Cis-Diammine(Pyridine)Chloroplatinum(II), a Monofunctional Platinum(II) Antitumor Agent: Uptake, Structure, Function, And Prospects

Journal Article · Tue May 19 04:00:00 EDT 2009 · Proc. Nat. Acad. Sci. 105:8902,2008

OSTI ID:953094

Lovejoy, K S; Todd, R C; Zhang, S; McCormick, M S; D'Aquino, J A; Reardon, J T; Sancar, A; Giacomini, K M; Lippard, S J

We have identified unique chemical and biological properties of a cationic monofunctional platinum(II) complex, cis-diammine(pyridine)chloroplatinum(II), cis-[Pt(NH{sub 3}){sub 2}(py)Cl]{sup +} 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-{l_brace}Pt(NH{sub 3}){sub 2}(py){r_brace}{sup 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{prime} 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 {l_brace}Pt(dien){r_brace}{sup 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.

• Research Organization: Stanford Linear Accelerator Center (SLAC)
• Sponsoring Organization: USDOE
• DOE Contract Number: AC02-76SF00515
• OSTI ID: 953094
• Report Number(s): SLAC-REPRINT-2009-190
• Journal Information: Proc. Nat. Acad. Sci. 105:8902,2008, Journal Name: Proc. Nat. Acad. Sci. 105:8902,2008 Journal Issue: 26 Vol. 105; ISSN 0027-8424; ISSN PNASA6
• Country of Publication: United States
• Language: English

Related Subjects

36 MATERIALS SCIENCE
ADDUCTS
ATOMS
BEARINGS
CATIONS
CRYSTAL STRUCTURE
DNA
EXCISION REPAIR
GUANOSINE
NEOPLASMS
NUCLEOTIDES
Other
OTHER
RESIDUES
SUBSTRATES
THERAPY
TRANSCRIPTION