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Title: Experimental determination of the optimal means of combining topotecan and [¹³¹I] MIBG therapies for the treatment of neuroblastoma
Author: McCluskey, Anthony Gerald
ISNI:       0000 0001 3623 1589
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 2005
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Introduction: Neuroblastoma has a long-term survival rate of only 15%. While patients with early stage disease can usually be treated surgically, those with inoperable disease require intensive treatment. However, there has been no substantial improvement in the survival rates of patients with advanced disease. Targeted radiotherapy, using [131I] meta-iodobenzylguanidine ([131I]MIBG) has induced favourable remissions in some patients when used as a single agent. However, the full potential of this therapy may only be realised when it is combined with other agents. One class of agents with the potential to improve [131I]MIBG therapy are the inhibitors of topoisomerase I, which have previously shown synergy when used in combination with radiotherapy. Furthermore [131I]MIBG therapy could be improved by the rapid selection of patients who may derive benefit from this treatment. Aims: The aims of this study were to develop a molecular assay for MIBG active uptake, and to determine the efficacy of [131I]MIBG in combination with the topoisomerase I inhibitor topotecan in vitro and in vivo. Results: RT-PCR analysis of NAT expression by neuroblastoma biopsies was predictive of tumour uptake of MIBG. However RT-PCR negativity failed to correctly determine MIBG uptake capacity with a frequency of 45%. The combined effects of topotecan and [131I]MIBG were assessed, in tumour cells expressing the noradrenaline transporter, using three treatment schedules: topotecan administered 24h before [i], after [ii] or simultaneously with [iii] [131I]MIBG. Pre-treatment with TPT enhanced the intracellular concentration of [131I]MIBG. However, analysis of TPT and [131I]MIBG interactions in vitro and in vivo demonstrated that this was not the optimal order of administration for combination therapy. While supra-additive toxicity was observed in vitro by all combination schedules, schedule [i] was less effective than schedules [ii] and [iii]. This was reflected in failure to repair DNA damage. With respect to delay of growth of NAT-expressing xenografts in nude mice, combinations of topotecan and [131I]MIBG were more effective than single agent treatments. Combination schedules [ii] and [iii] were superior to combination schedule [i]. Combination treatment caused negligible myelotoxicity according to platelet production, or stem cell clonogenic capacity. Conclusions: Real-time PCR evaluation of primary neuroblastoma tumours has significant capability to reflect their capacity for the accumulation of MIBG, however PCR-based assessment of NAT gene expression cannot fully predict MIBG uptake. Inhibition of DNA repair and supra-additive toxicity to NAT expressing cells and xenografts were achieved using combinations of topotecan and [131I]MIBG. Effectiveness was dependent on the order of administration of the two agents. If the synergy demonstrated in the model systems used in this study can be replicated in patients with neuroblastoma, there is potential for real therapeutic gain.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available