McKeage M J, Haddad G G, Ding L, Galettis P, Screnci D, Zhuang L, Baguley B C
Department of Pharmacology and Clinical Pharmacology, Faculty of Medicine and Health Sciences, University of Auckland, New Zealand.
Oncol Res. 1999;11(6):287-93.
Paclitaxel and cisplatin are associated with dose-limiting neurotoxicity that may result from their differing effects on microtubule stability in peripheral nerves. We hypothesized that such different actions of paclitaxel and cisplatin could be exploited to minimize their neurotoxicity by giving them in combination. Paclitaxel (9-18 micromol/kg/week or 7.7-15.4 mg/kg/week) and cisplatin (5-10 micromol/kg/week or 1.5-3 mg/kg/week) were given alone and in combination to female Wistar rats. Treatment was given once per week for a total of 7-10 weeks. Paclitaxel and cisplatin were given 24 h apart when they were given in combination. Changes in sensory nerve conduction velocity (SNCV) and dorsal root ganglia (DRG) morphology were measured. The nature of their interaction was analyzed using an isobologram. Their antitumor activity alone or in combination was also determined in C57B1/6 mice bearing colon 38 tumors. Reductions in SNCV occurred with paclitaxel alone (P = 0.009), cisplatin alone (P = 0.012), and cisplatin given 24 h before paclitaxel (P < 0.0001). In contrast, there was no significant change in SNCV with paclitaxel given 24 h before cisplatin (P = 0.11). An isobologram showed that the SNCV effects of the drug combinations were less than additive or antagonistic. Cisplatin-induced morphometric changes in DRG neurons were less marked when cisplatin was given with paclitaxel (P = 0.004). Concentrations of platinum in dorsal root ganglia, sural nerves, and sciatic nerves were not altered by giving paclitaxel before cisplatin. Tumor growth delays (TGD) were greater after treatment with paclitaxel (23.4 micromol/kg or 20 mg/kg) given 24 h before cisplatin (23.3 micromol/kg or 7 mg/kg) (TGD = 7.5 days) than after paclitaxel (23.4 micromol/kg or 20 mg/kg) (TGD = 2.0 days) or cisplatin (23.3 micromol/kg or 7 mg/kg) (TGD = 3.5 days) alone. Paclitaxel and cisplatin antagonized each other's neurotoxicity in Wistar rats. Combining cytotoxic agents with opposing effects on peripheral nerves has potential for minimizing neurotoxicity in patients.
紫杉醇和顺铂具有剂量限制性神经毒性，这可能源于它们对周围神经微管稳定性的不同影响。我们推测，通过联合使用紫杉醇和顺铂，可以利用它们的这种不同作用来最小化其神经毒性。将紫杉醇（9 - 18微摩尔/千克/周或7.7 - 15.4毫克/千克/周）和顺铂（5 - 10微摩尔/千克/周或1.5 - 3毫克/千克/周）单独及联合给予雌性Wistar大鼠。每周给药一次，共给药7 - 10周。当联合给药时，紫杉醇和顺铂间隔24小时给药。测量感觉神经传导速度（SNCV）和背根神经节（DRG）形态的变化。使用等效线图分析它们的相互作用性质。还在携带结肠38肿瘤的C57B1/6小鼠中测定了它们单独或联合使用时的抗肿瘤活性。单独使用紫杉醇（P = 0.009）、单独使用顺铂（P = 0.012）以及在紫杉醇前24小时给予顺铂（P < 0.0001）时，SNCV均降低。相比之下，在顺铂前24小时给予紫杉醇时，SNCV无显著变化（P = 0.11）。等效线图显示，药物组合对SNCV的影响小于相加或拮抗作用。当顺铂与紫杉醇联合给药时，顺铂诱导的DRG神经元形态计量学变化不那么明显（P = 0.004）。在顺铂前给予紫杉醇不会改变背根神经节、腓肠神经和坐骨神经中的铂浓度。在顺铂（23.3微摩尔/千克或7毫克/千克）前24小时给予紫杉醇（23.4微摩尔/千克或20毫克/千克）治疗后的肿瘤生长延迟（TGD）（TGD = 7.5天）大于单独使用紫杉醇（23.4微摩尔/千克或20毫克/千克）（TGD = 2.0天）或单独使用顺铂（23.3微摩尔/千克或7毫克/千克）（TGD = 3.5天）后的肿瘤生长延迟。在Wistar大鼠中，紫杉醇和顺铂相互拮抗对方的神经毒性。将对周围神经有相反作用的细胞毒性药物联合使用，有可能使患者的神经毒性最小化。
