Synergistic interaction of ultrasonic shock waves and hyperthermia in the Dunning prostate tumor R3327-AT1

Pulsed high-energy ultrasound shock waves (PHEUS), similar to those used for clinical lithotripsy, can deposit energy deep in tissue and thereby destroy the microvasculature of solid tumors. We investigated the potential of PHEUS, generated by an electromagnetic shockwave source (19 kV capacitor voltage, 1 Hz pulse frequency), as a local cancer-therapy modality alone and in combination with local tumor hyperthermia (43.5 +/- 0.1 degrees C, 30 min). Copenhagen rats transplanted with the anaplastic Dunning-prostate-tumor sub-line R3327-AT1 received 1000 PHEUS pulses, which delayed tumor growth by one tumor-doubling time (5 days). Histopathology revealed hemorrhage, disruption of tumor vasculature, and necrosis in the focus of the sound field. Bromodeoxyuridine (BUdR) incorporation was significantly lower in PHEUS-treated tumors than in controls. Dynamic magnetic resonance imaging (MRI) studies using gadolinium-DTPA as contrast agent showed a strong reduction of tumor perfusion after PHEUS treatment, although this effect was partly reversible within 3 days after PHEUS. While hyperthermia alone produced no significant delay in tumor growth, the combination of PHEUS and hyperthermia produced tumor-growth delay by 2 tumor-volume-doubling times. The maximum growth delay was achieved when PHEUS and hyperthermia were separated by 24 hr at the time of maximum perfusion reduction indicated by MRI. Thus, the cytotoxic effect of PHEUS was enhanced by hyperthermia in the anaplastic prostate tumor R3327-AT1 grown on Copenhagen rats in a synergistic manner, due to blood-flow reduction. In conjunction with other agents, such as hyperthermia, PHEUS might become a local cancer-therapy modality in solid tumors accessible to ultrasound.