The Clinical And Basic Study Of Oxaliplatin-Related Neurotoxicity

Purpose: Oxaliplatin is a new diammine cyclohexane platinum derivative that is a new widely used anticancer drug and is active in several solid tumor types, especially in some cisplatin/carboplatin refractory diseases such as colorectal cancer . Peripheral sensory neurotoxicity is its dose-limiting toxicity which causes significant discomfort, alters patient quality of life, and may be accompanied by significant disability. Based on different hypothesis of the mechanisms of oxaliplatin-related neurotoxicity, various attempts and investigations about the prevention have been carried out. Studies indicate that when Ca²⁺ and Mg²⁺ infusion is used for preventing oxaliplatin-induced acute neurotoxicity, the neurotoxic symptom was highly reduced. This study is in the interest of further investigation of the mechanisms of oxaliplatin-related neurotoxicity and the effect of Ca²⁺ and Mg²⁺ infusion for preventing acute neurotoxicity in patients treated with oxaliplatin.Method: This study includes two parts :Controlled randomized clinical trial and basic study, (1)the clinical trial involves the tumor patients who received treatments of oxaliplatin in the gesttrointestinal tumor Medical Department of 307 hospital from June 2004 to April 2007.These patients were randomized to two groups to determine the effect of Ca²⁺ and Mg²⁺ infusion for preventing acute neurotoxicity. (2)we use the patch clamp technique to investigate the effect of oxaliplatin on neuron voltage-dependent sodium current of dorsal root ganglion(DRG) of Wistar mouse .Results: Nearly 90% of the patients had various oxaliplatin-induced neurotoxicity .The prevalence and the severity of the neurotoxicity are dose-dependent. Patients without neurotoxic symptoms were only appeared in the groups of low and middle dose, while patients with neurotoxic symptoms of≥grade II were all in the groups of middle and high dose P<0.001 ) .The prevalence and the severity of the neurotoxicity were significantly reduced by Ca²⁺ and Mg²⁺ infusion, whether the acute neuromuscular manifestations, especially distal and lingual paresthesi, or the cumulative grade 3 neuropathy (P<0.05 ) .The patients in the control who can not tolerate severe neurotoxic symptoms feel better after the use of Ca²⁺ and Mg²⁺ infusion and continue the treatment with oxaliplatin. Intracellular application of oxaliplatin caused a marked inhibition of the current amplitude at 5min,10min and 15min (p<0.05 ) , and the inhibition rate is significant higher in the small cells than in the big and middle cells (p<0.05 ) , indicating that oxaliplatin is much more active when applied to the small cells.Conclusion: The clinical use of oxaliplatin can induce neurotoxic symptoms, which is dose-dependent. The prevalence and the severity of the neurotoxicity can be significantly reduced by Ca²⁺ and Mg²⁺ infusion, therefore Ca²⁺ and Mg²⁺ infusion can improves the patients' quality of life. Intracellular application of oxaliplatin caused a marked inhibition of the current amplitude of neuron voltage-dependent sodium current of DRG of Wistar mouse, and the inhibition is much higher in the small DRG cells.