Screnci D, McKeage M J, Galettis P, Hambley T W, Palmer B D, Baguley B C
Department of Pharmacology and Clinical Pharmacology, The University of Auckland, New Zealand.
Br J Cancer. 2000 Feb;82(4):966-72. doi: 10.1054/bjoc.1999.1026.
Previous work has shown platinum drugs to differ in their effects on the peripheral nervous system. To test whether their differential toxicity was due to differences in their partitioning into the peripheral nervous system, we correlated the hydrophobicity, reactivity, tissue accumulation and neurotoxicity of a series of eight platinum analogues. Neurotoxicity was detected by measuring sensory nerve conduction velocity (SNCV) in Wistar rats treated twice per week at the maximum tolerated dose. Tissue platinum concentrations were measured by inductively coupled plasma mass spectrometry. Hydrophobicity (log P) was measured using an octanol-aqueous shake-flask method. The half-life of platinum drug binding to plasma proteins in vitro was determined. The cumulative dose causing altered SNCV ranged from 15 to > 2050 micromol kg(-1). Ranking of the compounds by their neurotoxic potency in rats (oxaliplatin > R,R-(DACH)PtC4 > ormaplatin > S,S-(DACH)PtCl4 > S,S-(DACH)Pt oxalato > cisplatin > carboplatin > JM216) correlated with the frequency of neurotoxicity in patients (r> 0.99; P < 0.05). Ranking the compounds by their peripheral nerve accumulation was cisplatin > carboplatin > oxaliplatin > R,R-(DACH)PtCl4 = S,S-(DACH)PtCl4 and did not correlate with neurotoxicity. Log P ranged from - 2.53 to -0.16 but did not correlate with neurotoxicity. Log P correlated inversely with platinum accumulation in dorsal root ganglia (r2 = 0.99; P = 0.04), sural nerve (r2 = 0.85; P = 0.025), sciatic nerve (r2 = 0.98; P= 0.0012), spinal cord (r2 = 0.97, P= 0.018) and brain (r2 = 0.98, P= 0.001). Reactivity correlated with neurotoxicity potency in rats (r2 = 0.89, P = 0.0005) and with the frequency of neurotoxicity in patients (r2 = 0.99, P = 0.0002). The hydrophilicity of platinum drugs correlates with platinum sequestration in the peripheral nervous system but not with neurotoxicity. Differences in the reactivity of platinum complexes accounts for some of the variation in their neurotoxicity.
先前的研究表明，铂类药物对周围神经系统的作用存在差异。为了测试它们的毒性差异是否源于其在周围神经系统中的分布差异，我们对一系列八种铂类似物的疏水性、反应活性、组织蓄积和神经毒性进行了相关性分析。通过测量每周接受两次最大耐受剂量治疗的Wistar大鼠的感觉神经传导速度（SNCV）来检测神经毒性。采用电感耦合等离子体质谱法测量组织中的铂浓度。使用正辛醇-水摇瓶法测量疏水性（log P）。测定了铂药物在体外与血浆蛋白结合的半衰期。导致SNCV改变的累积剂量范围为15至>2050 μmol·kg⁻¹。根据化合物在大鼠中的神经毒性强度进行排序（奥沙利铂>R,R-(DACH)PtC4>奥马铂>S,S-(DACH)PtCl4>S,S-(DACH)Pt草酸酯>顺铂>卡铂>JM216），与患者神经毒性的发生频率相关（r>0.99；P<0.05）。根据化合物在周围神经中的蓄积情况进行排序为顺铂>卡铂>奥沙利铂>R,R-(DACH)PtCl4 = S,S-(DACH)PtCl4，且与神经毒性无关。log P范围为-2.53至-0.16，但与神经毒性无关。log P与背根神经节（r² = 0.99；P = 0.04）、腓肠神经（r² = 0.85；P = 0.025）、坐骨神经（r² = 0.98；P = 0.0012）、脊髓（r² = 0.97，P = 0.018）和脑（r² = 0.98，P = 0.001）中的铂蓄积呈负相关。反应活性与大鼠的神经毒性强度相关（r² = 0.89，P = 0.0005），也与患者神经毒性的发生频率相关（r² = 0.99，P = 0.0002）。铂类药物的亲水性与周围神经系统中的铂螯合有关，但与神经毒性无关。铂配合物反应活性的差异是其神经毒性差异的部分原因。
