Document Type

Theses, Ph.D

Rights

Available under a Creative Commons Attribution Non-Commercial Share Alike 4.0 International Licence

Disciplines

Biochemistry and molecular biology

Publication Details

Sucessfully submitted for the award of Doctor of Philosophy to the Technological University Dublin 1995.

Abstract

At the present time, the treatment plan for a patient with cancer is usually based on parameters such as tumour site, histological type, and tumour stage and performance status. However, it is well know that the radiosensitivity of human cancers varies widely from one patient to another (Fertil et al., 1981), and that even within these broad categories some tumours will show greater response to radiotherapy than others. If those patients unlikely to be cured by radiotherapy could be identified prior to commencement of treatment, alternative or more aggressive therapies might be selected which may give a better chance of cure than the standard therapy. The aim of this study was to develop an in vitro essay, the Mothersill outgrowth assay, to predict the individual patient response to chemo – and, in particular, radiotherapy. This assay involves culturing explants cut from a tumour and then treating them in situ with clinical equivalent doses of chemo- and radiotherapy. Two type of cancer were examined, oesophageal carcinoma and head and neck squamous cell carcinoma. The sensitivity of the tumour to treatment was evaluated in terms of the % growth inhibition in the treated cultures relative to the untreated control. The nature of this assay allowed other parameters to be examined immunocytochemically as potential indicators of tumour radiosensitivity. These parameters have previously been shown to be of prognostic significance in a range of cancers, they include: % Ki67 positive cells: expression of EGFr, c-Myc and BCl-2: co-express ion of c-Myc and Bcl-2: expression of the non-functional protein product of p53. The Mothersill outgrowth assay provided a system in which multiple parameters could be examined from limited tumour material. Due to the small patient number conclusive results could not be obtained regarding the parameter, % growth inhibition, as an indicator of patient response to treatment. To obtain these results a larger time scale would be required to allow for the accumulation of a large number of patients and a long follow up time. The results obtained indicated that % Ki67 positive cells measured after irradiation was indicative of patient in vitro radiosensitivity; expression of Ki67 correlated positively with radiosensitivity. EGFr expression measured before and after treatment differentiated the radio-sensitive and resistant tumours. High expression of EGRf correlated with radio-resistance. Express of c-Myc and Bcl-2 taken alone did not indicate tumour sensitivity, however tumours positive for c-Myc and negative for Bcl-2 were radiosensitive. Express of p53 protein did not significantly differentiate the radio- sensitive and resistant head and neck squamous cell carcinoma tumours, although when examined in cell lines derived from colorectal and bladder tumours, a significant correlation was found between radiosensitivity and p53 protein expression; high % of p53 positive cells correlated with radio-resistance. In conclusion, using the Mothersill assay it was possible to evaluate several parameters from a limited amount of tissues. Of these parameters, % Ki67, EGFr, c-Myc and Bcl-2 appear to have potential as indicators of tumour radiosensitivity. An increase in the number of head and neck squamous cell carcinoma patients and a longer follow up time will be required before any conclusions can be made regarding the potential of the parameter, % growth inhibition, to predict patient response to treatment.

DOI

https://doi.org/10.21427/D7902R

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