In the United Kingdom, although only 3% of all new cancer diagnoses among men and even less for women are of kidney cancer, reports have also shown that the incidence of kidney cancer has increased not only in the United Kingdom, but also worldwide. In fact, in the United Kingdom, kidney cancer mortality rates have increased by 71% since the early 1970s. In response, the treatment and management of kidney cancer depends on whether the disease is clinically localised or metastasised at initial diagnosis.In metastatic patients, molecularly targeted therapies, including those using tyrosine kinase inhibitors (TKI) sunitinib and pazopanib, have largely replaced therapies with immunotherapy agents, which are less efficacious and more toxic than TKI. However, fatigue remains a commonly reported side effect of kidney cancer treatment involving TKI, which might make them intolerable. Accordingly, accurately measuring fatigue and identifying possible reasons for its onset and increase are vital to its early management.In chapter 2, we measured fatigue in kidney cancer patients received sunitinib or pazopanib by using the Functional Assessment Chronic Illness Therapy for Fatigue (FACIT-F) tool. We also evaluated cancer symptoms and the impact of sunitinib and pazopanib on the quality of life of patients according to core items on the M. D. Anderson Symptom Inventory in four consecutive cycles. Among the 65 recruited patients receiving treatment at Beatson West of Scotland Cancer Centre in Glasgow, who participated in the study, 47 completed all four treatment cycles.Our results showed that the mean fatigue score range, based on the FACIT-F tool, in participants was 29.5–31.8, which considered diagnostic fatigue of <34 based on the cutoff point of FACIT-F. Furthermore, we found that the severity of fatigue score increased when cancer symptoms increased in those patients.Such results encouraged us to investigate a combination therapy proposed in the literature to minimise the incidence of side effects with a combination of reduced dose of TKI, sunitinib or pazopanib, and radiotherapy. In chapter 3, we report a preclinical laboratory study that we conducted to examine the efficacy of sunitinib and pazopanib in killing renal cancer cells in vitro when used as single agents, as well as their potential use in combination studies.Our results demonstrated that combination therapy was superior to monotherapy and that both sunitinib and pazopanib as single agents and in combination therapy with radiotherapy could induce apoptosis in both renal cell lines, 786-O and ACHN. Furthermore, we report our investigation into the cytotoxic effects of disulfiram, an anti-alcoholism drug not previously interrogated, in renal cell cancer alone and in combination with radiotherapy. Disulfiram demonstrated a cytotoxic effect, but not in a dose-dependent manner.Our results additionally demonstrated that copper could enhance the cytotoxicity of disulfiram in renal cell lines only with a low dose of disulfiram ≤ 10 μM. By contrast, radiotherapy combined with disulfiram ± copper did not decrease cell viability, and disulfiram alone could induce apoptosis in renal cell lines.In sum, our results reveal that fatigue is a significant issue for most kidney cancer patients receiving sunitinib or pazopanib. TKI agents could improve the radiosensitivity of the renal cancer cell line and constitute an interesting option for managing kidney cancer in the hopes of discovering a novel combination regimen with the same efficacy and with less toxicity. In short, disulfiram exhibits potential anticancer properties in renal cancer cell lines.
|Date of Award||18 May 2017|
- University Of Strathclyde
|Supervisor||Alexander Mullen (Supervisor) & Marie Boyd (Supervisor)|