiobiology, University Hospital Rotterdam—Daniel den Hoed Cancer Center/Dijkzigt Hospital, Josephine Nefkens Institute, PO Box 1738, 3000 DR Rotterdam, The Netherlands ² Normal Tissue Radiobiology Research Group, Research Institute (University of Oxford), Churchill Hospital, Oxford OX3 7LJ, UK ³ Department of Pathology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands

Epidermal clonogenic cell survival and colony formation following irradiation were investigated and related to radiosensitivity. A rapid in vivo/in vitro assay was developed for the quantification of colonies arising from surviving clonogenic cells in pig epidermis after irradiation. Bromodeoxyuridine (BrdU)-labelled cells in full thickness epidermal sheets were visualized using standard immunohistochemistry. In unirradiated skin, 900 BrdU-positive cells mm^-2 were counted. In a time sequence experiment, BrdU-positive cell numbers increased from an average of 900 cells mm^-2 to approximately 1400 cells mm^-2 after BrdU-labelling for 2–24 h. In irradiated skin, colonies containing 16 BrdU-positive cells were seen for the first time at days 14/15 after irradiation. The number of these colonies per cm² as a function of skin surface dose yielded a cell survival curve with a D₀-value (±SE) of 3.9±0.6 Gy. This relatively high D₀-value is possibly due to a rapid fall off in depth dose distribution for the iridium-192 source and consequently a substantial contribution of hair follicular epithelium to colony formation. At 14/15 days after irradiation, the ED₅₀ level of 33.6 Gy for the in vivo response of moist desquamation corresponded with 2.7 colonies cm^-2. Surprisingly, the number of colonies increased with time after irradiation with an estimated doubling time of 4 days, while the D₀-value remained virtually unchanged. This increase in colony numbers could be due to migration of clonogenic cells, to the recruitment of dormant clonogenic cell survivors by elevated levels of cytokines, or to both. Although frequent biopsying caused increased cytokine levels, which had a systemic effect on unirradiated skin, it had no influence on colony formation in irradiated skin. Smaller colonies, containing 4–8 cells or 9–15 cells, were abundant, particularly after higher doses, which resulted in higher D₀-values. The majority of these small colonies were abortive and did not progress to larger colonies. There was no statistical evidence for significant variations in the interanimal responses.