Some Complexes of Cobalt(III) and Iron(III) Are Radiosensitizers of Hypoxic EMT6 Cells

Abstract

The radiosensitizing potential in hypoxic EMT6 cells of several complexes of Co(III) and Fe(III) has been examined. The cytotoxicity of each of the agents toward oxygenated and hypoxic EMT6 cells was tested over the concentration range of 1 to 500 micron for 1-h drug exposure. There was no statistically significant difference between the cytotoxicity of these complexes toward oxygenated and hypoxic cells. Based on these findings, 100 micron was selected as the drug concentration for the initial assessment of radiosensitizing potential. The radiation survival of EMT6 cells in the presence of 100 microM drug for a series of Co(III) complexes in which the number of nitro ligands was varied showed that the hexanitro and the triamine-trinitro complexes are very effective radiosensitizers. The trans-tetrammine dinitro complex was a more effective radiosensitizer than the corresponding cis-dinitro complex. The diethylenetriamine and 1,10-phenanthroline complexes were very effective radiosensitizers, producing dose-modifying factors of 2.4. The trans-tetrammine dichloro complex was moderately effective, giving a dose-modifying factor of 1.9. On the other hand, the hexammine and triammine tricyano complexes and the trans-dinitro complex with negatively charged acetylacetonate ligands were ineffective as radiosensitizers in this system. Finally, three complexes with cyclopentadienyl ligands were examined. The ferricenium salt itself was a moderately effective radiosensitizer, giving a dose-modifying factor of 2.0. However, both the dimethylferricenium salt and the analogous cobalt complex were ineffective. The FSaIIC fibrosarcoma was used to study radiosensitizing potential in vivo. The trans-tetramminedinitro complex was administered at doses of 100, 200, or 300 mg/kg as a single ip injection 1 h prior to irradiation or as three daily ip injections. There was increasing dose modification with increasing drug dosage. With a fractionated radiation protocol in which five daily fractions of 2, 3, or 4 Gy were administered to the tumor-bearing limb with ip drug injections of 100 or 200 mg/kg given 1 h prior to irradiation, a dose-modifying effect of 1.6 was observed with 5 X 200 mg/kg of the drug.