title: Effect of pH, oxygenation, and temperature on the cytotoxicity and radiosensitization by etanidazole.
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.
authors.affiliation: Department of Cancer Pharmacology, Dana-Farber Cancer Institute, Boston, MA 02115.
authors.forename: B A
authors.initials: BA
authors.lastname: Teicher
authors.forename: T S
authors.initials: TS
authors.lastname: Herman
authors.forename: S A
authors.initials: SA
authors.lastname: Holden
mesh_terms: D000818:Animals; D001562:Benzimidazoles; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects*; D017341:Etanidazole; D005354:Fibrosarcoma / Q000188:drug therapy / Q000532:radiotherapy / Q000628:therapy*; D005434:Flow Cytometry; D005456:Fluorescent Dyes; D006863:Hydrogen-Ion Concentration; D006979:Hyperthermia, Induced; D000860:Hypoxia; D009593:Nitroimidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D012513:Sarcoma, Experimental / Q000188:drug therapy / Q000532:radiotherapy / Q000628:therapy*; D013696:Temperature
chemical_list: D001562:Benzimidazoles; D005456:Fluorescent Dyes; D009593:Nitroimidazoles; D011838:Radiation-Sensitizing Agents; D017341:Etanidazole; C017807:bisbenzimide ethoxide trihydrochloride