Hamers F P, van der Hoop R G, Steerenburg P A, Neijt J P, Gispen W H
Department of Pharmacology, Rudolf Magnus Institute, State University Utrecht, The Netherlands.
Toxicol Appl Pharmacol. 1991 Dec;111(3):514-22. doi: 10.1016/0041-008x(91)90255-d.
One of the major side effects of cisplatin is its neurotoxicity. In rats, this neurotoxicity can be measured as a slowing of the H-reflex-related sensory nerve conduction velocity. In this study the ability of the neurotrophic peptide ORG 2766 (an ACTH4-9 analog) to prevent this neurotoxic side effect was investigated in rats subjected to a high-dose cisplatin regime (2 mg/kg, 2/wk). Furthermore, the efficacy of nimodipine (a calcium entry blocker of the 1,4-dihydropyridine type with presumed neurotrophic or neuroprotective activity) to prevent the neuropathy induced by both a low (1 mg/kg, 2/wk) and a high (2 mg/kg, 2/wk) dose cisplatin regime was studied. In cisplatin-treated rats concurrently treated with vehicle (saline for ORG 2766, polyethylene glycol for nimodipine) a significant slowing of the H-related sensory nerve conduction velocity was observed whereas in rats treated with both cisplatin and ORG 2766 or nimodipine, no decrease of this conduction velocity occurred. The possibility that nimodipine hampers the antitumor activity of cisplatin was investigated in an immunocytoma model in the LOU/M rat. Similar tumor regression was observed in cisplatin-treated rats concurrently treated with nimodipine or vehicle. These data suggest that both ORG 2766 and nimodipine protect from the induction of a cisplatin-induced neuropathy, at least in this animal model, and thus warrant investigation of their neuroprotective efficacy in humans subjected to a cisplatin-based chemotherapy.
顺铂的主要副作用之一是其神经毒性。在大鼠中，这种神经毒性可以通过与H反射相关的感觉神经传导速度减慢来衡量。在本研究中，研究了神经营养肽ORG 2766（一种促肾上腺皮质激素4-9类似物）对接受高剂量顺铂方案（2 mg/kg，每周2次）的大鼠预防这种神经毒性副作用的能力。此外，还研究了尼莫地平（一种具有假定神经营养或神经保护活性的1,4-二氢吡啶型钙通道阻滞剂）对预防低剂量（1 mg/kg，每周2次）和高剂量（2 mg/kg，每周2次）顺铂方案诱导的神经病变的疗效。在用赋形剂（ORG 2766用生理盐水，尼莫地平用聚乙二醇）同时处理的顺铂处理大鼠中，观察到与H相关的感觉神经传导速度显著减慢，而在用顺铂和ORG 2766或尼莫地平处理的大鼠中，这种传导速度没有下降。在LOU/M大鼠的免疫细胞瘤模型中研究了尼莫地平是否会阻碍顺铂的抗肿瘤活性。在用尼莫地平或赋形剂同时处理的顺铂处理大鼠中观察到相似的肿瘤消退。这些数据表明，至少在这个动物模型中，ORG 2766和尼莫地平都能保护免受顺铂诱导的神经病变，因此有必要在接受基于顺铂的化疗的人类中研究它们的神经保护疗效。
