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Experimental treatment of neuroblastoma using [¹³¹I]meta-iodobenzylguanidine and topotecan in combination

¹ Targeted Therapy Group, Division of Cancer Sciences, Faculty of Medicine, University of Glasgow, Cancer Research UK Beatson Laboratories, Garscube Estate, Glasgow G61 1BD, ² Radionuclide Dispensary, Western Infirmary, Glasgow G11 6NT UK, ³ Molecular Insight Pharmaceuticals, Inc., Cambridge, MA 02142, USA, ⁴ University College London Hospitals NHS Foundation Trust, Middlesex Hospital, Mortimer Street, London W1T 3AA,, ⁵ Department of Child Health, University of Glasgow, Cancer Research UK Beatson Laboratories, Garscube Estate, Glasgow G61 1BD, UK

Correspondence: R J Mairs, Targeted Therapy Group, University of Glasgow, Cancer Research UK Beatson Laboratories, Garscube Estate, Glasgow G61 1BD, UK. E-mail: r.mairs{at}beatson.gla.ac.uk

The radiopharmaceutical [¹³¹I]meta-iodobenzylguanidine ([¹³¹I]MIBG) and the topoisomerase I inhibitor topotecan are both effective as single-agent treatments of neuroblastoma. Our purpose was to assess the therapeutic potential of [¹³¹I]MIBG and topotecan in combination using SK-N-BE(2c) neuroblastoma cells and UVW/NAT glioma cells expressing the noradrenaline transporter transgene. Topotecan treatment was given (i) before, (ii) after or (iii) simultaneously with [¹³¹I]MIBG. DNA fragmentation was evaluated by comet assay and cell cycle redistribution was determined by fluorescence-activated cell sorting. Combination index analysis indicated that delivery schedules (ii) and (iii) were more effective than schedule (i) with respect to clonogenic cell kill. Similarly, significant DNA damage was observed following treatment schedules (ii) and (iii) (p <0.005), but not (i). Prior exposure to topotecan did not significantly enhance [¹³¹I]MIBG uptake in athymic mice bearing tumour xenografts. We conclude that the enhancement of the efficacy of [¹³¹I]MIBG by combining it with topotecan was the result of inhibition of DNA damage repair rather than an increase in expression of the noradrenaline transporter by tumour.