Pulsed High-Intensity Focused Ultrasound Enhances Apoptosis of Pancreatic Cancer Xenograft with Gemcitabine

Abstract We sought to investigate whether concurrent exposure to pulsed high-intensity focused ultrasound (HIFU) and the chemotherapeutic drug gemcitabine would enhance apoptosis in pancreatic cancer. A pancreatic cancer xenograft model was established using BALB/c nude mice and human pancreatic cancer cells (PANC-1). In the first study, mice were randomly allocated into one of four groups: control (n = 4), HIFU alone (n = 4), gemcitabine (GEM) alone (n = 28) and concurrent treatment with HIFU and gemcitabine (HIGEM) (n = 28). The GEM and HIGEM groups were subdivided into four subgroups (16 mice) according to the drug dose injected (50–200 mg/kg) and another four subgroups (16 mice) according to the time interval between drug injection and HIFU treatment (each subgroup, n = 4). Apoptosis rates were evaluated using the TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling) assay and percentage of necrosis, as evaluated with Harris' hematoxylin solution and eosin Y stain, 3 d after treatment. The second study was performed to evaluate tumor growth rates of the four groups. Each group was treated weekly for 3 wk, and tumor size was periodically measured for up to 4 wk from the beginning of treatment. In the first study, overall rates of apoptosis were significantly higher in the HIGEM group than in the GEM group ( p = 0.02). In a subgroup analysis, HIGEM was superior to GEM in enhancing apoptosis at gemcitabine dosages of 150–200 mg/kg gemcitabine and intervals between gemcitabine and HIFU less than 2 h ( p = 0.01). In the second study, HIGEM treatment resulted in the slowest tumor growth. However, despite a visible distinction, none of the differences found between the HIGEM and GEM groups were statistically significant ( p > 0.05). Treatment with both HIFU and gemcitabine might enhance cell apoptosis and reduce tumor growth in pancreatic carcinoma. For this concurrent treatment, a high dosage of gemcitabine and a short-term delay before HIFU are recommended to maximize the therapeutic effect.