Repopulation in Murine Skin after X-Ray Treatments with Multiple Fractions per Day

Abstract

The kinetics of repopulation of clonogens in skin after fractionated X-ray exposures was studied in a series of experiments using a top-up design. The feet of mice were exposed to small X-ray doses (1.5 or 2 Gy), given two or three times a day on consecutive days with a minimum interfraction interval of 8 h. A single top-up dose of d(4)-Be neutrons was then given at various intervals after the last X-ray fraction, typically on Days 1,4,8, 15, and 19. The acute skin reaction produced was scored an analyzed by both a standard 23-day averaging and a 7-day averaging procedure. Either method gave similar results and led to the same conclusions. The amount of top-up dose needed to produce a fixed skin reaction was used as a measure of the net effect of the X-ray treatments. This net effect is a result of the initial reduction in skin clonogens due to X rays, and their repopulation before the top-up dose was given. Repopulation was not detected during any of these courses of fractionated treatment, up to an overall time of at least 12 and possibly 16 days. On completion of X-ray schedules lasting 6-16 days, repopulation started 4 days later. In contrast, this delay lengthened to approximately 8 days for shorter overall treatment times of 3-4 days. Once repopulation started, it proceeded rapidly over 11 days so that by 15 days after the cessation of X rays, the skin was restored almost to its normal state with respect to radiosensitivity. The residual damage from Day 15 to Day 19 postirradiation was 3-13% of a full-effect level. The rate of repopulation can be expressed as a clonogen doubling time (Tclon), assuming that an average skin reaction of 1.5 is equivalent to a clonogen surviving fraction of 1.7 x 10(-5). Tclon varied inversely with the amount of initial damage inflicted by the X rays, with the shortest values (1-1.3 days) seen following X-ray doses that gave an initial damage level of 60-80% of full effect. These data are consistent with a hypothesis that damage is "sensed" only 10-12 days after the first X-ray fraction, which provides the stimulus for repopulation of the target cells in the basal layer, the keratinoblasts.(ABSTRACT TRUNCATED AT 250 WORDS)

The influence of a seventy-two hour gap on the acute response of mouse skin and oesophagus

“…Although some studies suggest that compensatory proliferation in rodent skin starts at ~10 days (Denekamp, 1973;Ang et al, 1984) after the first fraction, others have reported a significantly longer time factor (Moulder & Fischer, 1976;Tsang et al, 1990). Since a variety of time-dose-fractionation schedules have been used in repopulation studies, a single time factor for different X-ray regimes is probably inappropriate.…”

“…the daily dose rate), in regimes using the same number of fractions and overall time, greatly influenced the amount of compensatory proliferation in lip mucosa. Recently, we have observed that the rate of accelerated repopulation depends on the degree of initial damage, with the fastest rate of repopulation obtained in treatments continued into the time when skin reactions were seen, suggesting that for rapid healing to ensue, the gap should only be placed after the tissue has started to express functional damage (Tsang et al, 1990). Using a 36 fraction 12 day schedule (1.2-2.3 Gy per fraction, and therefore well within the clinical dose range), given as 3 fractions/day at 6 h intervals, the latent period, the rate of appearance and the peak levels and time to healing of skin reactions were no different from when a 12 fraction 12 day regime was used (Rojas & Ninis, 1987).…”

“…Reactions were scored three times a week from 7 to 40 days after the first X-ray treatment. An average score was calculated for each mouse over a period of 14-36 days after the first X-ray treatment, or an equivalent period if the reaction appeared slightly earlier or later (Denekamp, 1973;Tsang et al, 1990). The mean reaction +1 sem was then calculated for each group.…”

“…We therefore investigated the sparing effect of a 72 h interval, during the course of a fractionated regime, on mouse skin and oesophagus and whether such a gap positioned early on, midway or towards the end of treatment would be more or less effective at sparing acute normal tissue damage. Oesophagus and skin were chosen as examples of early reacting normal tissues because the former is inevitably included in the treatment beam of most thoracic tumours and the latter may have a time scale for expression of and healing from radiation damage similar to human oral-pharyngeal mucosa (Withers, 1989;Tsang et al, 1990), which along with the oesophagus is a dose-limiting site with CHART.…”

Changes in the effect of dose fractionation during daily fractionated irradiation: studies in mouse oral mucosa

“…However, the protocol applied in these studies of mouse skin was comprised of continuous administration of fractions, without the treatment break of 72 h introduced in clinical protocols that span the weekends. Moreover, in independent studies of the same mouse strain, repopulation processes in mouse foot skin were not identified before 1-2 weeks of treatment with 5 ϫ 3 Gy per week (30). Hence, a potential effect of repopulation-associated changes on recovery from sublethal damage per se, i.e., on the equal effect per fraction, could not be detected.…”