Kiburg B, Moorer-van Delft C, Heimans J J, Huijgens P C, Boer H H
Graduate School Neurosciences, Amsterdam, The Netherlands.
J Neurooncol. 1996 Dec;30(3):173-80. doi: 10.1007/BF00177268.
The use of the cytostatic agent vincristine (VCR) is limited by the occurrence of peripheral neuropathy. This side-effect is probably caused by interference with axonal microtubules. VCR depolymerizes microtubules and reacts with tubulin to form paracrystals. The potential of a neurotrophic ACTH(4-9) analogue, Org 2766, to counteract peripheral neuropathy caused by cytostatic agents is being investigated. In the present ultrastructural study, modulatory effects of Org 2766 on VCR-induced neurotoxicity were studied in vivo in neurons of the pond snail Lymnaea stagnalis, which has been shown previously to be a suitable test system to investigate neurotoxic side-effects of cytostatic agents. 24 h after treatment with VCR (25 microM), 68.4 +/- 34.7 paracrystals were counted per cross-section of the cerebral commissure and the number of microtubules in the axons had been lowered to 46% of the control level. After a survival period of two weeks all paracrystals had disappeared. By that time, no recovery of the axonal microtubular system could be observed. However, post-treatment with Org 2766 (10(-6) M) on day 6 after VCR treatment had induced a significant increase in the number of microtubules (+55%) on day 7. This beneficial effect lasted for the rest of the experimental period (14 days). These results suggest that post-treatment with Org 2766, i.e. after VCR clearance, can induce long-lasting beneficial effects on VCR-induced neurotoxicity in vivo.
细胞毒性药物长春新碱（VCR）的使用因周围神经病变的发生而受到限制。这种副作用可能是由于对轴突微管的干扰所致。VCR使微管解聚，并与微管蛋白反应形成副晶体。目前正在研究一种神经营养性促肾上腺皮质激素（4 - 9）类似物Org 2766对抗细胞毒性药物引起的周围神经病变的潜力。在本超微结构研究中，在椎实螺神经元体内研究了Org 2766对VCR诱导的神经毒性的调节作用，此前已证明该螺是研究细胞毒性药物神经毒性副作用的合适测试系统。用VCR（25 microM）处理24小时后，在脑连合的每个横切面中计数到68.4±34.7个副晶体，轴突中的微管数量已降至对照水平的46%。在两周的存活期后，所有副晶体均消失。到那时，未观察到轴突微管系统的恢复。然而，在VCR处理后第6天用Org 2766（10^(-6) M）进行后处理，在第7天诱导微管数量显著增加（+55%）。这种有益作用在实验期的剩余时间（14天）持续存在。这些结果表明，在VCR清除后用Org 2766进行后处理可在体内对VCR诱导的神经毒性产生持久的有益作用。
