Introduction: Malignant melanoma is highly resistant to conventional cancer therapies, characterised by a broad spectrum of radio resistance combined with a low response to chemotherapeutics. This state is compounded by inadequate dose delivery of conventional radiotherapy options. A targeted approach to radiotherapy exploiting native features of the melanoma cells such as melanin may in combination with radiosensitizing agents may improve the effectiveness of therapy towards the disease. Aims: The aims of this study were three-fold: • To assess the effectiveness of the melanin binding radionuclide [131I]MIP1145 in the treatment of malignant melanoma in vitro and in vivo. • To investigate whether malignant melanoma cell lines and xenografts can berendered susceptible to [131I]MIBG radionuclide therapy via transfection invitro with noradrenaline transporter (NAT) and via gene delivery in vivo withthe HSV1716/NAT vector. • To screen novel DNA repair and IKKβ Inhibitors in combination with X-Ray radiation to determine suitability for future targeted radiotherapy/drug combination therapy approaches. Results: [131I]MIP1145 demonstrated accumulation and retention accompanied by considerable reductions in cell survival and tumour burden in melanotic melanomacell lines and tumour Xenografts. Additionally, a modest uptake and cytotoxic effect of [131I]MIBG was observed following transfection with the noradrenaline transporter in vitro. Xenografts bearing NAT transfected melanoma cells demonstrated tumour growth delay when treated with [131I]MIBG. HSV1716/NAT Successfully delivered the NAT gene to melanoma tumours in vivo demonstrated high tumour specificity and tumour growth delay. The MRE11 inhibitor Mirin produced cytoxicity in vitro but not in vivo when combined with 2Gy X-ray radiation, reducing but not inhibiting γH2AX foci clearance post radiation treatment. The novel IKKβ Inhibitors SU567 and SU182 produce effects consistent with IKKβ inhibition and are cytotoxic to melanoma celllines, enhancing 1Gy X-ray induced DNA damage and produce marked alterations in the cell cycle of treated cells. Conclusions: Melanoma tumours can be successfully targeted both endogenously and exogenously with radionuclide therapy. Investigations with novel radiosensitising agents identified that the MRE11 inhibitor Mirin produced a mild reduction in cell survival at drug concentrations as both as a single treatment and as a pre-treatment to 2Gy X-ray irradiation. Novel IKKβ inhibitors induce cytotoxity and enhance 1GY Xr-ray [sic] toxicity compared to X-ray treatment alone.
|Date of Award
|26 Sept 2018
- University Of Strathclyde
|Cancer Research UK CRUK
|Marie Boyd (Supervisor) & Annette Sorensen (Supervisor)