Ultrasound-enhanced effects of adriamycin against murine tumors

Earlier studies from out and other laboratories have demonstrated that ultrasound (US) enhances the cytotoxicity in vitro of the antitumor agent Adriamycin (Adr) (Harrison et al.1991; Loverock et al. 1990; Saad and Hahn 1987, 1989; Yang et al. 1991; Yumita et al. 1987, 1989). We have now tested the possibility that this additional cytotoxicity can be translated into antitumor activity in vivo. Mice, bearing either a fibrosarcoma (RIF-1) or a melanoma (B-16) on their thighs, were injected with a single dose of Adr (10–20 mg/kg). The tumors were then heated locally to 41°–43°C for 30 min, either by insonation with US or by immersion of the animals' limbs into hot water baths. Antitumor efficacy was scored two ways: by serial measurements of tumor volume to determine the time for the tumor to double in size, or by determining the X-ray dose required to sterilize 50% of the tumors (TCD 50) after the Adr-hyperthermia treatment. Both assays gave similar results. Ultrasound-induced hyperthermia was substantially more effective in enhancing Adr activity than was hyperthermia induced by the water bath. The mean-doubling time was 13 days for tumors treated with the combination of Adr and US and 6 days for tumors heated with a water bath immediately after injection of Adr. The TCD 50 was 21.2 ±0.8 Gy for the combination of US and Adr and 36.1 ± 0.9 Gy for the water bath heating and Adr. Because of fears that US might enhance metastatic rates, perhaps by mechanically dislodging cells from tumors, we tested that possibility in the B-16 melanoma system by quantifying formation of lung colonies. No effects of US on frequency of metastatic formation were seen. Our data, therefore, suggest that the combination of Adr and US-induced hyperthermia should be effective in the treatment of those malignancies accessible to ultrasound heating.