The long-term objective of this research is to establish quantitative criteria for evaluating the potential effectiveness of altered fractionation schedules in radiotherapy, and thus to improve the results of these cancer treatments. This is to be accomplished by developing models of tissue and tumor responses to repeated small doses of radiation, and by performing new experiments to test the models. The objective of the present proposal is to gain more precise understanding of the mechanisms by which the compensatory proliferative response of epithelia tocytotoxic injury is controlled. The underlying hypothesis is that growth control is manifest by changes in two kinetic parameters: (1) Proliferation rate, defined as the growth fraction divided by the cell-cycle time, and (2) Net clonogen production rate, defined as the growth rate of the clonogenic population in the tissue. The perturbations to be applied are radiation-induced cell killing and mechanical exfoliation of superficial differentiated layers. The proliferation rate will be measured using double labelling with CldUrd and IdUrd, and the net clonogen production rate will be determined from the extent of repopulation during split-dose survival experiments. In this way the effect on these parameters of four different control situations can be evaluated, which are of direct clinical relevance (cell killing during fractionated treatments, and mechanical exfoliation by AgNO3 lavage to spare acute effects prior to head and neck treatments). These studies will ultimately provide the radiotherapist with guidelines for the use of accelerated fractionation and hyperfractionation in sites where doses are limited by mucosal damage, by establishing limits on the number and size of daily treatments that can be tolerated and defining optimal scheduling to be used in conjunction with pretreatment conditioning of normal mucosa.
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