Comparative neurotoxicity of oxaliplatin, cisplatin, and ormaplatin in a Wistar rat model.
Oxaliplatin (4 mg/kg), cisplatin (2 mg/kg with 20 mg/kg mannitol) and ormaplatin (2 mg/kg) were administered i.p. twice weekly for 4.5 weeks. Lactose injections (0.9%) were used as a control for oxaliplatin and 0.9% saline injections were used as a control for cisplatin and ormaplatin. Morphometric changes to dorsal root ganglia L4-L6 were quantitated as a measure of neurotoxicity. Drug treatment resulted in a decrease in cell and nuclear area and an increase in the percentage of cells with eccentric nucleoli for neuronal cell bodies in the DRG. Immediately following treatment the order of morphometric changes was ormaplatin > cisplatin > or = oxaliplatin. The accumulation of platinum in the DRG was measured by inductively coupled plasma mass spectrometry. The order of accumulation was cisplatin > oxaliplatin > ormaplatin. Following an 8-week recovery period the order of morphometric changes to the DRG was ormaplatin approximately equal to oxaliplatin > cisplatin. This correlated with a greater retention of platinum by the DRG for ormaplatin and oxaliplatin than for cisplatin. The results suggest that ormaplatin is uniquely neurotoxic immediately following treatment in the Wistar rat model. However, following an 8-week recovery period both ormaplatin and oxaliplatin are more neurotoxic than cisplatin and this neurotoxicity correlates with a greater retention of platinum by the DRG.
Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill 27599, USA.
J
J
Holmes
J
J
Stanko
M
M
Varchenko
H
H
Ding
V J
VJ
Madden
C R
CR
Bagnell
S D
SD
Wyrick
S G
SG
Chaney
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects; D002945:Cisplatin / Q000493:pharmacokinetics / Q000633:toxicity*; D005727:Ganglia, Spinal / Q000187:drug effects* / Q000648:ultrastructure; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D009944:Organoplatinum Compounds / Q000493:pharmacokinetics / Q000633:toxicity*; D000077150:Oxaliplatin; D051381:Rats; D017208:Rats, Wistar
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D002945:Cisplatin; C049777:ormaplatin