Evaluation of effects of copper histidine on copper transporter 1-mediated accumulation of platinum and oxaliplatin-induced neurotoxicity in vitro and in vivo
Ip, V and Liu, JJ and McKeage, MJ, Evaluation of effects of copper histidine on copper transporter 1-mediated accumulation of platinum and oxaliplatin-induced neurotoxicity in vitro and in vivo, Clinical and Experimental Pharmacology and Physiology, 40, (6) pp. 371-378. ISSN 0305-1870 (2013) [Refereed Article]
1. The purpose of the present study was to determine
whether copper histidine could inhibit copper transporter
1 (Ctr1)-mediated transport of oxaliplatin in vitro and
thereby limit the accumulation of platinum and neurotoxicity
of oxaliplatin in dorsal root ganglion (DRG) tissue
2. In HEK293 cells overexpressing rat Ctr1, copper histidine
was shown to be transported by Ctr1 and to inhibit their
Ctr1-mediated uptake of oxaliplatin.
3. Pilot in vivo dose-finding studies showed that copper
histidine at doses up to 2 mg/kg, p.o., daily for 5 days/week
could be added to maximum tolerated doses of oxaliplatin
(1.85 mg/kg, i.p., twice weekly) for 8 week combination treatment
studies in female Wistar rats.
4. After treatment, rats showed significant changes in sensory
neuron size profiles in DRG tissue induced by oxaliplatin
that were not altered by its coadministration with copper
5. The expression of copper transporters (Ctr1 and coppertransporting
P-type ATPase 1 (Atp7a)) in DRG tissue
appeared unchanged following treatment with oxaliplatin
given alone or with copper histidine.
6. Platinum and copper tissue levels were higher in DRG
than in most other tissues, but were unaltered by the addition
of copper histidine to oxaliplatin treatment.
7. In conclusion, copper histidine inhibited cellular uptake
of oxaliplatin mediated by Ctr1 in vitro without altering the
accumulation of platinum or neurotoxicity of oxaliplatin in
DRG tissue in vivo at doses tolerated in combination with