Cisplatin-induced peripheral neuropathy: Neuroprotection by erythropoietin without affecting tumour growth Roberto Bianchi a , Alessandra Gilardini b , Virginia Rodriguez-Menendez b , Norberto Oggioni b , Annalisa Canta b , Tina Colombo a , Giulia De Michele a , Sara Martone a , Alessandra Sfacteria c , Giuseppe Piedemonte c , Giovanni Grasso d , Patrizia Beccaglia e , Pietro Ghezzi a , Maurizio D’Incalci a , Giuseppe Lauria f , Guido Cavaletti b, * a Mario Negri Institute of Pharmacological Research, Milan, Italy b Department of Neuroscience and Biomedical Technologies, University of Milan ‘Bicocca’, Monza, Italy c University of Messina, Messina, Italy d University of Palermo, Palermo, Italy e Medical Affairs Department, Janssen Cilag, Milan, Italy f National Neurological Institute Milan, Italy ARTICLE INFO Article history: Received 7 August 2006 Received in revised form 11 September 2006 Accepted 19 September 2006 Available online 23 January 2007 Keywords: Cisplatin Erythropoietin Peripheral neuropathy Tumour growth Neurophysiology Pathology Rat ABSTRACT This study examined the dose-dependent efficacy of erythropoietin (EPO) for preventing and/or treating cisplatin (CDDP) induced peripheral neurotoxicity (CINP), and its influence on tumour treatment and growth. Rats received eight intraperitoneal (ip) injections of 2 mg/kg CDDP twice weekly. EPO co-administered (50 or 10 lg/kg ip, three times/week) had a dose-dependent effect, partially preventing CINP, but 0.5 lg/kg ip was not effective. The neuroprotective effect lasted at least 5 weeks after the last dose of EPO and CDDP. In addi- tion, EPO (50 lg/kg ip three times/week) after the last injection of CDDP still induced a sig- nificant recovery of CINP. In a separate experiment in rats bearing mammary carcinoma EPO treatment (50 lg/kg ip) given concurrently with CDDP (1.0 and 1.5 mg/kg twice a week for four weeks) was neuroprotective without influencing the effectiveness of the treatment or tumour growth. EPO thus appears to be an effective neuroprotectant that does not inter- fere with tumour treatment. Ó 2006 Elsevier Ltd. All rights reserved. 1. Introduction Erythropoietin (EPO) is a cytokine originally used for its effect on erythropoiesis, since it supports the survival, proliferation and differentiation of erythroid progenitor cells. However, in the past few years it has become clear that EPO is a multifunc- tional trophic factor 1–6 with potent neurotrophic activity on a variety of neural cells in the central and peripheral nervous system. 7–11 EPO acts by binding with its receptors (EPOR), cyto- kines belonging to the receptor type I superfamily. 3,12,13 EPOR are expressed in nerve axons, in Schwann cells and in dorsal root ganglia. They are over-expressed after nerve injury, which is the basis for therapeutic use of exogenous EPO. 3,5,14 In vivo experimental models allowed to demonstrate that EPO can both prevent and treat diabetic peripheral neuropathy. 15 Several chemotherapeutic drugs, including cisplatin (CDDP), 0959-8049/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.ejca.2006.09.028 * Corresponding author: Tel.: +39 02 64488114; fax: +30 02 64488250. E-mail address: guido.cavaletti@unimib.it (G. Cavaletti). EUROPEAN JOURNAL OF CANCER 43 (2007) 710 – 717 available at www.sciencedirect.com journal homepage: www.ejconline.com