A new ruthenium radiosensitizer: RuCl2(DMSO)2(4-nitroimidazole)2.
Earlier studies on Ru complexes, such as, cis-RuCl2(DMSO)4, as antineoplastic agents, have suggested a DNA binding mechanism similar to that of the clinically successful platinum complex, cis-diammine(dichloro)platinum(II), (cis-DDP). As part of our study on metal-radiosensitizer complexes, cis-RuCl2(DMSO)4 is used as a precursor for synthesis of Ru(II)-nitroimidazole complexes. These complexes were identified and characterized and their toxicity and radiosensitizing abilities were examined in vitro. In the series of Ru(II)-nitroimidazole complexes synthesized, RuCl2(DMSO)2(4-nitroimidazole)2, "Ru-(4-nitro)," was the most effective radiosensitizer. At 200 microM, Ru-(4-nitro) produced a sensitizer enhancement ratio (SER) of 1.6 in hypoxic Chinese hamster ovary (CHO) cells, but did not sensitize oxic CHO cells. Other Ru-nitroimidazole complexes gave SER values of 1.2-1.4 at 200 microM. These Ru(II)-nitroimidazole complexes also showed lower toxicity than the free nitroimidazoles alone at equimolar concentration. The enhanced radiosensitizing effect of Ru-(4-nitro) may be due to the metal's ability to target the sensitizer to DNA, or may be related to changes in reduction potential: from -685 mV for the free ligand to -355 mV and -615 mV for the complex. This complex did not deplete non-protein sulfhydryls (NPSH) at the time intervals and concentrations used. DNA binding was studied using inhibition of restriction enzyme activity on plasmid DNA.
D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D006224:Cricetinae; D066298:In Vitro Techniques; D009593:Nitroimidazoles / Q000494:pharmacology*; D009942:Organometallic Compounds / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology* / Q000633:toxicity; D012428:Ruthenium / Q000494:pharmacology*
D009593:Nitroimidazoles; D009942:Organometallic Compounds; D011838:Radiation-Sensitizing Agents; D012428:Ruthenium