The thymidine analog iododeoxyuridine (IUdR) has been the subject of several recent investigations because of its potential role as a clinical radiosensitizer, especially in the treatment of rapidly proliferating, poorly radioresponsive tumors located in relatively quiescent normal tissues. Most earlier biological and clinical studies of IUdR radiosensitization have used acute high dose rate irradiations. In this project, the radiobiology of combined treatments of IUdR perfusions plus continuous low dose rate irradiation (CLDRI) will be examined. Specifically, the dependence of IUdR radiosensitization on photon energy and dose rate will be studied in order to evaluate the therapeutic potential of IUdR in brachytherapy. Previous studies indicate that radiosensitization by IUdR can be enhanced substantially through the use of photons of energy just greater than 33.2 keV, the K-absorption edge of iodine. It has been proposed that the enhanced IUdR radiosensitization results from Auger electron cascades induced by photons that knock out an electron from the K-shell of an iodine atom. These Auger electrons produce a high LET-type lesion in the immediate vicinity of the iodine atom. The proposed studies will compare CLDRI using brachytherapy sources (Am-241) emitting photons with energies just greater than the K-absorption edge of iodine with CLDRI using Ir-192 and Ra-226 which emit higher energy photons, and I-125 which emits photons with energies lower than the K-edge. Studies will be carried out with Chinese hamster cells and BA1112 sarcoma cells irradiated in vitro. Conditions for optimum lUdR incorporation, including the modulation of biochemical pathways of IUdR metabolism using FUdR, will be determined using HPLC. These data will be used to develop a Monte Carlo model which simulates the time evolution of a cell population under acute or chronic treatment with radiation and/or drugs. Age-specific survival data for acute treatments, which are used as an input by this model, will be determined using flow cytometric cell sorting techniques. From these radiobiological data defining IUdR radiosensitization as a function of IUdR concentration, treatment time, radiation dose, dose rate, percent thymidine substitution and photon energy, it should be possible to make reasonable predictions of the IUdR radiosensitization in brachytherapy. To validate these findings in an animal model, lUdR radiosensitization will be examined using a solid rat tumor (BA1112 sarcoma) irradiated in vivo and assayed for tumor cell survival using an in vitro colony formation assay. Finally, tumor cure experiments in the same solid rat tumor system, with and without IUdR infusions, will be conducted to investigate the effects of IUdR, photon energy and dose rate on local tumor control.
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