Overcoming the Mechanism of Radioresistance in Neuroblastoma.

摘要

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-BE(2) tumors between PRT and SRT at 5 days (p=0.008) and 21 days (p=0.014) post treatment, and for the entire timeframe (p=0.006). Endpoint criteria was reached at 43 days for SRT but 56 days after PRT (p=0.012). Furthermore, tumors treated with PRT demonstrated a significant increase in FDG PET maximum standardized uptake value after treatment (SUVmax=1.13 SRT, 1.79 PRT, p=0.03). This increase was also significant when compared to pre-treatment values for PRT (SUVmax PreTreatment=1.04, p=0.001).