Hematotoxicity response in rats by the novel copper-based anticancer agent: casiopeina II.
The in vivo toxicity of the novel copper-based anticancer agent, casiopeina II (Cu(4,7-dimethyl-1,10-phenanthroline)(glycine)NO3) (CII), was investigated. Casiopeinas are a family of copper-coordinated complexes that have shown promising anticancer activity. The major toxic effect attributed to a single i.v. administration of CII (5 mg/kg dose) in the rat was an hemolytic anemia (reduced hemoglobin concentration (HB), red blood cell (RBC) count and packed cell volume (PCV) accompanied by a marked neutrophilic leukocytosis) 12 h and 5 days after administration, attributed to a direct erythrocyte damage. Increased reticulocyte levels and presence of normoblasts in peripheral blood 5 days post-administration indicated an effective erythropoietic response with recovery at 15 days. Increase in spleen weight and the morphological evidence of congestion of the red pulp (RP) with erythrocytes (E) resulting in a higher ratio of red to white pulp (WP) was consistent with increased uptake of damaged erythrocytes by the reticuloendothelial system observed by histopathology and electron microscopy. Extramedullary hemopoiesis was markedly increased at 5 days giving further evidence of a regenerative erythropoietic response that had an effective recovery by 15 days. Morphological changes in spleen cellularity were consistent with hematotoxicity, mainly a reduction of the red pulp/white pulp ratio, increase in erythrocyte content at 12 h, and an infiltration of nucleated cells in the red pulp at 5 days, with a tendency towards recovery 15 days after administration. The erythrocyte damage is attributed to generation of free radicals and oxidative damage on the membrane and within cells resulting from the reduction of Cu(II) and the probable dissociation of the CII complex.
De Vizcaya-Ruiz
A
A
School of Biomedical and Life Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UK. avizcaya@mail.cinvestav.mx
Rivero-Müller
A
A
Ruiz-Ramirez
L
L
Howarth
J A
JA
Dobrota
M
M
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D001772:Blood Cell Count; D003300:Copper / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000166:cytology / Q000187:drug effects* / Q000648:ultrastructure; D007275:Injections, Intravenous; D007962:Leukocytes / Q000166:cytology / Q000187:drug effects* / Q000648:ultrastructure; D008297:Male; D008854:Microscopy, Electron; D009929:Organ Size / Q000187:drug effects; D009942:Organometallic Compounds / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D013154:Spleen / Q000187:drug effects* / Q000648:ultrastructure; D013997:Time Factors; D018675:Toxicity Tests
D000970:Antineoplastic Agents; D009942:Organometallic Compounds; C409443:casiopeina II; D003300:Copper