Organic cation transporters modulate the uptake and cytotoxicity of picoplatin, a third-generation platinum analogue.
Picoplatin, a third-generation platinum agent, is efficacious against lung cancers that are otherwise resistant or become refractory during platinum treatment. This effort was aimed at the determination of the influence of organic cation transporters 1, 2, and 3 (OCT1, OCT2, and OCT3) and their genetic variants on cellular uptake of picoplatin and on the individual components of the ensuing cytotoxicity such as DNA adduct formation. The effect of OCT1 on picoplatin pharmacokinetics and antitumor efficacy was determined using OCT knockout mice and HEK293 xenografts stably expressing OCT1. The uptake and DNA adduct formation of picoplatin were found to be significantly enhanced by the expression of the OCTs. Expression of OCT1 and OCT2, but not OCT3, significantly enhanced picoplatin cytotoxicity, which was reduced in the presence of an OCT inhibitor. Common reduced functional variants of OCT1 and OCT2 led to reduction in uptake and DNA adduct formation of picoplatin in comparison with the reference OCT1 and OCT2. Pharmacokinetic parameters of picoplatin in Oct1(-/-) and Oct1(+/+) mice were not significantly different, suggesting that the transporters do not influence the disposition of the drug. In contrast, the volume of OCT1-expressing xenografts in mice was significantly reduced by picoplatin treatment, suggesting that OCT1 may enhance the antitumor efficacy of picoplatin. These studies provide a basis for follow-up clinical studies that would seek to examine the relationship between the anticancer efficacy of picoplatin and expression levels of OCTs and their genetic variants in tumors. Mol Cancer Ther; 9(4); 1058-69. (c)2010 AACR.
More
Swati S
SS
Department of Bioengineering and Therapeutic Sciences, University of California, 1550 4th Street, San Francisco, CA 94158, USA.
Li
Shuanglian
S
Yee
Sook Wah
SW
Chen
Ligong
L
Xu
Zhidong
Z
Jablons
David M
DM
Giacomini
Kathleen M
KM
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002927:Cimetidine / Q000494:pharmacology; D018736:DNA Adducts / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology; D051379:Mice; D027701:Organic Cation Transport Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017671:Platinum Compounds / Q000493:pharmacokinetics* / Q000494:pharmacology*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D014018:Tissue Distribution / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D018736:DNA Adducts; D027701:Organic Cation Transport Proteins; D017671:Platinum Compounds; D002927:Cimetidine