Therapeutic angiogenesis inhibits or rescues chemotherapy-induced peripheral neuropathy: Taxol- and thalidomide-induced injury of vasa nervorum is ameliorated by VEGF
Therapeutic angiogenesis inhibits or rescues chemotherapy-induced peripheral neuropathy: Taxol- and thalidomide-induced injury of vasa nervorum is ameliorated by VEGF
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DOI：
10.1038/sj.mt.6300019
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发表时间：
2007-01-01
影响因子：
12.4
通讯作者：
Losordo, Douglas W.
中科院分区：
文献类型：
--
作者：
Kirchmair, Rudolf;Tietz, Anne B.;Losordo, Douglas W.
中毒性神经病是使用化疗药物紫杉醇和沙利度胺的重要临床问题。感觉神经病变发病率高，缺乏有效的治疗方法，是这些药物的剂量限制因素。这些神经病变的致病基础尚不清楚。我们研究了紫杉醇和沙利度胺的实验性毒性神经病变的假设，从破坏神经血管的结果，可以逆转的血管生成细胞因子的管理。在紫杉醇和沙利度胺诱导的神经病变的动物模型中，神经血流量已经减弱，神经血管的数量已经减少。肌肉内基因转移裸质粒DNA编码的VEGF-1管理与紫杉醇注射平行完全抑制神经功能的恶化和周围神经血管的减少。在已建立的紫杉醇或沙利度胺诱导的神经病变的动物中进行基因治疗导致血管再生和神经电生理学的改善。这些发现暗示微血管损伤是中毒性神经病的基础，并表明血管生成生长因子可能构成这种疾病的新治疗方法。
Toxic neuropathy represents an important clinical problem in the use of the chemotherapeutic substances Taxol and thalidomide. Sensory neuropathy has a high incidence, lacks an effective treatment and is the dose-limiting factor for these drugs. The pathogenic basis of these neuropathies is unknown. We investigated the hypothesis that the experimental toxic neuropathies from Taxol and thalidomide results from destruction of vasa nervorum and can be reversed by the administration of an angiogenic cytokine. In animal models of Taxol- and thalidomide-induced neuropathy, nerve blood flow has been attenuated and the number of vasa nervorum has been reduced. Intramuscular gene transfer of naked plasmid DNA encoding VEGF-1 administered in parallel with Taxol injections completely inhibited deterioration of nerve function and diminution of the peripheral nerve vasculature. Gene therapy in animals with established Taxol- or thalidomide-induced neuropathies resulted in recovery of vascularity and improved nerve electrophysiology. These findings implicate microvascular damage as the basis for toxic neuropathy and suggest that angiogenic growth factors may constitute a novel treatment for this disorder.