The overall objective of the work proposed in this application is to increase the clinical efficacy of continuous low dose rate irradiation (CLDRI) through the use of halogenated pyrimidines as radiation sensitizers. The focus of this proposal is on gastrointestinal malignancies. Although forms of CLDRI, such as implant brachytherapy, radiolabeled monoclonal antibodies, and 90Y microspheres are promising advances in the treatment of advanced gastrointestinal malignancies, the great majority of patients still succumb to their disease. 5-iodo-2'-deoxyuridine (IdUrd), a thymidine analogue, is a radiation sensitizer when it is incorporated into DNA. Incorporation can be modulated by concurrent treatment with fluorodeoxyuridine (FdUrd) and 5-fluorouracil (5-FU), which are also radiosensitizing agents when used alone. It is hypothesized that the appropriate administration of these halogenated pyrimidines will increase the therapeutic index of CLDRI sufficiently to improve tumor control. The long term goals of this proposal are: 1) to quantify the potential for halogenated pyrimidine mediated radiosensitization of CLDRI and 2) to determine the conditions necessary to produce selective tumor radiosensitization . These long term goals will be addressed by two specific aims. The first is to assess the potential for and predictors of radiosensitization in two human colon cancer cell lines with widely different radiation sensitivity (HT29 and LS174T). The use of a cell culture system permits screening many conditions expeditiously, thus decreasing the number of permutations that must be explored through animal trials. The second goal is to determine, through the use of athymic nude mice bearing subcutaneous xenografts of the same tumor cell lines used for the in vitro studies, the conditions for improving the therapeutic index of CLDRI through the use of halogenated pyrimidines. The nude mouse xenograft system permits an assessment of the importance of three dimensional cellular architecture and physiology on IdUrd incorporation and the resulting radiosensitization of tumor compared to normal tissue. In addition to average tumor incorporation, attention will be focused on quantifying the heterogeneity of incorporation among cells within the tumor by using immunohistochemical techniques and on determining the impact of such heterogeneity on tumor response to subsequent CLDRI. These data will be critical in constructing rational clinical trials that combine halogenated pyrimidines with brachytherapy, radiolabeled monoclonal antibodies, and 90Y microspheres in the treatment of gastrointestinal malignancies.
