title: Systemic toxicity induced by paclitaxel in vivo is associated with the solvent cremophor EL through oxidative stress-driven mechanisms.
abstract: The toxic effects of paclitaxel (PTX) and its solubilizing agent cremophor EL (CREL) have been well established in vitro; however, the in vivo mechanisms underlying this toxicity remain unclear. Thus, the aim of this study was to analyze the in vivo toxicity induced by infusion of PTX and CREL and to investigate the involvement of oxidative stress as a potential mechanism for this toxicity. We treated male Wistar rats with PTX and/or CREL for 1h using human-equivalent doses (PTX+CREL/ethanol+NaCl 175mg/m(2) or CREL+ethanol+NaCl) and sacrificed immediately or 24h after these drug infusions to systemic biochemical evaluations. Hidrosoluble vitamin E (vitE, Trolox) was added as a control in some groups. The oxidative profile was determined by measuring erythrocyte and plasma lipid peroxidation, superoxide dismutase and catalase activities, reduced glutathione (GSH) levels, red blood cell (RBC) counts, hemoglobin profile, plasma total radical-trapping antioxidant parameter (TRAP), plasma lipid peroxidation, nitric oxide levels and malondialdehyde levels. Our findings showed that CREL infusion triggered immediate high plasma lipid peroxidation and augmented TRAP, while PTX caused immediate TRAP consumption and metahemoglobin formation. Pronounced oxidative effects were detected 24h after infusion, when CREL treatment enhanced RBC counts and plasma lipid peroxidation, increased catalase activity, and decreased TRAP levels. On the other hand, after 24h, PTX-infused rats showed reduced catalase activity and reduced metahemoglobin levels. These data indicate the existence of a continuous oxidative stress generation during CREL-PTX treatment and highlight CREL as primarily responsible for the in vivo oxidative damage to RBCs.
authors.affiliation: Laboratory of Physiopathology and Free Radicals, Department of Pathology, State University of Londrina, Londrina, Paraná, Brazil.
authors.forename: Fernanda C
authors.initials: FC
authors.lastname: Campos
authors.affiliation: Faculty of Medicine, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Vanessa J
authors.initials: VJ
authors.lastname: Victorino
authors.affiliation: Department of Physiological Sciences, State University of Londrina, Londrina, Paraná, Brazil.
authors.forename: Marli Cardoso
authors.initials: MC
authors.lastname: Martins-Pinge
authors.affiliation: Laboratory of Physiopathology and Free Radicals, Department of Pathology, State University of Londrina, Londrina, Paraná, Brazil.
authors.forename: Alessandra L
authors.initials: AL
authors.lastname: Cecchini
authors.affiliation: Laboratory of Physiopathology and Free Radicals, Department of Pathology, State University of Londrina, Londrina, Paraná, Brazil; State University of West Paraná, UNIOESTE, Francisco Beltrão, Paraná, Brazil.. Electronic address: carolpanis@sercomtel.com.br.
authors.forename: Carolina
authors.initials: C
authors.lastname: Panis
authors.affiliation: Laboratory of Physiopathology and Free Radicals, Department of Pathology, State University of Londrina, Londrina, Paraná, Brazil.
authors.forename: Rubens
authors.initials: R
authors.lastname: Cecchini
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity*; D002374:Catalase / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004906:Erythrocyte Count; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism; D005978:Glutathione / Q000097:blood; D005990:Glycerol / Q000031:analogs & derivatives* / Q000633:toxicity; D006454:Hemoglobins / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008315:Malondialdehyde / Q000097:blood; D009569:Nitric Oxide / Q000097:blood; D018384:Oxidative Stress / Q000187:drug effects*; D017239:Paclitaxel / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D013482:Superoxide Dismutase / Q000097:blood
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D006454:Hemoglobins; D009569:Nitric Oxide; D008315:Malondialdehyde; C000515:cremophor EL; D002374:Catalase; D013482:Superoxide Dismutase; D005978:Glutathione; D017239:Paclitaxel; D005990:Glycerol
keywords: Cremophor; Hematological toxicity; Oxidative stress; Paclitaxel