cis-Diammine(pyridine)chloroplatinum(II), a monofunctional platinum(II) antitumor agent: Uptake, structure, function, and prospects.

Abstract

We have identified unique chemical and biological properties of a cationic monofunctional platinum(II) complex, cis-diammine(pyridine)chloroplatinum(II), cis-[Pt(NH(3))(2)(py)Cl](+) or cDPCP, a coordination compound previously identified to have significant anticancer activity in a mouse tumor model. This compound is an excellent substrate for organic cation transporters 1 and 2, also designated SLC22A1 and SLC22A2, respectively. These transporters are abundantly expressed in human colorectal cancers, where they mediate uptake of oxaliplatin, cis-[Pt(DACH)(oxalate)] (DACH = trans-R,R-1,2-diaminocyclohexane), an FDA-approved first-line therapy for colorectal cancer. Unlike oxaliplatin, however, cDPCP binds DNA monofunctionally, as revealed by an x-ray crystal structure of cis-{Pt(NH(3))(2)(py)}(2+) bound to the N7 atom of a single guanosine residue in a DNA dodecamer duplex. Although the quaternary structure resembles that of B-form DNA, there is a base-pair step to the 5' side of the Pt adduct with abnormally large shift and slide values, features characteristic of cisplatin intrastrand cross-links. cDPCP effectively blocks transcription from DNA templates carrying adducts of the complex, unlike DNA lesions of other monofunctional platinum(II) compounds like {Pt(dien)}(2+). cDPCP-DNA adducts are removed by the nucleotide excision repair apparatus, albeit much less efficiently than bifunctional platinum-DNA intrastrand cross-links. These exceptional characteristics indicate that cDPCP and related complexes merit consideration as therapeutic options for treating colorectal and other cancers bearing appropriate cation transporters.

• Authors: Katherine S Lovejoy, Ryan C Todd, Shuzhong Zhang, Michael S McCormick, J Alejandro D'Aquino, Joyce T Reardon, Aziz Sancar, Kathleen M Giacomini, Stephen J Lippard
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 105 Issue 26 Pg. 8902-7 (Jul 01 2008) ISSN: 1091-6490 [Electronic] United States
• PMID: 18579768 (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
• Organic Cation Transporter 1
• Organoplatinum Compounds
• Solutions
• cis-diammine(pyridine)chloroplatinum(II)
• Oxaliplatin
• DNA
• RNA Polymerase II
• Cisplatin

Topics

• Animals
• Antineoplastic Agents (chemistry, metabolism, pharmacology)
• Binding Sites
• Cell Line
• Cell Survival (drug effects)
• Cisplatin (chemistry)
• Crystallography, X-Ray
• DNA (chemistry, metabolism)
• DNA Adducts (chemistry)
• DNA Repair (drug effects)
• Dogs
• Drug Screening Assays, Antitumor
• Humans
• Organic Cation Transporter 1 (metabolism)
• Organoplatinum Compounds (chemistry, metabolism, pharmacology)
• Oxaliplatin
• RNA Polymerase II (chemistry, metabolism)
• Solutions
• Transcription, Genetic (drug effects)