ABSTRACT
The two current second generation radiosensitizers SR-2508 (etanidazole) and Ro 03-8799 (pimonidazole) have different dose-limiting toxicities in humans. SR-2508 produces peripheral neuropathy, whereas Ro 03-8799 causes acute CNS toxicity. Overall toxicity can be minimized while increasing maximal radiosensitization by combining the two sensitizers. The additivity of their radiosensitizing properties was tested using clinically relevant SR-2508 and Ro 03-8799 concentrations in two human tumor xenografts: a rectal adenocarcinoma (HRT18) and a pigmented melanoma (Na11+). Drug concentrations were determined by a High Performance Liquid Chromatography method. Tumor response was assayed by clonogenic cell survival. The maximal radiosensitizing effect was determined using a single dose of radiation and high doses of drugs. For HRT18, the maximal radiosensitization was achieved when SR-2508 and Ro 03-8799 were given 45 and 30 min, respectively, before irradiation. For Na11+, the maximal radiosensitizing effect was lower than for HRT18 and not significant, but a trend was observed at about 30 min before irradiation for both drugs. Using clinically relevant doses, mean Sensitizing Enhancement Ratio (SER) values for HRT18 were: 1.3 (Ro 03-8799: 0.1 mg/gram body weight (gbw) or SR-2508: 0.2 mg/gbw), and 1.5 (Ro 03-8799: 0.1 mg/gbw + SR-2508: 0.2 mg/gbw). Mean SER values for Ro 03-8799 0.2 mg/gbw, SR-2508 0.4 mg/gbw, and Ro 03-8799 0.2 mg/gbw + SR-2508 0.4 mg/gbw were 1.5, 1.5, and 1.8, respectively. No significant radiosensitizing effect was observed on Na11+ with either drug administered singly or in combination and at the same concentrations. Our results suggest that the effectiveness of the two sensitizers administered alone or in combination may be tumor-dependent and that melanomas may not be good candidates.
