The role of nitric oxide as a hypoxic cell radiosensitizer

Description

Many tumours contain regions of hypoxia which are difficult to treat by conventional radiotherapy. There is much interest in the ability of nitric oxide (^•NO) to radiosensitize hypoxic mammalian cells as a possible adjunct to radiotherapy but mechanisms for its action are unclear. It has been proposed that ^•NO may radiosensitize cells by ‘fixing’ radiation-induced DNA free radicals, and elevated radiation response by ^•NO in cells has been partly attributed to increased formation of DNA double strand breaks. In the work carried out for this thesis it is shown that reaction of ^•NO with radiation-induced nucleobase radicals produces some novel products. New pathways for the reactions of radiation-induced hydroxyl radicals with purine radicals are proposed. In addition, the effects of ^•NO on the yields of radiation-induced single strand breaks in anoxic plasmid DNA, and on anoxic mammalian cell radiosensitivity are investigated. Kinetics of formation and repair of radiation-induced double strand breaks indicate different effects of ^•NO on radiation-induced clustered and non-clustered DNA damage involving replication-induced DNA breaks. As ^•NO is an inhibitor of ribonucleotide reductase, some of the radiosensitizing properties of ^•NO may be due to reduction in the availability of 2-deoxyribonucleotides. Through studying reactions of ^•NO with tyrosine radicals, essential components of ribonucleotide reductase, this work has enhanced understanding into how ^•NO may inhibit the enzyme, which may offer new insights into the development of ^•NO-releasing anti-cancer agents. The potential for delivery of ^•NO to hypoxic tissue for radiotherapy has also been investigated in this work, through the development of bioreductively-activated pro-drugs. These novel agents are stable until reduced by one-electron reductants, when a ^•NO-releasing pro-drug is rapidly evolved, only in those regions which are sufficiently hypoxic. By increasing our understanding into the mechanisms involved in the ability of ^•NO to radiosensitize hypoxic cells, especially the reactivity of ^•NO with DNA radicals, knowledge has been gained into the identification, development and repair of radiation-induced DNA damage in cells, including clustered damage, in the presence of ^•NO. These studies contribute to further development of novel anti-cancer therapies based upon the release of ^•NO in hypoxic cells.

Links & Downloads

1. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.669848

Tags

616.99

Additional Fields

Identifer	oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:669848
Date	January 2013
Creators	Folkes, Lisa K.
Contributors	O'Neill, Peter ; Vojnovic, Borivoj
Publisher	University of Oxford
Source Sets	Ethos UK
Detected Language	English
Type	Electronic Thesis or Dissertation
Source	http://ora.ox.ac.uk/objects/uuid:f5ada357-8d85-48fb-8427-158e05d19f8b