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.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:586846 |
| Date | January 2013 |
| Creators | Tesson, Mathias Christian Stephane |
| Publisher | University of Glasgow |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://theses.gla.ac.uk/4760/ |
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