Pulsed high-intensity focused ultrasound enhances apoptosis and growth inhibition of squamous cell carcinoma xenografts with proteasome inhibitor bortezomib.
OBJECTIVE
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.


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 mm(3), 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 mm(3) 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).


CONCLUSIONS
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.
Diagnostic Radiology Department, Clinical Center and Head and Neck Surgery Branch, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA.
Jason A
JA
Poff
Clint T
CT
Allen
Bryan
B
Traughber
Aric
A
Colunga
Jianwu
J
Xie
Zhong
Z
Chen
Bradford J
BJ
Wood
Carter
C
Van Waes
King C P
KC
Li
Victor
V
Frenkel
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000628:therapy*; D003131:Combined Modality Therapy; D051379:Mice; D011719:Pyrazines / Q000494:pharmacology*; D011897:Random Allocation; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D014464:Ultrasonic Therapy
D000970:Antineoplastic Agents; D001897:Boronic Acids; D011719:Pyrazines; D000069286:Bortezomib