title: Evaluation of effects of copper histidine on copper transporter 1-mediated accumulation of platinum and oxaliplatin-induced neurotoxicity in vitro and in vivo.
abstract: 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 in vivo. In HEK293 cells overexpressing rat Ctr1, copper histidine was shown to be transported by Ctr1 and to inhibit their Ctr1-mediated uptake of oxaliplatin. 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. 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 histidine. The expression of copper transporters (Ctr1 and copper-transporting P-type ATPase 1 (Atp7a)) in DRG tissue appeared unchanged following treatment with oxaliplatin given alone or with copper histidine. 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. 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 oxaliplatin treatment.
authors.affiliation: Department of Pharmacology and Clinical Pharmacology and Auckland Cancer Society Research Centre, The University of Auckland, Auckland, New Zealand.
authors.forename: Virginia
authors.initials: V
authors.lastname: Ip
authors.forename: Johnson J
authors.initials: JJ
authors.lastname: Liu
authors.forename: Mark J
authors.initials: MJ
authors.lastname: McKeage
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D027682:Cation Transport Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D003300:Copper / Q000378:metabolism; D000079923:Copper Transporter 1; D000073840:Copper-Transporting ATPases; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004347:Drug Interactions; D005260:Female; D005727:Ganglia, Spinal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D057809:HEK293 Cells; D020260:Heavy Metal Poisoning, Nervous System / Q000473:pathology / Q000517:prevention & control*; D006639:Histidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D009942:Organometallic Compounds / Q000494:pharmacology*; D009944:Organoplatinum Compounds / Q000493:pharmacokinetics / Q000633:toxicity*; D000077150:Oxaliplatin; D010984:Platinum / Q000378:metabolism*; D051381:Rats; D014162:Transfection
chemical_list: D027682:Cation Transport Proteins; D000079923:Copper Transporter 1; D009942:Organometallic Compounds; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D010984:Platinum; D006639:Histidine; D003300:Copper; C098468:copper histidine; D000251:Adenosine Triphosphatases; D000073840:Copper-Transporting ATPases