Effect of Treatment Sequencing on the Tumor Response to Combined Treatment With Ultrasound-Stimulated Microbubbles and Radiotherapy.

Abstract

To investigate whether timing and sequencing of ultrasound-stimulated microbubbles (USMBs) and external beam radiotherapy (XRT) affect the treatment response in a preclinical prostate cancer model. Prostate cancer xenografts were treated with ultrasound-stimulated lipid microspheres before and after 8-Gy XRT. Treatments were separated by 0, 3, 6, 12, and 24 hours, with 5 tumors per group. Tumor effects were evaluated by microvessel density (measured by CD31 staining), cell death (terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end-labeling and hematoxylin-eosin staining), and hypoxia (carbonic anhydrase 9 staining). Administering USMBs 6 hours before XRT showed the maximum treatment effect using all 3 assays. At this time, the mean cell death index ± SD was 36% ± 10%, compared with 19% ± 4% for no separation between USMB treatment and XRT; the microvessel density was 9 ± 3 counts per field (19 ± 5 without separation); and the percentage of hypoxic cells was 10% ± 5% (21% ± 4%). The observed treatment effect was greater with USMBs before XRT than when administering XRT first, but these differences were not statistically significant. The maximum tumor effect was observed with USMBs delivered 6 hours before XRT. The sequencing of treatment did not have a significant effect on the tumor response.