The efficacy of radiotherapy is limited ultimately by normal tissue toxicity. For many tissues, commonly-used assays of radiation injury are based on functional endpoints. A better understanding of the production and repair of radiation damage at the genomic level of both normal and tumor tissues is the key to development of nev strategies to increase the therapeutic ratio. In this project we propose to study the question using the technique of premature chromosome condensation to directly measure chromosome damage and repair in normal and tumor tissues after in vivo irradiation. In particular, we propose to determine the amount of initial in vivo chromosome damage and the rate and extent of its repair in three rodent normal tissues (lung, liver, and CNS) and two human tumor xenografts; determine the effect of fractionated radiation doses on the accumulation and repair of chromosome damage; and determine whether repair inhibition (5FU and F-AraA) can differently alter chromosome damage accumulation in normal and tumor tissues.
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