Additivity of radiosensitization by the combination of SR 2508 (etanidazole) and Ro 03-8799 (pimonidazole) in a murine tumor system.
The nitroimidazole radiosensitizers SR 2508 and Ro 03-8799 have different dose-limiting toxicities in man and hence can be used in combination. Such therapy will be beneficial only if their radiosensitizing properties are additive, which this study sought to determine using clinically relevant radiosensitizer concentrations in the EMT6 tumor in the flanks of BALB/c mice. 240 mg/kg of each drug gave tumor concentrations (+/- 2 se) 55 min after i.v. administration of the combination of 50.4 +/- 10.6 micrograms/g (236 +/- 50 nmol/g) for SR 2508 and 39.7 +/- 9.0 micrograms/g (137 +/- 31 nmol/g) for Ro 03-8799. The radiosensitization by both agents administered both singly and in combination at 240 mg/kg and singly at 480 mg/kg was measured, giving sensitizers 30 min before 20 Gy of 250 kV X rays. Tumor response was assayed by clonogenic cell survival. SER values (with 95% confidence limits) were 1.28 (1.20-1.37) for 240 mg/kg SR 2508, 1.20 (1.10-1.30) for 240 mg/kg Ro 03-8799, 1.46 (1.33-1.59) for 240 mg/kg of both drugs in combination, 1.46 (1.38-1.55) for 480 mg/kg SR 2508 and 1.46 (1.31-1.62) for 480 mg/kg Ro 03-8799. These data confirm the additivity of radiosensitization by the two drugs administered in combination.
Honess
D J
DJ
University Department of Clinical Oncology and Radiotherapeutics, Cambridge, England.
Wasserman
T H
TH
Workman
P
P
Ward
R
R
Bleehen
N M
NM
D000818:Animals; D002470:Cell Survival; D004359:Drug Therapy, Combination; D017341:Etanidazole; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental / Q000532:radiotherapy*; D009593:Nitroimidazoles / Q000008:administration & dosage / Q000627:therapeutic use; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics
D009593:Nitroimidazoles; D011838:Radiation-Sensitizing Agents; D017341:Etanidazole; C033815:pimonidazole