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  • Title: Effect of pH, oxygenation, and temperature on the cytotoxicity and radiosensitization by etanidazole.
    Author: Teicher BA, Herman TS, Holden SA.
    Journal: Int J Radiat Oncol Biol Phys; 1991 Apr; 20(4):723-31. PubMed ID: 1825994.
    Abstract:
    The effect of etanidazole was examined in vitro and in vivo in the FSaIIC tumor system. At pH 7.40 and 37 degrees C, etanidazole at 5-500 microM for 1 hr was minimally cytotoxic. At 42 degrees C and 43 degrees C, however, the cytotoxicity of etanidazole increased. Etanidazole was more cytotoxic at pH 6.45 and 37 degrees than at pH 7.40 by about 1 log. Increasing the temperature to 42 degrees C or 43 degrees C at pH 6.45 during drug exposure, however, caused little increase in drug killing above the lethality of hyperthermia. When the radiosensitizing abilities of etanidazole were tested in vitro, there was a radiation dose modifying factor of 2.40 at pH 7.40, but only 1.70 at pH 6.45. In vivo, etanidazole (1 g/kg) produced a radiation dose modifying factor of 1.47, whereas 43 degrees C for 30 min produced a radiation dose modifying factor of 1.38. The combination resulted in a radiation dose modifying factor of 2.29. When the cytotoxicities of hyperthermia (43 degrees C x 30 min), etanidazole (500 mg/kg or 1 mg/kg), and radiation (10 Gy) combinations were assayed by Hoechst 33342 dye selected tumor subpopulations, 43 degrees C x 30 min increased the killing of irradiated dim cells by approximately 9.2-fold but by only 2.9-fold in bright cells. Etanidazole (1 g/kg) increased radiation killing of bright cells by about 3-fold and dim cells by about 4.3-fold. The combination of hyperthermia and etanidazole increased the killing of both dim and bright cells exposed to radiation by approximately 10-fold versus 10 Gy alone.
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