PT  - JOURNAL ARTICLE
AU  - Alison K. Holzer
AU  - Gerald H. Manorek
AU  - Stephen B. Howell
TI  - Contribution of the Major Copper Influx Transporter CTR1 to the Cellular Accumulation of Cisplatin, Carboplatin, and Oxaliplatin
AID  - 10.1124/mol.106.022624
DP  - 2006 Oct 01
TA  - Molecular Pharmacology
PG  - 1390--1394
VI  - 70
IP  - 4
4099  - http://molpharm.aspetjournals.org/content/70/4/1390.short
4100  - http://molpharm.aspetjournals.org/content/70/4/1390.full
SO  - Mol Pharmacol2006 Oct 01; 70
AB  - The goal of this study was to determine the ability of the major copper influx transporter CTR1 to mediate the cellular accumulation of cisplatin (DDP), carboplatin (CBDCA), and oxaliplatin (L-OHP). Wild-type murine embryonic fibroblasts (CTR1+/+) and a subline in which both alleles of CTR1 were deleted (CTR1-/-) were tested for their ability to accumulate platinum when exposed to increasing concentrations of DDP, CBDCA, or L-OHP for 1 h. They were also tested for their sensitivity to the growth-inhibitory effect of each drug. Platinum content was measured by ion-coupled plasmon mass spectroscopy. The experimental model was validated by measuring copper accumulation and cytotoxicity. CTR1-/- cells accumulated only 5.7% as much copper as CTR1+/+ cells during a 1-h exposure to 2 μM copper. When exposed to DDP, CBDCA, or L-OHP at 2 μM, accumulation in the CTR1-/- cells was only 35 to 36% of that in the CTR1+/+ cells. When tested at a 5-fold higher concentration, this deficit remained for DDP and CBDCA, but accumulation of L-OHP was no longer CTR1-dependent. There was an association between the effect of loss of CTR1 function on uptake of the platinum drugs and their cytotoxicity. The CTR1-/- cells were 3.2-fold resistant to DDP, 2.0-fold resistant to CBDCA, but only 1.7-fold resistant to L-OHP. Thus, whereas CTR1 controls the cellular accumulation of all three drugs at low concentrations, accumulation of L-OHP is not dependent on CTR1 at higher concentrations. We conclude that L-OHP is a substrate for some other cellular entry mechanism, a feature consistent with its different clinical spectrum of activity. The American Society for Pharmacology and Experimental Therapeutics