Antitumor Activity And Mechanism Of Seven Rare Earth Complexes In Vitro And In Vivo

OBJECTIVE: To provide pharmacological basis for developing these rare earth complexes as a new kind of antitumor drug, the antitumor activity of seven (Erbium, Cerium, Yttrium, Lanthanum, Samarium, Dysprosium, Gadolinium) complexes rare earth (RE) in vitro and in vivo and mechanism of their antitumor activities in vitro were studied. METHODS: In vitro, the cytotoxicity of seven rare earth complexes and Fliorouracil (ligand) in six human tumor cell lines, six rare earth Nitrates in BGC-823 was measured by modified MTT or SRB assay. A human gastric carcinoma cell (BGC-823) xenograft model in nude mice was set up. Then nude mice were treated with Yttrium complex and Samarium complex i.p for four weeks. The effects of the rare earth complexes on growth of human gastric carcinoma, the weight and pathological changes of mice's main organs were observed. The induction of apoptosis in BGC-823 cell was detected with fluorescent microscope, the alteration of cell cycle was assayed by flow cytometry, DNA damage in cell was observed by SCGE. RESULTS: The IC50 of seven complexes in six human tumor cell lines is less than 10μg/ml. At the same concentration (mol/L), each IC50 of the above seven RE complexes is less than that ofFludrouracil in all human tumor cell lines tested. Each IC50 of six RE (Cerium, Yttrium, Lanthanum, Samarium, Dysprosium, Gadolinium) complexes in BGC-823 is less than that of these rare earth Nitrates.The growth of human gastric carcinoma was inhibited significantly by Yttrium, Samarium complexes and 5-FU (p<0.01) without changes of the weight and morpholog of main organs. Compared to Fludrouracil (FU), there is no significant difference between the weight of carcinoma of the two rare earth complexes. A considerable number of BGC-823 cells treated with seven RE complexes underwent apoptosis, the alteration of cell cycle and DNA damage can be obviously observed by fluorescent microscope in BGC-823 cells that were treated with Samarium, Yttrium, Lanthanum complexes. CONCLUSION: Seven RE complexes exhibit strong cytotoxicity in all human tumor cell lines tested. Antitumor activity of seven RE complexes is stronger than that of RE cations and ligand. Yttrium and Samarium complexes can significantly inhibit the growth of human gastric carcinoma. There is no significant difference in antitumor activity and toxicity between two RE complexes and FU. It is suggested that the antitumor activity of seven RE complexes were probably realized by blocking cells in G0/G1 phase or inducing apoptosis by damaging cells DNA.