This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Walton, M. I. Articles by Workman, P. Search for Related Content PubMed PubMed Citation Articles by Walton, M. I. Articles by Workman, P.

Stimulation by Localized Tumor Hyperthermia of Reductive Bioactivation of 2-Nitroimidazole Benznidazole in Mice

MRC Unit and University Department of Clinical Oncology and Radiotherapeutics, Hills Rd, Cambridge, CB2 2QH, UK

We have investigated the effects of localized tumor hyperthermia (LTH; 43.5°C x 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.

¹ To whom requests for reprints should be addressed.

Received 7/ 7/88. Revised 1/13/89. Accepted 1/23/89.