Parker, Anthony William (1985) Excited state studies of pyramidine bases and radiosensitizing drugs by laser flash photolysis. PhD thesis, University of Warwick.

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Abstract

The mechanism whereby radiosensitizing drugs act in the radio- therapeutic treatment of cancer is yet to be fully elucidated. The prevailing current view (the so-called charge sequestration model) is that cancer cell death is initiated by charge separation induced by the ionising radiation, yielding radical anions (of thymine) and cations (of guanine) in the DNA polymer chain. The radiosensitizer, by virtue of its electron-affinic properties, removes the electron from the (thymine) radical anion, thereby preventing charge recombination and allowing the radical cation to 'fix' the damage via Secondary reactions. To date, most efforts to verify this model have involved the observation of various DNA radical ions by electron spin resonance and pulse radiolysis techniques. However, excited states of DNA or the drug, as well as radical ions, may be involved in the sensitizing action, and there have been a variety of laser flash photolysis studies of reaction between the excited radiosensitizer and ground state nucleic acid bases. The main body of this thesis (Chapter 3) has been to determine, using 249 nm laser flash photolysis, whether reaction in solution occurs between triplet excited nucleic acid bases (in particular thymine and uracil) and (ground state) radiosensitizing drugs. (Such a study has only recently been made feasible by the development of powerful ultraviolet pulsed lasers which are able to produce measurable concentrations of these triplet states in solution; even so, monitoring systems are extended to their limits of detection.)

The triplet states of thymine and uracil (in acetonitrile) were quenched by a variety of electron acceptor molecules, including radiosensitizing drugs. The quenching kinetics correlated with the electron affinities of the electron acceptors according to the Weller equation for excited state electron transfer. This constitutes positive evidence that triplet DNA bases can produce the radical cations which are presumed to lead to cell death. Further, in certain cases, the radical anions of the acceptors were observed optically and their yields measured.

In Chapter 4 are presented studies of the triplet states of two radiosensitizing drugs, metronidazole and misonidazole (principally by laser flash photolysis), including measurements of their triplet energies. The reduction potentials of these drugs (in acetonitrile) were determined by three methods, which gave comparable results. Attempts were made to develop a fluorescent probe which could be used to measure intracellular concentrations of radiosensitizing drugs.

In Chapter 5, the efficient quenching of both excited uranyl ion and triplet benzophenone by nucleic acid bases is detailed. From the results it is concluded that for uranyl ion, the mode of quenching is by an exciplex or reversible charge transfer mechanism, while for triplet benzophenone, chemical quenching occurs. The appendices are mainly concerned with various computer-based techniques developed for this study. An original method is described for analysing oscilloscope transient decays by photographing the oscilloscope screen using a video camera and transferring and digitising the resulting image into a micracomputer screen ram area, where it is manipulated to yield the transient decay constant. Also given is a computer program developed to enable optimum fitting of quenching data to the Weller equation, when the donor oxidation potential is unknown. Finally, evidence for the triplet state of 5-nitroindole is reported.

A part of this work has been published, viz. "Electron-transfer Quenching of Triplet State Thymine and Uracil", T.J. Kemp, A.W. Parker, and P. Hardman, J. Chem. Soc, Chem. Commun., 1985, 1377.

Item Type:	Thesis (PhD)
Subjects:	Q Science > QC Physics Q Science > QD Chemistry
Library of Congress Subject Headings (LCSH):	Excited state chemistry, Radiation-sensitizing agents, Laser photochemistry
Official Date:	November 1985
Dates:	Date Event November 1985 UNSPECIFIED
Institution:	University of Warwick
Theses Department:	Department of Chemistry
Thesis Type:	PhD
Publication Status:	Unpublished
Supervisor(s)/Advisor:	Kemp, T. J. (Terence James)
Sponsors:	Science and Engineering Research Council (Great Britain) ; Cancer Research Campaign (Great Britain)
Extent:	xiv, 187 leaves : illustrations
Language:	eng

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