Tom R. Tritton
Vermont Cancer Ctr. and Dept. of Pharmacology, Univ. of Vermont, Burlington, VT 05405
Univ. of Vermont, Burlington, VT 05405
Univ. of Illinois at Urbana--Champaign, Urbana, IL 61801
Continuous wave 1-MHz ultrasound at the therapeutic intensity of 1 W/cm[sup 2] was found to enhance significantly the hydroxyl radical production from two clinically employed redox cycling drugs, viz., Adriamycin (Doxorubicin) and Mitomycin C, with respect to the control drug-free insonicated phosphate buffer suspension. Benzoic acid (Bz) was employed as a sensitive chemical probe to detect hydroxyl radicals (OH[sup (centered dot)]). Bz is initially nonfluorescent and upon aromatic hydroxylation becomes permanently fluorescent. A series of time course studies up to one-half hour were performed on drug suspensions to characterize the OH[sup (centered dot)] generation in the presence and absence of ultrasound at 37 (degrees)C. Identical ultrasound treatments on non-redox cycling clinical drugs 5-Fluorouracil and Methotrexate did not yield any significant enhancement in the production of OH[sup (centered dot)] in comparison to the drug-free insonicated phosphate buffer suspension. One-half hour ultrasound exposures did not yield measurable changes in the chemical constitution of the four drugs as assessed through high-pressure liquid chromatography. Identical ultrasound treatments at 3 MHz did not produce at OH[sup (centered dot)] in the presence or in the absence of these four anti-cancer drugs. Free radical scavengers such as mannitol, superoxide dismutase, catalase, and a transition metal chelating agent were employed independently to discern the chemical species and pathways involved in the production of the OH[sup (centered dot)]. The findings strongly implicate an active role of acoustically induced cavitation in potentiating redox cycling drugs via chemical reduction and, thereafter, production of the OH[sup (centered dot)] via Fenton's pathway.