Neuroprotective interactions in rats between paclitaxel and cisplatin.
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.
McKeage
M J
MJ
Department of Pharmacology and Clinical Pharmacology, Faculty of Medicine and Health Sciences, University of Auckland, New Zealand. m.mckeage@auckland.ac.nz
Haddad
G G
GG
Ding
L
L
Galettis
P
P
Screnci
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D
Zhuang
L
L
Baguley
B C
BC
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000494:pharmacology*; D002945:Cisplatin / Q000008:administration & dosage / Q000493:pharmacokinetics; D003110:Colonic Neoplasms / Q000188:drug therapy; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005727:Ganglia, Spinal / Q000737:chemistry / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D009431:Neural Conduction / Q000187:drug effects*; D017239:Paclitaxel / Q000008:administration & dosage / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar
D017239:Paclitaxel; D002945:Cisplatin