The role of nitric oxide as a hypoxic cell radiosensitizer

Thesis

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.

Authors: Folkes, L

• Publication date: 2013
• DOI: 10.5287/ora-eog8xw4w8
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: tumour hypoxia; nitric oxide; DNA damage; radosensitizer
• Subjects: Tumours; Medical sciences; Radiation