Pulsed High-Intensity Focused Ultrasound Enhances Apoptosis and Growth Inhibition of Squamous Cell Carcinoma Xenografts with Proteasome Inhibitor Bortezomib

Abstract

Purpose: To investigate whether combining pulsed high-intensity focused ultrasound (HIFU) with the chemotherapeutic drug bortezomib could improve antitumor activity against murine squamous cell carcinoma (SCC) tumors. Materials and Methods: All experiments were conducted with animal care and use committee approval. Murine SCC cells were implanted subcutaneously in C3H mice. When tumors reached 100 mm3, mice were randomized to one of three groups for twice weekly intraperitoneal injections of 1.5 mg of bortezomib per kilogram of body weight, a proteasome inhibitor (n = 10); 1.0 mg/kg bortezomib (n = 11); or a control vehicle (n = 12). Within each group, half of the mice received pulsed HIFU exposure to their tumors immediately prior to each injection. The time for tumors to reach 650 mm3 was compared among groups. Additional tumors were stained with terminal deoxynucledotidyl transferase-mediated dUTP nick end labeling and CD31 to assess apoptotic index and blood vessel density, respectively. Results: Tumors in the control group, pulsed HIFU and control group, and 1.0 mg/kg of bortezomib alone group reached the size end point in 5.2 days ± 0.8 (standard deviation), 5.3 days ± 0.8, and 5.6 days ± 1.1, respectively. However, pulsed HIFU and 1.0 mg/kg bortezomib increased the time to end point to 9.8 days ± 2.9 (P < .02), not significantly different from the 8.8 days ± 2.1 in tumors treated with 1.5 mg/kg bortezomib alone (P > .05). Combination therapy was also associated with a significantly higher apoptotic index (P < .05). Conclusion: Treatment of tumors with pulsed HIFU lowered the threshold level for efficacy of bortezomib, resulting in significant tumor cytotoxicity and growth inhibition at lower dose levels.

Effects of High‐Intensity Focused Ultrasound for Treatment of Abdominal Lymph Node Metastasis From Gastric Cancer

“…16 At present, palliative chemotherapy remains the main therapeutic approach used to treat advanced gastric cancer, but the response rates to combined chemotherapy range from approximately 26% to 47.9%. 13,17,18 In this study, 185 patients were subjected to 5-fluorouracil-based chemotherapy and the objective response rate of group A was 34.3%, which was similar to that in a previous study. 19 With the high incidence of lymph node metastasis and the lack of effective therapies, HIFU has been considered a strong candidate for treatment combined with chemotherapy.…”

Pulsed focused ultrasound exposures enhance locally administered gene therapy in a murine solid tumor model

“…pFUS exposures similar to those employed in the present study have been used to non-invasively and nondestructively enhance the delivery of a variety of systemically administered agents in murine solid tumors including plasmid DNA (Dittmar et al, 2005), small molecules (Poff et al, 2008), nanoparticles (Frenkel et al, 2006), and monoclonal antibodies (Khaibullina et al, 2008). More recently, in a study in the murine skeletal muscle, the same exposures were shown to enhance the delivery of both systemically and locally administered nanoparticles (Hancock et al, 2009).…”

“…As a result, temperature elevations may be just a few degrees Celsius (and hence non-destructive), allowing for more delicate, non-thermal mechanisms to occur (Frenkel, 2008). pFUS exposures have demonstrated the ability to noninvasively enhance the delivery of a variety of systemically administered agents to solid tumors, including small molecules (Poff et al, 2008), plasmid DNA (Dittmar et al, 2005), monoclonal antibodies (Khaibullina et al, 2008), and nanoparticles (Dittmar et al, 2005;Frenkel et al, 2006). More recently, these exposures were shown to enhance the distribution of locally administered nanoparticles in skeletal muscle (Hancock et al, 2009).…”

MR Guided Pulsed High Intensity Focused Ultrasound Enhancement of Docetaxel Combined with Radiotherapy for Prostate Cancer Treatment

“…Recent studies have suggested that pFUS exposure may alter vascular or cell membrane permeability to enhance drug delivery in tumors in animal models (Bednarski et al 1997, Nelson et al 2002, Dittmar et al 2005, Yuh et al 2005, Frenkel V et al 2006a, Hancock et al 2009and Chen et al 2010. Enhancement of drug delivery to the tumor target by pFUS exposures and its effect on tumor growth inhibition in vivo has been reported by other investigators (Dittmar et al 2005, Dromi et al 2007and Poff et al 2008.…”