We have investigated the effects of localized tumor hyperthermia (LTH; 43.5°C × 30 min) on the reductive bioactivation of the 2-nitroimidazole benznidazole in C3H mouse normal tissues and KHT tumors. Mice were allocated to one of three treatment groups: (a) unrestrained controls, (b) sham tumor treatment, and (c) LTH. Concentrations of benznidazole and its amine metabolite were determined by high-performance liquid chromatography. Conscious mice were given LTH or sham treatment 2.5 h after 2.5 mmol/kg benznidazole i.p. This gave steady-state plasma benznidazole concentrations of 120–170 µg/ml at 2–5 h in all three groups. Plasma amine concentrations were very low at 0.1–1 µg/ml in all cases. Liver benznidazole concentrations were similar to plasma but amine concentrations were 30–40-fold greater at 20–40 µg/g in all three groups, implicating the liver as a major site of reductive metabolism. Benznidazole concentrations in tumors from unrestrained mice were comparable to those in plasma and liver, with tumor/plasma ratios of 85–113%. Tumor amine concentrations were intermediate at about 2–3 µg/g, indicating reductive bioactivation had occurred. Sham treatment decreased tumor benznidazole concentrations by 25–50%, particularly at later times, and amine concentrations were correspondingly increased. This may be a result of sham tumor treatment at 37°C, a temperature 3–4°C higher than in unrestrained controls. More importantly, LTH further decreased tumor benznidazole concentrations over sham treatment, e.g., by 59% from 114 to 47 µg/g (P < 0.01) immediately after heating. Amine concentrations were correspondingly elevated, e.g., by 40% from 5.1 to 8.4 µg/g (P < 0.01). These results clearly show that LTH can selectively enhance the reductive bioactivation of benznidazole in KHT tumors in mice, and support a particular role for the use of bioreductive agents with heat.

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