The overall goal of this program project is to study the cellular effects and radiotherapeutic interactions of the halopyrimidines and to apply such knowledge to the treatment of intrahepatic malignancies and pancreatic cancer. The drugs that will be the focus of investigation are bromodeoxyuridine (BUDR), fluorodeoxyuridine (FUDR), and fluorouracil (FU). The work performed during the current award period has shown that the chemotherapeutic agents FUDR and FU are radiosensitizers when used alone and improve the efficacy of the thymidine analog and radiosensitizer BUDR by increasing its incorporation into the DNA of tumor cells. this proposal seeks to gain new insights into the mechanism of action of these agents and to apply knowledge gained in our previous preclinical studies to clinical trials. Project 1 extends recent findings concerning the basis for fluoropyrimidine-induced cytotoxicity and DNA damage, and proposes to test hypotheses that: a) the activities of dUTPase and/or uracil-DNA-glycosylase may be the limiting determinants for sensitivity of human colorectal tumor cells to high concentrations of fluoropyrimidines (as are applied during regional administration), and b) in certain tumor cells, resistance to fluoropyrimidines may be overcome by coadministration of a dUTPase inhibitor. Project 2 seeks to determine the mechanism by which BUDR affects radiation induced DNA damage at the individual chromosomal and subchromosomal level through the use of pulsed field gel electrophoresis and fluorescence in situ hybridization. The goals are to determine if BUDR incorporation alters the type and number of DNA lesions produced by radiation and to identify the lesions most closely associated with radiation sensitivity. Project 3 will systematically study the effect of liver impairment (loss of hepatocyte mass vs. loss of function) on the disposition kinetics of FU and BUDR after systemic and regional administration. The studies in Project 3 will have direct relevance to proposed clinical studies involving regional drug infusion in patients with reduced liver function. for clinical studies (Project 4), the approach taken will be to generate regional chemo-radiosensitization regimens combining BUDR with precise, 3-D planned focal external beam radiotherapy. A biopsy study will be conducted of tumor and normal tissue uptake of BUDR (by GC/MS assay and by immunohistochemical assay) given on a relevant infusional schedule (hepatic arterial for hepatic and intravenous IV for pancreatic tumors) to determine whether significant (>5%) incorporation occurs. Based upon our preclinical studies, a concurrent BUDR infusion will be used in hepatic tumors and a BUDR infusion with a """"""""washout"""""""" period will be studied in pancreatic cancers to maximize tumor to dose-limiting normal tissue uptake of drug. In summary, this proposal defines an approach furthering basic understanding of these agents while combining pharmacologic data with sophisticated technology to rationally generate unique clinical protocols with potentially improved potency in the treatment of these common, exceptionally lethal GI malignancies.
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