Neale, Michael Howard; (2001) Ex vivo chemosensitivity of melanoma and other solid tumours. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

An ex vivo ATP-based Tumour Chemosensitivity Assay (ATP-TCA) has been used here to assess the chemosensitivity of uveal and cutaneous melanomas biopsies. As has previously been seen in other tumour types there is a large degree of heterogeneity of response to chemotherapy in both melanoma types. Cutaneous melanoma samples were more sensitive than the uveal melanomas, mirroring the results achieved in clinical trials. However the number of each tumour type resistant to all drugs tested was similar with 12% of uveal and 18% of cutaneous melanomas. The combination of treosulfan and gemcitabine was found to be the most effective combination using the ATP-TCA, and clinical trials of this combination in both uveal and cutaneous melanomas are now taking place as a consequence of this work, with promising early results. 69 ovarian adenocarcinomas were also tested using the ATP-TCA as part of a phase II and a randomised phase III trial of the ATP-TCA. The 69 ovarian adenocarcinoma samples had all previously been treated with platinum containing drugs and were clinically resistant. 97% of the ovarian adenocarcinoma samples tested showed ex vivo resistance to cisplatin with the ATP-TCA. Two experimental drugs, XR5000 and liposomal doxorubicin, were also assessed using the ATP-TCA in cutaneous melanoma and ovarian adenocarcinoma. The results of this has been used to plan further laboratory and clinical trials of these and similar acting agents. The results presented throughout this thesis highlight the usefulness of the ATP-TCA for many different studies including drug and regimen design and development, patient treatment, identifying potential molecular correlates of resistance, and directing future research.

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