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Title: Targeting replication-specific DNA repair pathways to enhance the therapeutic ratio of brain tumour radiotherapy
Author: Dungey, Fiona A.
ISNI:       0000 0004 2681 0335
Awarding Body: University of Sussex
Current Institution: University of Sussex
Date of Award: 2009
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Glioblastoma multiforme is associated with poor prognosis and resistance to standard therapy. However the non-dividing nature of normal brain provides an opportunity for enhancing the therapeutic ratio by combining radiation with inhibitors of replication-specific DNA repair pathways. KU-0059436, an inhibitor of the base excision repair (BER) protein poly(ADP-ribose) polymerase (PARP), was demonstrated to specifically radiosensitise glioma cells during S-phase and to increase lonising radiation (IR)-induced γH2AX and Rad51 foci. This radiosensitisation was enhanced using fractionated radiation, possibly because more cells were exposed to IR whilst in S-phase. A model is proposed whereby PARP inhibition decreases repair of radiation-induced single strand breaks (SSB) which are converted at collapsed replication forks to double strand breaks (DSB) requiring homologous recombination (HR) for repair. To investigate whether inhibition of downstream HR repair potentiates the radiosensitising effect of KU-0059436, and in the absence of specific HR inhibitors, the heat shock protein 90 (HSP90) inhibitor 17-AAG was used. This compound exhibits tumour-specific cytotoxic and radiosensitising properties and downregulates the HR proteins BRCA2 and Rad5l. Work in this thesis confirmed that 17-AAG inhibits HRR and radiosensitises glioma cells. Radiosensitisation was replication-dependent and was increased in the presence of KU-0059436. The combined effect was at least partially replication-dependent, was associated with increased γH2AX foci in G2 cells, and was absent in non-malignant CHO cells. Since Rad5l-depleted cells were also radiosensitised by 17-AAG, this effect could not be attributed entirely to HRR inhibition. 17-AAG inhibits multiple tumour survival and DNA repair pathways that may contribute to its enhancement of the replication-dependent effects of KU-0059436. These multiple mechanisms may be difficult to elucidate but are likely to be therapeutically beneficial. In summary, the combination of HSP90 and PARP inhibitors may potentially improve brain tumour radiotherapy by mechanisms that include but are not restricted to inhibition of the BER and HRR DNA repair pathways.
Supervisor: Not available Sponsor: Not available
Qualification Name: Not available Qualification Level: Doctoral
EThOS ID:  DOI: Not available