GENOTOXIC ACTIVITY OF NEWLY SYNTHESIZED IMIDAZOLYL DERIVATIVES IN MOUSE LYMPHOMA AND BONE MARROW CELLS
A.K. Nersesyan1,*, G.S. Melikyan2, R.E. Muradyan3, H. Stopper4
1Cancer Research Centre, Yerevan, Armenia 2State University, Yerevan, Armenia 3Institute of Fine Organic Chemistry, Yerevan, Armenia 4Institute of Pharmacology and Toxicology, Wuerzburg 97078, Germany
Abstract. Aim: to investigate the genotoxic activity of three newly synthesized imidazolyl derivatives (two lactones (IPATB and IPMOSD) and lactame (IPATP)) with antitumor properties. Methods: the genotoxicity of the compounds was studied both in vitro on L5178Y mouse lymphoma cells (micronucleus (MN) inducing and DNA-damaging activities) and in vivo (MN inducing activity) on Swiss albino mice’s bone marrow polychromatic erythrocytes (PCEs). Results: in L5178Y mouse lymphoma cells, IPATB and IPMOSD did not induce MN (at the highest available concentration and at the dose of 1000 µg/ml, respectively), while IPATP induced them only at doses of 500 and 1000 µg/ml (3-fold and 4-fold higher than in negative control, respectively). IPATB and IPMOSD were not toxic for lymphoma cells at maximal used doses, but IPATP significantly decreased the number of cells (by 57 and 39% at doses of 500 and 1000 µg/ml respectively, compared to negative control). By the comet assay we did not reveal any evidence of DNA damage. In vivo studies have shown that IPATP and IPATB induced MN in murine PCEs only at doses equal to ½ of LD50. IPATP was a more potent MN inductor: it yielded 5-fold increase compared to the negative control in contrast to 2-fold increment by IPATB. Administration of the substances in the doses equal to 1/5 of LD50 did not induce any significant increase of MN in mouse bone marrow PCEs. IPMOSD was not active in MN assay. A high dose of IPATP was slightly toxic for hemopoietic cells, and decreased significantly the number of PCEs. Conclusion: IPATP and IPMOSD possessing weak or no genotoxic potency, and comparatively low toxicity, along with their in vitro antitumor activity offer good chance for successful in vivo antitumor studies in rodents.
