McKeage M J, Boxall F E, Jones M, Harrap K R
Drug Development Section, Institute of Cancer Research, Belmont, Sutton, Surrey, United Kingdom.
Cancer Res. 1994 Feb 1;54(3):629-31.
This study compared the effect on sensory nerve conduction velocity in the hind limb of chronically treated age-matched rats of a novel lipophilic p.o. platinum complex [bisacetatoamminedichlorocyclohexylamine-platinum(IV)], with that of neurotoxic platinum complexes cisplatin and tetraplatin. Tetraplatin (i.p.) first caused slowing of sensory nerve conduction (-14.4% of controls; P < 0.05) at a dose (1 mg/kg) that was free of constitutional toxicity. Cisplatin (i.p.) first caused slowing of sensory nerve conduction (-17.5% of control; P < 0.05) at a dose (2 mg/kg) approximating the maximal tolerated dose. Bisacetatoamminedichlorocyclohexylamineplatinum(IV) (p.o.) showed no slowing of sensory nerve conduction either after 20.5 weeks of treatment at a dose (25 mg/kg) approximating the maximal tolerated dose or after 6 weeks of treatment at a dose (50 mg/kg) which eventually proved intolerable. In conclusion, p.o. bisacetatoamminedichlorocyclohexylamineplatinum(IV) shows a lack of neurotoxicity compared to parenterally administered cisplatin and tetraplatin at the maximal tolerated dose in rats.
本研究比较了新型亲脂性口服铂配合物[双乙酸氨基二氯环己胺铂(IV)]与神经毒性铂配合物顺铂和四铂对慢性治疗的年龄匹配大鼠后肢感觉神经传导速度的影响。四铂(腹腔注射)在无全身毒性的剂量(1mg/kg)下首先导致感觉神经传导减慢(为对照组的-14.4%；P<0.05)。顺铂(腹腔注射)在接近最大耐受剂量的剂量(2mg/kg)下首先导致感觉神经传导减慢(为对照组的-17.5%；P<0.05)。双乙酸氨基二氯环己胺铂(IV)(口服)在接近最大耐受剂量的剂量(25mg/kg)下治疗20.5周后，或在最终证明无法耐受的剂量(50mg/kg)下治疗6周后，均未显示感觉神经传导减慢。总之，在大鼠最大耐受剂量下，与胃肠外给药的顺铂和四铂相比，口服双乙酸氨基二氯环己胺铂(IV)显示出缺乏神经毒性。
