Relationships between hydrophobicity, reactivity, accumulation and peripheral nerve toxicity of a series of platinum drugs.
Relationships between hydrophobicity, reactivity, accumulation and peripheral nerve toxicity of a series of platinum drugs.
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DOI：
10.1054/bjoc.1999.1026
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发表时间：
2000-02
影响因子：
8.8
通讯作者：
Baguley BC
中科院分区：
文献类型：
--
作者：
Screnci D;McKeage MJ;Galettis P;Hambley TW;Palmer BD;Baguley BC
先前的研究表明，铂类药物对周围神经系统的影响不同。为了测试它们的不同毒性是否由于它们在周围神经系统中的分配不同，我们将一系列8种铂类似物的疏水性、反应性、组织蓄积和神经毒性联系起来。以最大耐受剂量每周给药两次的Wistar大鼠，通过测量感觉神经传导速度（SNCV）检测神经毒性。采用电感耦合等离子体质谱法测定组织铂浓度。疏水性（log P）采用辛醇-水摇瓶法测定。测定铂类药物体外与血浆蛋白结合的半衰期。引起SNCV改变的累积剂量范围为15 ~ 50 μmol kg−1。化合物对大鼠的神经毒性强弱排序(奥沙利铂>R,R -(DACH)PtC4> ormaplatin >S,S -（DACH)PtCl4>S,S -(DACH)Pt草拉拉托>顺铂>卡铂> JM216）与患者神经毒性发生频率相关（R > 0.99；P< 0.05）。周围神经蓄积排序为顺铂>卡铂>奥沙利铂>R,R -(DACH)PtCl4≈S,S -(DACH)PtCl4，与神经毒性无关。Log P范围从- 2.53到- 0.16，但与神经毒性无关。logp与铂在背根神经节（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）的积累呈负相关。反应性与大鼠神经毒性效力相关（r2= 0.89, P = 0.0005），与患者神经毒性发生频率相关（r2= 0.99, P = 0.0002）。铂类药物的亲水性与铂在周围神经系统的隔离有关，而与神经毒性无关。铂配合物反应性的差异是其神经毒性变化的部分原因。©2000癌症研究运动
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 μmol 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)PtCl4and 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. © 2000 Cancer Research Campaign
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影响因子：
45.3
作者：
GREGG, RW;MOLEPO, JM;STEWART, DJ
通讯作者：
STEWART, DJ
影响因子：
50.5
作者：
Judson, I;Cerny, T;Hanauske, A
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Hanauske, A
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2.3
作者：
OROURKE, TJ;WEISS, GR;VONHOFF, DD
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影响因子：
3
作者：
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影响因子：
11.8
作者：
CANETTA, R;ROZENCWEIG, M;CARTER, SK
通讯作者：
CARTER, SK