Objective: The majority of current high intensity focused ultrasound (HIFU) applications involve long continuous exposures that produce significant temperature elevations for tissue ablation. Pulsed-HIFU exposures, on the other hand, produce minimal temperature elevations, and instead are non-destructive. Our pre-clinical investigations have shown that these exposures can generate reversible structural effects in the tissue that enhance its permeability for improved delivery of both systemically and locally injected materials to targeted tissues. This enhancement allows for improved efficacy of therapeutic agents. We wanted to determine if pulsed-HIFU exposures could enhance the efficacy of the proteasome inhibitor Bortezomib as well as tumor necrosis factor alpha (TNFα) plasmid in a murine head and neck squamous cell carcinoma (HNSCC). Additional experiments presently being carried out will determine if a synergistic effect could be obtained by combining the two agents.

Methods: Experiments were carried out with a murine SCCVII tumor line grown subcutaneously in the flanks of female C3H mice. The effects of a sub-therapeutic dose of Bortezomib for SCCVII (1 mg/kg), given systemically, and TNFα,(50 μg) administered intratumorally, on growth of the tumors was studied, with and without preceding pulsed-HIFU exposures. Control (untreated) tumors were also used, as well those only receiving exposures. Histological analysis of tumors was carried out for both studies.

Results: Bortezomib alone had no effect on the growth rate of tumors when compared to controls. However, when combined with pulsed-HIFU, it caused a significant reduction in growth. TNFα, on the other hand caused a significant reduction in growth when administered alone. And a further significant reduction occurred when combined with the exposures. In both experiments, pulsed-HIFU alone did not effect tumor growth. These results were corroborated by both H&E and TUNEL staining of histological sections of experimental tumors.

Conclusion: The pulsed-HIFU exposures were able to non-invasively enhance the therapeutic efficacy of both anti-cancer agents. Additional experiments will determine if combining both agents with the exposures could further improve their anti-tumor effects, which has to date only been shown in vitro. Such combination therapy could be beneficial for treatment of human HNSCC and other malignancies responsive to these agents.