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

Publication Type:

Journal Article

Authors:

Lovejoy, Katherine S; Todd, Ryan C; Zhang, Shuzhong; McCormick, Michael S; D'Aquino, J Alejandro; Reardon, Joyce T; Sancar, Aziz; Giacomini, Kathleen M; Lippard, Stephen J

Source:

Proc Natl Acad Sci U S A, Volume 105, Issue 26, p.8902-7 (2008)

Keywords:

Animals, Antineoplastic Agents, Binding Sites, Cell Line, Cell Survival, Cisplatin, Crystallography, X-Ray, DNA, DNA Adducts, DNA Repair, Dogs, Drug Screening Assays, Antitumor, Humans, Organic Cation Transporter 1, Organoplatinum Compounds, RNA Polymerase II, Solutions, Transcription, Genetic

Abstract:

<p>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.</p>