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
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.
https://doi.org/10.1158/1078-0432.CCR-05-2177
Nerve Fibers
Peripheral Nervous System Diseases
carbamylated erythropoietin
Hematocrit
Wistar Rats
Bianchi, R., Brines, M., Lauria, G., Savino, C., Gilardini, A., Nicolini, G., ... Cavaletti, G. (2006). Protective effect of erythropoietin and its carbamylated derivative in experimental cisplatin peripheral neurotoxicity. Clinical Cancer Research, 12(8), 2607-2612. https://doi.org/10.1158/1078-0432.CCR-05-2177
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.
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 R, Brines M, Lauria G, Savino C, Gilardini A, Nicolini G et al. Protective effect of erythropoietin and its carbamylated derivative in experimental cisplatin peripheral neurotoxicity. Clinical Cancer Research. 2006 Apr 15;12(8):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.
@article{4949d0628fe34df78576f77ef005309d,
title = "Protective effect of erythropoietin and its carbamylated derivative in experimental cisplatin peripheral neurotoxicity",
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.",
author = "Roberto Bianchi and Michael Brines and Giuseppe Lauria and Costanza Savino and Alessandra Gilardini and Gabriella Nicolini and Virginia Rodriguez-Menendez and Norberto Oggioni and Annalisa Canta and Paola Penza and Raffaella Lombardi and Claudio Minoia and Anna Ronchi and Anthony Cerami and Pietro Ghezzi and Guido Cavaletti",
doi = "10.1158/1078-0432.CCR-05-2177",
journal = "Clinical Cancer Research",
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
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.
AB - 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.
U2 - 10.1158/1078-0432.CCR-05-2177
DO - 10.1158/1078-0432.CCR-05-2177
JO - Clinical Cancer Research
JF - Clinical Cancer Research
10.1158/1078-0432.CCR-05-2177