The objective of this project is to evaluate the hypothesis that chemotherapy can be potentiated by novel forms of low-level ultrasound (US) which by itself causes no tissue heating or cell killing. The main innovation of the project is the use of spatially uniform bursts of continuous-wave or pulsed US, including high-pressure amplitudes at low duty cycles. The specific goals related to US methodology are to develop US source/transducer systems producing a selected variety of treatment fields, and then to optimize field parameters (frequency, exposure time, temporal peak intensity, duty cycle, and wave-form shape) based on response of Chinese hamster ovary (CHO) cells to combined exposure to US and adriamycin at 1 microgram/ml. the US beam parameters producing the most effective combined treatment will serve as a baseline for testing other drugs and cell lines. Next, other anti-neoplastics (cisplatin, nitrogen mustard, hematoporphyrin derivative, r-fluorouracil, vincristine, and tamoxifen) will be screened using US and CHO cells. Effective drugs will then be tested against wild-type and multi-drug-resistant MCF-7 human breast carcinoma cell lines. In each test, survival curves will be obtained as a function of drug concentration, with and without US, to evaluate US enhancement. Mechanisms of US-enhanced drug activity will be investigated by in vitro measurements of US-induced changes in labelled drug uptake, free radical production, and treatment effectiveness in normal vs. drug-resistant cells. Any dependence of these endpoints with the US beam parameters mentioned above will provide valuable clues concerning possible athermal US interaction mechanisms such as intracellular streaming, finite amplitude effects, or transient cavitation. Primary emphasis in US technique development and biological experimentation will be placed on determining the potential of low-level US as a practical clinical adjuvant to improve chemotherapy.
