Modulation of repopulation processes in oral mucosa: experimental results

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Abstract
Purpose: Repopulation processes, i.e. the tissue regeneration responses to radiotherapy with increasing overall treatment time, are the predominant factors defining the radiation tolerance of turnover tissues, such as squamous epithelia of the skin or gastrointestinal tract. The purpose was to assess experimental approaches for the modulation, i.e. stimulation of repopulation, in normal oral mucosa. Materials and methods: Numerous studies have been performed to identify and quantify the efficacy of repopulation processes in oral mucosa in experimental animal models, mainly mouse lip and tongue mucosa, and in some clinical studies. However, only a few investigations focused on the stimulation of these processes, aiming at a reduction in oral mucosal side‐effects of radiotherapy. The present review summarizes the biological mechanisms underlying effective repopulation, and delineates experimental approaches for effective stimulation of these processes, eventually resulting in an increase in oral mucosal radiation tolerance. Results: Repopulation in oral mucosa is a complex process dominated by a substantial reorganization of the proliferative structure, including a loss of the stem cell division asymmetry and acceleration of stem cell proliferation, as well as abortive divisions of ‘sterilized’ cells. Repopulation in mouse oral mucosa is more effective if the initial dose intensity (weekly dose) during the first treatment week(s) is increased. Stem cell production occurs mainly during the treatment weeks, while during treatment breaks, including weekends, differentiating (transit) cells are preferentially produced. Stimulation of superficial cell loss, e.g. by topical administration of mild astringent agents, stimulates mucosal proliferation. This translates into increased radiation tolerance to fractionated irradiation in experimental systems, like mouse tongue mucosa. In clinical studies, a reduction of oral mucosal reactions using the same approach was found during an accelerated radiotherapy regimen, but not during conventionally fractionated protocols. Keratinocyte growth factor has been demonstrated to reduce oral mucosal reactions significantly to single dose and fractionated irradiation. This effect is presumably based on an interaction with repopulation processes. Conclusions: Repopulation in oral mucosa is a highly complex process, which includes a substantial reorganization of the proliferative structure. In experimental models, its efficacy can be modulated by changes in the fractionation protocol, but more effectively by intervention in the regulation processes, e.g. by stimulation of proliferation through enhancement of cell loss. An alternative promising approach is the administration of growth factors, like keratinocyte growth factor, for effective modulation of oral mucosal repopulation. However, selectivity for the normal tissue, as well as biological mechanisms, must be studied in detail in relevant animal models.