The advantageous use of hypoxic tumour cells in cancer therapy: Identical chemosensitization by metronidazole and misonidazole at moderately elevated temperatures

Abstract

Chemosensitization by two nitroimidazoles (NIs), metronidazole (METRO) and misonidazole (MISO), of the anti-tumour effect of alkylating agents was studied at three different temperatures: room temperature (RT), 37 and 41·5°C. Three alkylating agents, cyclophosphamide (CY), 1,3 bis(2-chloroethyl)-N-nitrosourea (BCNU) and melphalan (L-PAM) were tested when the tumours reached an average diameter of 4 mm. Tumours were 4th generation isotransplants of a spontaneous fibrosarcoma, FSa-II. Treatment at 37 or 41·5°C was given by immersing the tumour-bearing foot for 60 min in a water bath set at these temperatures. The test agents were injected ip immediately before immersing the foot in the water bath, whereas METRO or MISO (2·5 mmol/kg) was given ip 30 min before the injection of a test agent. Following treatment the tumour growth (TG) time, i.e. the time required for one-half of treated tumours to reach 1000 mm³ after the treatment day, was studied. For CY, MISO was a better sensitizer than METRO at RT and 37°C, but the magnitude of the chemosensitization by MISO and METRO became identical at 41·5°C. Notably, the chemosensitization was substantially enhanced at 41·5°C, whereas neither 41·5°C-heat, NIs or combined NI and heat prolonged the TG time. Although no chemosensitization was observed for BCNU at RT, both METRO and MISO equally enhanced the effect of BCNU at 41·5°C. The anti-tumour effect of L-PAM was not potentiated either at RT or 41·5°C, but the thermal enhancement at 41·5°C of L-PAM was greatest among the three agents tested. These results suggest that METRO, which is less toxic in the clinic than MISO, can be an excellent chemosensitizer at moderately elevated temperatures for selected alkylating agents. This treatment modality might be one of the most effective methods for using hypoxic tumour cells advantageously in cancer treatment, since chemosensitization by nitroimidazoles requires nitroreduction under hypoxic conditions. Although MISO and METRO have been used as model nitroimidazoles in this study, the same concept can be applied to newly-developed bioreductive agents.

Key Words:

• Chemosensitization
• MISO
• METRO
• hypoxia
• thermal enhancement