The purpose of the proposed research is to arrive at a better understanding of how halogenated pyrimidines can be used as radiosensitizers in radiobiology and cancer therapy. Comparisons will be made between iododeoxyuridine (IdUrd) and bromodeoxyuridine (BrdUrd) as radiation sensitive thymidine analogs. Attempts will be made to correlate similarities and differences in behavior at the macroscopic level with the photochemical properties of the individual deoxynucleosides, particularly as to how these properties are modified upon incorporation into an ordered polymer. Various methods will be examined for measuring the release of the halogen atom into the solvent following radiation. The methodology developed will be used to monitor radiation induced changes as a function of a variety of experimental parameters. A sensitive method for measuring low levels of either I- or Br- will be used to monitor the uptake of halogenated base analogs into the DNA of exposed cells. This method will also be used to investigate the mechanism by which 33258 Hoechst plus 365 nm irradiation induces dehalogenation in substituted DNA. The chemical reactivity of the uracil-5-yl radical or the secondary racials induced by it will be studied in order to better understand the mechanisms of formation of chain breaks, alkali-labile bonds, protein DNA cross links, and the 5,5' -diuracilyl coupled product. Previous studies on the extent of energy transfer in IdUrd-DNA will be extended to BrdUrd-DNA and will involve excitation spectral analysis as a function of the state of the DNA. The sequence dependence of the photolysis in defined oligonucleotides or polynucleotides will be examined by means of polyacrylamide gel electrophoresis and high resolution proton magnetic resonance spectroscopy. Oligonucleotides will be prepared containing BrdUrd or IdUrd in fixed positions relative to variable neighboring sequences. The influence of neighboring bases on the rate of photolysis and the nature of the sugar damage will be reflected in the location and intensity of the bands on the gels and in the modification of the PMR for those sugar protons directly effected by hydrogen abstraction.
| Rahn, R O (1993) Use of potassium iodide as a chemical actinometer. Photochem Photobiol 58:874-80 |
| Rahn, R O (1992) Photochemistry of halogen pyrimidines: iodine release studies. Photochem Photobiol 56:9-15 |
