PURPOSE: Cisplatin is one of the most effective cytotoxic agents in the treatment of solid malignancies, but its use is limited by several side effects. Among them, peripheral neurotoxicity can be dose limiting. A liposomal formulation of cisplatin, Lipoplatin™, was developed to reduce the systemic toxicity of cisplatin but without preventing its efficacy. The aim of this study was to use an animal model to establish, through a multimodal approach, whether chronic treatment with two different schedules of Lipoplatin™, selected within the range of its anticancer effective dose, is less neurotoxic than cisplatin administration. METHODS: Female Wistar rats were treated intraperitoneally with cisplatin at a dose of 4 mg/kg or with Lipoplatin™ at doses delivering 12 or 24 mg/kg of cisplatin once weekly for 4 weeks. General toxicity was assessed by daily observation, body weight change, hematological and blood chemistry analysis, and histopathology of liver and kidney. The onset of peripheral neurotoxicity was assessed by measuring tail nerve conduction velocity (NCV), morphological and morphometric analysis of dorsal root ganglia (DRG), and morphological analysis of the sciatic nerve. RESULTS: Cisplatin induced a statistically significant reduction in body weight, the development of renal failure, and impairment in NCV with pathological alterations in the DRG and sciatic nerve. By contrast, Lipoplatin™ was markedly less nephrotoxic, and no significant weight gain reduction was observed in animals treated with both doses of the drug. Moreover, the lowest dose induced less severe damage to the peripheral nervous system with a moderate decrease in NCV and mild pathological alterations in DRG and the sciatic nerve. CONCLUSIONS: The results suggest that Lipoplatin™ 12 mg/kg is less neurotoxic than cisplatin 4 mg/kg, thus opening up the possibility of using this new formulation in future studies where its anticancer activity and the peripheral neurotoxicity will be assessed in parallel.
PURPOSE:Cisplatin is one of the most effective cytotoxic agents in the treatment of solid malignancies, but its use is limited by several side effects. Among them, peripheral neurotoxicity can be dose limiting. A liposomal formulation of cisplatin, Lipoplatin™, was developed to reduce the systemic toxicity of cisplatin but without preventing its efficacy. The aim of this study was to use an animal model to establish, through a multimodal approach, whether chronic treatment with two different schedules of Lipoplatin™, selected within the range of its anticancer effective dose, is less neurotoxic than cisplatin administration. METHODS: Female Wistar rats were treated intraperitoneally with cisplatin at a dose of 4 mg/kg or with Lipoplatin™ at doses delivering 12 or 24 mg/kg of cisplatin once weekly for 4 weeks. General toxicity was assessed by daily observation, body weight change, hematological and blood chemistry analysis, and histopathology of liver and kidney. The onset of peripheral neurotoxicity was assessed by measuring tail nerve conduction velocity (NCV), morphological and morphometric analysis of dorsal root ganglia (DRG), and morphological analysis of the sciatic nerve. RESULTS:Cisplatin induced a statistically significant reduction in body weight, the development of renal failure, and impairment in NCV with pathological alterations in the DRG and sciatic nerve. By contrast, Lipoplatin™ was markedly less nephrotoxic, and no significant weight gain reduction was observed in animals treated with both doses of the drug. Moreover, the lowest dose induced less severe damage to the peripheral nervous system with a moderate decrease in NCV and mild pathological alterations in DRG and the sciatic nerve. CONCLUSIONS: The results suggest that Lipoplatin™ 12 mg/kg is less neurotoxic than cisplatin 4 mg/kg, thus opening up the possibility of using this new formulation in future studies where its anticancer activity and the peripheral neurotoxicity will be assessed in parallel.
Authors: Xue Xue; Matthew D Hall; Qiang Zhang; Paul C Wang; Michael M Gottesman; Xing-Jie Liang Journal: ACS Nano Date: 2013-12-10 Impact factor: 15.881
Authors: C Ceresa; G Nicolini; S Semperboni; V Gandin; M Monfrini; F Avezza; P Alberti; A Bravin; M Pellei; C Santini; Guido Cavaletti Journal: Neurotox Res Date: 2018-01-17 Impact factor: 3.911
Authors: L Ansaloni; F Coccolini; L Morosi; A Ballerini; M Ceresoli; G Grosso; P Bertoli; L M Busci; M Lotti; F Cambria; M Pisano; D Rossetti; L Frigerio; M D'Incalci; M Zucchetti Journal: Br J Cancer Date: 2014-12-02 Impact factor: 7.640