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Overcoming the Mechanism of Radioresistance in Neuroblastoma

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Final rept. 30 Sep 2012-30 Mar 2014

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Patient survival for highly aggressive advanced-stage neuroblastoma remains poor despite a multidisciplinary approach involving aggressive surgery, chemotherapy and adjuvant radiotherapy RT. The large RT treatment volume, and concerns about the proximity of radiosensitive normal structures, restricts the tumoricidal dose of radiotherapy that can be delivered which limits the effectiveness of adjuvant RT. To address this, we delivered radiotherapy using an entirely novel treatment schedule designed to minimize normal tissue damage. The concept was to deliver 10 pulses of low-dose RT PRT, 10 x 0.2 Gy using a 3 minute inter-pulse interval to introduce the RT-induced damage at a level that spares tumor vasculature in order to prevent the development of treatment-induced hypoxia, since this increases tumor resistance to radiation and chemotherapy. Moreover, damage produced at this dose level evades ATM dose-dependent DNA damage detection and repair mechanisms. In vitro, a single 2 Gy dose of PRT was not inferior to SRT in any of the 4 neuroblastoma cell lines despite the prolonged delivery time. In vivo, PRT and SRT were equally effective at controlling MC-IXC and SK-N-SH subcutaneous tumors. However, significant differences in tumor volume and regrowth were evident for MYCN-amplified SK-N-BE2 tumors between PRT and SRT at 5 days p0.008 and 21 days p0.014 post treatment, and for the entire timeframe p0.006. Endpoint criteria was reached at 43 days for SRT but 56 days after PRT p0.012. Furthermore, tumors treated with PRT demonstrated a significant increase in FDG PET maximum standardized uptake value after treatment SUVmax1.13 SRT, 1.79 PRT, p0.03. This increase was also significant when compared to pre-treatment values for PRT SUVmax PreTreatment1.04, p0.001.

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  • Anatomy and Physiology
  • Medicine and Medical Research

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