Concurrent pulsed high-intensity focused ultrasound and gemcitabine treatment in animal models of pancreatic cancer

Abstract

Introduction: We sought to investigate whether concurrent exposure to pulsed high-intensity focused ultrasound (HIFU) and the chemotherapeutic drug gemcitabine could enhance apoptosis in pancreatic cancer.

Methods: 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 the following four groups: control (n = 4), HIFU alone (n = 4), gemcitabine alone (GEM) (n = 28), and concurrent treatment of HIFU with gemcitabine (HIGEM) (n = 28). The GEM and HIGEM groups were subdivided into four subgroups according to the injected drug dose (50 - 200 mg/kg) in 16 mice and another four subgroups according to the time interval between drug injection and HIFU treatment in 16 mice (each subgroup, n = 4). Apoptotic ratios were evaluated using the terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assay and percentage of necrosis, as evaluated with Harris hematoxylin solution and eosin Y (H & E) staining, three days after treatment. The second study was performed to evaluate tumor growth rates of the four groups. Each group was treated weekly for three weeks, and the tumor size was periodically measured for up to four weeks from the beginning of treatment.

Results: In the first study, the overall apoptotic ratios in the HIGEM group were significantly higher than the GEM group (p = 0.02). In a subgroup analysis, HIGEM was superior to GEM in generating apoptosis when 150-200 mg/kg gemcitabine and short-term intervals less than 2 hours were used (p = 0.01). In the second study, HIGEM treatment exhibited the slowest tumor growth. However, despite a visible distinction, no statistically significant difference was found between HIGEM and GEM groups (p > 0.05).

Conclusion: Treatment with both HIFU and gemcitabine might enhance cell apoptosis and reduce tumor growth in pancreatic carcinoma. For this concurrent treatment, high dosage of gemcitabine with a short-term delay would be recommended to maximize therapeutic effect.