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Title: The radiotherapeutic potential of the epidermal growth factor receptor
Author: Carlin, Sean Denis
ISNI:       0000 0001 3520 1409
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 1998
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The epidermal growth factor receptor (EGFR) is overexpressed in a wide range of tumour types. Molecules which target and sterilise EGFR-overexpressing cells, or increase their sensitivity to conventional therapies may have a beneficial effect in the clinical management of these tumours. This study describes two approaches adopted to target EGFR-overexpressing cells. Firsdy, we examined the effect of exogenous epidermal growth factor (EGF), a polypeptide growth factor which binds to and activates EGFR, on the radiation sensitivity of a panel of cell lines with a wide range of EGFR expression. This effect was assessed by colony forming assay and the results obtained were analysed using the linear quadratic model of cell survival. Our results indicated that the presence of EGF did not alter the radiosensitivity of any of the cell lines examined. This suggests that the use of EGF as a radiosensitising agent is unlikely to be of benefit in a clinical setting. The second approach adopted was to investigate the possibility of using EGF as a means of delivering therapeutic ultra-short range radionuclides to EGFR- overexpressing cells. The short range of the particles emitted from these radionuclides (Auger electrons) requires that decay occurs in close proximity to cellular DNA for a radiobiological effect to be observed. For EGF to act as an effective delivery vehicle for these radionuclides, it must be capable of delivering the radionuclide to the nucleus of the target cell. Studies were carried out to assess the sub-cellular distribution of EGF after receptor binding and internalisation. Using both light and elctron microscopic techniques along with cell fractionation, we established that exogenous EGF does accumulate in the nucleus of some EGFR-overexpressing cell lines under the appropriate conditions. These results suggested that EGF may be suitable as a delivery vehicle for Auger-emitting radionuclides. Finally, we examined the effect of EGF conjugated to the Auger-emitting radionuclide 1231 on the clonogenic survival of a cell line panel with a wide range of EGFR expression. We observed that 123I-EGF was able to sterilise some EGFR-overexpressing cell lines, and that cell lines with a higher EGFR expression were more senitive tol23l-EGF than those with a lower EGFR expression. It was also observed that incubation conditions which abolished the nuclear uptake of EGF also abolished 1231-EGF-mediated cytotoxicity, suggesting that 123I-EGF sensitivity is dependent upon the nuclear uptake of the radioconjugate. The function of nuclear EGF remains to be established, as does the nuclear translocation mechanism. However, the possibility of EGFR-targeted therapies based upon this phenomenon, as outlined in this report, implies that further studies into the nuclear accumulation of EGF and other polypeptide growth factors are warranted.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Nuclear EGF; Tumour radiobiology