Organic cation transporters are determinants of oxaliplatin cytotoxicity.

Abstract

Although the platinum-based anticancer drugs cisplatin, carboplatin, and oxaliplatin have similar DNA-binding properties, only oxaliplatin is active against colorectal tumors. The mechanisms for this tumor specificity of platinum-based compounds are poorly understood but could be related to differences in uptake. This study shows that the human organic cation transporters (OCT) 1 and 2 (SLC22A1 and SLC22A2) markedly increase oxaliplatin, but not cisplatin or carboplatin, accumulation and cytotoxicity in transfected cells, indicating that oxaliplatin is an excellent substrate of these transporters. The cytotoxicity of oxaliplatin was greater than that of cisplatin in six colon cancer cell lines [mean +/- SE of IC(50) in the six cell lines, 3.9 +/- 1.4 micromol/L (oxaliplatin) versus 11 +/- 2.0 micromol/L (cisplatin)] but was reduced by an OCT inhibitor, cimetidine, to a level similar to, or even lower than that of, cisplatin (29 +/- 11 micromol/L for oxaliplatin versus 19 +/- 4.3 micromol/L for cisplatin). Structure-activity studies indicated that organic functionalities on nonleaving groups coordinated to platinum are critical for selective uptake by OCTs. These results indicate that OCT1 and OCT2 are major determinants of the anticancer activity of oxaliplatin and may contribute to its antitumor specificity. They also strongly suggest that expression of OCTs in tumors should be investigated as markers for selecting specific platinum-based therapies in individual patients. The development of new anticancer drugs, specifically targeted to OCTs, represents a novel strategy for targeted drug therapy. The results of the present structure-activity studies indicate specific tactics for realizing this goal.

• Authors: Shuzhong Zhang, Katherine S Lovejoy, James E Shima, Leah L Lagpacan, Yan Shu, Anna Lapuk, Ying Chen, Takafumi Komori, Joe W Gray, Xin Chen, Stephen J Lippard, Kathleen M Giacomini
• Journal: Cancer research (Cancer Res) Vol. 66 Issue 17 Pg. 8847-57 (Sep 01 2006) ISSN: 1538-7445 [Electronic] United States
• PMID: 16951202 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antineoplastic Agents
• DNA Adducts
• Octamer Transcription Factor-1
• Organic Cation Transport Proteins
• Organic Cation Transporter 2
• Organoplatinum Compounds
• POU2F1 protein, human
• Pyridines
• SLC22A2 protein, human
• oxiplatin
• Platinum
• RNA
• Cisplatin

Topics

• Animals
• Antineoplastic Agents (toxicity)
• Cell Line
• Cisplatin (toxicity)
• DNA Adducts
• Dogs
• Genetic Vectors
• Humans
• Kidney
• Octamer Transcription Factor-1 (genetics, metabolism)
• Organic Cation Transport Proteins (genetics, metabolism)
• Organic Cation Transporter 2
• Organoplatinum Compounds (toxicity)
• Platinum
• Pyridines (toxicity)
• RNA (genetics, isolation & purification)
• Reverse Transcriptase Polymerase Chain Reaction
• Structure-Activity Relationship
• Transfection