Protective effect of erythropoietin and its carbamylated derivative in experimental cisplatin peripheral neurotoxicity

Roberto Bianchi, Michael Brines, Giuseppe Lauria, Costanza Savino, Alessandra Gilardini, Gabriella Nicolini, Virginia Rodriguez-Menendez, Norberto Oggioni, Annalisa Canta, Paola Penza, Raffaella Lombardi, Claudio Minoia, Anna Ronchi, Anthony Cerami, Pietro Ghezzi, Guido Cavaletti

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Abstract

Purpose: Antineoplastic drugs, such as cisplatin (CDDP), are severely neurotoxic, causing disabling peripheral neuropathies with clinical signs known as chemotherapy-induced peripheral neurotoxicity. Cotreatment with neuroprotective agents and CDDP has been proposed for preventing or reversing the neuropathy. Erythropoietin given systemically has a wide range of neuroprotective actions in animal models of central and peripheral nervous system damage. However, the erythropoietic action is a potential cause of side effects if erythropoietin is used for neuroprotection. We have successfully identified derivatives of erythropoietin, including carbamylated erythropoietin, which do not raise the hematocrit but retain the neuroprotective action exerted by erythropoietin. Experimental Design: We have developed previously an experimental chemotherapy-induced peripheral neurotoxicity that closely resembles CDDP neurotoxicity in humans. The present study compared the effects of erythropoietin and carbamylated erythropoietin (50 μg/kg/d thrice weekly) on CDDP (2 mg/kg/d i.p. twice weekly for 4 weeks) neurotoxicity in vivo. Results: CDDP given to Wistar rats significantly lowered their growth rate (P <0.05), with slower sensory nerve conduction velocity (P <0.001) and reduced intraepidermal nerve fibers density (P <0.001 versus controls). Coadministration of CDDP and erythropoietin or carbamylated erythropoietin partially but significantly prevented the sensory nerve conduction velocity reduction. Both molecules preserved intraepidermal nerve fiber density, thus confirming their neuroprotective effect at the pathologic level. The protective effects were not associated with any difference in platinum concentration in dorsal root ganglia, sciatic nerve, or kidney specimens. Conclusions: These results widen the spectrum of possible use of erythropoietin and carbamylated erythropoietin as neuroprotectant drugs, strongly supporting their effectiveness.

Original languageEnglish
Pages (from-to)2607-2612
Number of pages6
JournalClinical Cancer Research
Volume12
Issue number8
DOIs
Publication statusPublished - Apr 15 2006

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Erythropoietin
Cisplatin
Neuroprotective Agents
Neural Conduction
Nerve Fibers
Drug Therapy
Peripheral Nervous System
Spinal Ganglia
Peripheral Nervous System Diseases
Sciatic Nerve
carbamylated erythropoietin
Platinum
Hematocrit
Antineoplastic Agents
Wistar Rats
Research Design
Central Nervous System
Animal Models
Kidney
Growth

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Protective effect of erythropoietin and its carbamylated derivative in experimental cisplatin peripheral neurotoxicity. / Bianchi, Roberto; Brines, Michael; Lauria, Giuseppe; Savino, Costanza; Gilardini, Alessandra; Nicolini, Gabriella; Rodriguez-Menendez, Virginia; Oggioni, Norberto; Canta, Annalisa; Penza, Paola; Lombardi, Raffaella; Minoia, Claudio; Ronchi, Anna; Cerami, Anthony; Ghezzi, Pietro; Cavaletti, Guido.

In: Clinical Cancer Research, Vol. 12, No. 8, 15.04.2006, p. 2607-2612.

Research output: Contribution to journalArticle

Bianchi, R, Brines, M, Lauria, G, Savino, C, Gilardini, A, Nicolini, G, Rodriguez-Menendez, V, Oggioni, N, Canta, A, Penza, P, Lombardi, R, Minoia, C, Ronchi, A, Cerami, A, Ghezzi, P & Cavaletti, G 2006, 'Protective effect of erythropoietin and its carbamylated derivative in experimental cisplatin peripheral neurotoxicity', Clinical Cancer Research, vol. 12, no. 8, pp. 2607-2612. https://doi.org/10.1158/1078-0432.CCR-05-2177
Bianchi, Roberto ; Brines, Michael ; Lauria, Giuseppe ; Savino, Costanza ; Gilardini, Alessandra ; Nicolini, Gabriella ; Rodriguez-Menendez, Virginia ; Oggioni, Norberto ; Canta, Annalisa ; Penza, Paola ; Lombardi, Raffaella ; Minoia, Claudio ; Ronchi, Anna ; Cerami, Anthony ; Ghezzi, Pietro ; Cavaletti, Guido. / Protective effect of erythropoietin and its carbamylated derivative in experimental cisplatin peripheral neurotoxicity. In: Clinical Cancer Research. 2006 ; Vol. 12, No. 8. pp. 2607-2612.
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T1 - Protective effect of erythropoietin and its carbamylated derivative in experimental cisplatin peripheral neurotoxicity

AU - Bianchi, Roberto

AU - Brines, Michael

AU - Lauria, Giuseppe

AU - Savino, Costanza

AU - Gilardini, Alessandra

AU - Nicolini, Gabriella

AU - Rodriguez-Menendez, Virginia

AU - Oggioni, Norberto

AU - Canta, Annalisa

AU - Penza, Paola

AU - Lombardi, Raffaella

AU - Minoia, Claudio

AU - Ronchi, Anna

AU - Cerami, Anthony

AU - Ghezzi, Pietro

AU - Cavaletti, Guido

PY - 2006/4/15

Y1 - 2006/4/15

N2 - Purpose: Antineoplastic drugs, such as cisplatin (CDDP), are severely neurotoxic, causing disabling peripheral neuropathies with clinical signs known as chemotherapy-induced peripheral neurotoxicity. Cotreatment with neuroprotective agents and CDDP has been proposed for preventing or reversing the neuropathy. Erythropoietin given systemically has a wide range of neuroprotective actions in animal models of central and peripheral nervous system damage. However, the erythropoietic action is a potential cause of side effects if erythropoietin is used for neuroprotection. We have successfully identified derivatives of erythropoietin, including carbamylated erythropoietin, which do not raise the hematocrit but retain the neuroprotective action exerted by erythropoietin. Experimental Design: We have developed previously an experimental chemotherapy-induced peripheral neurotoxicity that closely resembles CDDP neurotoxicity in humans. The present study compared the effects of erythropoietin and carbamylated erythropoietin (50 μg/kg/d thrice weekly) on CDDP (2 mg/kg/d i.p. twice weekly for 4 weeks) neurotoxicity in vivo. Results: CDDP given to Wistar rats significantly lowered their growth rate (P <0.05), with slower sensory nerve conduction velocity (P <0.001) and reduced intraepidermal nerve fibers density (P <0.001 versus controls). Coadministration of CDDP and erythropoietin or carbamylated erythropoietin partially but significantly prevented the sensory nerve conduction velocity reduction. Both molecules preserved intraepidermal nerve fiber density, thus confirming their neuroprotective effect at the pathologic level. The protective effects were not associated with any difference in platinum concentration in dorsal root ganglia, sciatic nerve, or kidney specimens. Conclusions: These results widen the spectrum of possible use of erythropoietin and carbamylated erythropoietin as neuroprotectant drugs, strongly supporting their effectiveness.

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