Copper-dependent enhancement of targeted radiotherapy by combination with the radiosensitiser disulfiram

Tesson, Mathias Christian Stephane (2013) Copper-dependent enhancement of targeted radiotherapy by combination with the radiosensitiser disulfiram. PhD thesis, University of Glasgow.

Abstract

The purpose of this research was to enhance the targeted radiotherapy of two metastatic malignant diseases: neuroblastoma and prostatic carcinoma.

By virtue of its high affinity for the norepinephrine transporter (NET), [131I]meta-iodobenzylguanidine ([131I]MIBG) has been used for the therapy of tumours of neuroectodermal origin for more than 25 years. Although not yet universally adopted, [131I]MIBG targeted radiotherapy remains a highly promising means of management of neuroblastoma. MIP-1095, a glutamate-urea-lysine dipeptide has high affinity for prostate-specific membrane antigen (PSMA) and has recently demonstrated exquisite specificity for PSMA-expressing, metastatic prostatic carcinoma. Preliminary imaging studies in patients, using [123I]MIP-1095, revealed tumour-selective binding and prolonged retention only in malignant sites. This indicates the therapeutic potential of this agent when labeled with Iodine-131.

Our aim is to make the most effective use of [131I]MIBG and [131I]MIP-1095 for the treatment of neuroblastoma and prostatic carcinoma by combining the [131I]-labelled radiopharmaceutical with radiosensitiser drugs.

The thiol-containing molecule disulfiram was selected for combination with targeted radiotherapy because of its reported inhibition of the 26S proteasome and NF-kB activity, its ability to chelate copper and its pro-oxidative effects. The copper-dependence of the cytotoxicity and radiosensitising activity of disulfiram was established in neuroblastoma cell models. Radiation dose enhancement values at the 50% toxicity level were 4.24 and 2.00 in SK-N-BE(2c) and UVW/NAT cells, respectively. The radiosensitising mechanism of disulfiram-copper was shown to involve the inhibition of cell cycle arrest in G2. The enhancement of the cytotoxicity of [131I]mIBG and of [131I]MIP-1095 by disulfiram-copper was demonstrated by delay of the growth of multicellular tumour spheroids.

Finally, the screening of the enhancing effect of chemotherapeutic agents on the spheroid growth delay induced by [131I]MIP-1095 indicated that combinations with topotecan, nutlin-3, bortezomib or olaparib have good prospects for therapy of metastatic prostate carcinoma. In conclusion, it is expected that DSF:Cu will enhance the outcome of patients undergoing targeted radiotherapy due to its radiosensitising properties.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Keywords: Disulfiram, targeted radiotherapy, radiosensitiser, neuroblastoma, prostate cancer
• Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Supervisor's Name: Mairs, Professor Robert J.
• Date of Award: 2013
• Depositing User: Mr Mathias C S Tesson
• Unique ID: glathesis:2013-4760
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 10 Jan 2014 11:36
• Last Modified: 10 Jan 2014 15:00
• URI: https://theses.gla.ac.uk/id/eprint/4760