[131I]-Meta-Iodobenzylguanidine Treatment of Neuroblastoma: Experimental Evaluation of Strategies to Improve Clinical Results

Cunningham, Shona H (1997) [131I]-Meta-Iodobenzylguanidine Treatment of Neuroblastoma: Experimental Evaluation of Strategies to Improve Clinical Results. PhD thesis, University of Glasgow.

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Neuroblastoma is a paediatric tumour prone to early and widespread dissemination. At present the majority of older patients with metastatic disease are destined to die from their malignancy despite recent advances in chemotherapy and the fact that it is a radiosensitive tumour. New therapeutic approaches are therefore urgently sought. One agent which has shown promise is meta-iodobenzylguanidine (MIBG). MIBG is a noradrenaline analogue which is specifically taken up by sympathetically innervated tissues and tumours derived from these. Radiolabelled MIBG has been successfully used to image tumours of neural crest origin such as neuroblastoma. In combination with conventional therapy modalities 131I labelled MIBG is now being used to treat neuroblastoma patients. The results of these studies are encouraging and suggest that [131I]MIBG will become an established part of the therapeutic regimen for late stage neuroblastoma patients. It is therefore essential that it is used to its optimal effect. The work contained in this thesis is an investigation of experimental strategies aimed at improving the use of radiolabelled MIBG. Using in vitro and in vivo models of neuroblastoma a number of factors have been investigated. It is predicted that the use of no-carrier-added [131I]MIBG, rather than conventional low specific activity preparation will result in an enhanced therapeutic ratio because of different transport processes in neuroblastoma compared with most normal tissues. No-carrier-added [131I]MIBG was synthesised and its stability, uptake and biodistribution investigated. Results revealed that the preparation was stable at radioactive concentrations up to 25MBq / ml. The no-carrier-added preparation behaved identically to conventional [131I]MIBG prepared by iodide exchange with respect to uptake in cultured neuroblastoma cells. The accumulation of no-carrier-added [131I]MIBG was significantly greater in tumour, adrenal, heart, and skin of tumour bearing mice than that of the conventional therapy preparation of [131I]MIBG. These data indicate that there may be clinical advantages in the use of no-carrier-added [131I]MIBG rather than conventional [131I]MIBG. As the ability of neuroblastoma cells to actively accumulate MIBG is crucial to the success of this therapy, the effect of chemotherapeutic agents on this uptake capacity needs to be investigated. Initial experiments examined the effect of cisplatin pretreatment on the neuroblastoma cell line SK-N-BE(2c). After treating these cells with therapeutically relevant concentrations of cisplatin (2 and 20 ?M), a stimulation in uptake of was observed. Reverse transcription-polymerase chain reaction analysis demonstrated that this effect was due to increased expression of the noradrenaline transporter. These results suggest that appropriate scheduling of cisplatin and may lead to an increase in tumour uptake of this radiopharmaceutical with consequent increases in radiation dose to the tumour. Currently MIBG therapy consists of administration of the beta emitting 131I labelled conjugate. However, the emission properties of this radioisotope are predicted to be non-ideal for the treatment of micrometastatic disease. The potential of Auger electron emitting radioiodine conjugates of benzylguanidine to treat micrometastases was therefore investigated. Three MIBG species, labelled with 123I- 125I- and 131I were synthesised and their in vitro toxicity compared in neuroblastoma cell irionolayers, and small and large spheroids. The Auger electron emitting conjugates ([123I]MIBG and [125I]MIBG were highly toxic to monolayers and small spheroids whilst the beta emitting conjugate, [131I]MIBG, was relatively ineffective. In contrast, the Auger electron emitters were ineffective in the treatment of larger spheroids whilst the beta emitter showed greater efficacy. These findings suggest that short range emitters would be well suited to the treatment of circulating tumour cells or small clumps whilst beta emitters would be superior in the treatment of subclinical metastases or macroscopic tumours. The data provide support for a clinical strategy of combinations ('cocktails') of radioconjugates in targeted radiotherapy. To validate the results of laboratory studies a suitable in vivo model, which provides a realistic reflection of the disease under investigation, is required. Studies were undertaken to develop a murine metastatic model of neuroblastoma by inoculating nude mice with human neuroblastoma cells and then tracking the fate of these cells using a PCR based assay. Preliminary results demonstrated the feasibility of the approach and indicate that human neuroblastoma cells spread to a variety of organs. The findings presented in this thesis suggest that a number of strategies have the potential to enhance the therapeutic efficacy of MIBG targeted radiotherapy. The future availability of a suitable murine model of metastatic neuroblastoma should allow the merits of these strategies to be tested in vivo.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Additional Information: Adviser: R J Mairs
Keywords: Oncology, Neurosciences
Date of Award: 1997
Depositing User: Enlighten Team
Unique ID: glathesis:1997-74879
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 27 Sep 2019 15:43
Last Modified: 27 Sep 2019 15:43
URI: http://theses.gla.ac.uk/id/eprint/74879

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