Evaluation of CNS xenograft brain tumour response to MRI-guided focused ultrasound in combination with radiation therapy

BACKGROUND: In recent years, treating solid tumours with focused ultrasound (FUS) has emerged as a novel therapeutic technique because of its noninvasive nature. Recent work has demonstrated the ability of focused ultrasound-stimulated microbubble (FUS + MB) treatments to enhance radiation effects on tumours significantly. In this study, a rabbit model of brain metastasis was used to evaluate the therapeutic effect of FUS + MB-based therapy and radiation therapy (XRT). METHODS: Experiments were performed with brain-tumour bearing rabbits generated using human prostate cancer xenografts (PC3). Animals were randomized into four groups: control (untreated), FUS + MB alone, XRT alone, and a combined therapy (FUS + MB + XRT). Single treatment regimens and multiple-treatment regimens were evaluated with single-dose and fractionated radiotherapy, respectively. Tumour response was evaluated 24 hours and for up to 1 week after treatment to evaluate longitudinal responses. RESULTS: Tumour cell death and vascular damage was found to be minimal within 24 hour following treatment. However, results obtained following 1 week of multiple treatments demonstrated that combined treated tumour xenografts exhibited a greater extent of cellular and vascular damage confirmed using hematoxylin and eosin (H&E) and factor VIII immunohistochemical staining, respectively. Lesser number of proliferative cells were also observed in the combined treated group as compared to the other groups. Additionally, significant increase in acid sphingomyelinase (ASMase) staining was observed following a combined treatment of FUS + MB and XRT confirming the involvement of ASMase/ceramide pathway in enhanced tumour response. CONCLUSION: These results indicate enhancement of radiation effect to CNS-based tumours through ultrasound-stimulated microbubbles.