Evaluation of genotoxic activity of cis-(dichloro) tetr aammineruthenium (iii) chloride compound on cultured human peripheral blood lymphocytes

Abstract

Several metallic compounds, recognized as potent antitumor agents, have been developed and tested in vivo and in vitro. Among the first metallic complexes used in the treatment of solid tumors we can mention cisplatin. However, these complexes frequently lose their efficiency due to their toxic effects and tumor resistance, which leads to the formation of secondary tumors. Ruthenium compounds, one of the metals in the platinum group, have been calling the attention as possible antitumor agents. Preclinical studies using some ruthenium compounds [KP1019, RM175, MMI/ONCO4403, RAP, NAMI, NAMI-A, cis-tetraamineoxalateruthenium (III) ditionate, and cis-dichlorotetraammineruthenium(III) chloride] revealed promising results in the treatment of tumors, since their systemic action reached metastases and liquid tumors. Among the medicines tested, ruthenium compounds showed promising results due to their antimetastatic properties, which represents an important milestone in the development of new antitumor drugs. Conside  ng the DNA as a target, several ruthenium compounds have been developed and their linking properties have been tested. The two properties attributed to ruthenium compounds – activation by reduction and selective transportation via transferrin system – might explain their antitumor characteristics. In the initial stages of pharmaceutical discoveries, when only minimum information is available on the properties of a new molecule, simple predictive triages are adequate. In the present study, we investigated the genotoxic effects of different concentrations of cis-dichlorotetraammineruthenium(III) chloride in human lymphocytes culture in vitro using the mitotic index (MI), the chromosomal aberrations (CAs), and the comet assay. Human lymphocyte cultures were treated with this ruthenium compound at the concentrations of 1, 10, 100, and 1000 ?g.mL-1; doxorubicin chloridate was employed as positive control and complete medium as negative control. At the concentrations of 1, 10, 100, and 1000 ?g.mL-1 the MI were 5.9   4.6%, 3.9%, and 0%, respectively. We found chromosomal aberrations considered spontaneous (1-2%) at the concentrations of 1, 10, and 100 ?g.mL-1, presenting statistically different results when compared with the positive control. For the comet assay, the experiments were carried out in duplicate and 100 nuclei were analyzed (50 nuclei for each duplicate). The comets were classified into classes using the software CometScore 15. The result of the present study demonstrated that cis-dichlorotetraammineruthenium(III) has no genotoxic potential in vitro.