Overcoming the Mechanism of Radioresistance in Neuroblastoma
Abstract
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 clonogenic survival experiments demonstrated that a single dose of PRT was not inferior to a continuously delivered standard 2 Gy dose (SRT). PRT was delivered at 0.25 Gy/min and SRT at 0.69 Gy/min using a Faxitron 160 kVp animal X-irradiator (0.5 mm Cu and Al filters; HVL: 0.77 (mm CU)). Female CB-17/SCID mice were xenotransplanted subcutaneously in the flank at 6-8 weeks of age with either SK-N-SH, SK-N-BE or MC-IXC neuroblastoma cells and the subsequent tumors irradiated with a total dose of 20 Gy given over 10 consecutive days (2 Gy/day) as either PRT or SRT. Tumor response was evaluated by physical measurements three times a week and by imaging using F18-FDG PET/CT 1 day prior to and 2 days post radiation treatment. For SK-N-BE tumors, significant differences in CT volume between PRT and SRT were evident at 5 days (p=0.008) and 21 days (p=0.014) post treatment, and animals reached endpoint criteria at 56 days after PRT compared with 43 days for SRT (p=0.012).
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2013
- Accession Number
- ADA598375
Entities
People
- Brian Marples