Open Accesscis -Diammine(pyridine)chloroplatinum(II), a monofunctional platinum(II) antitumor agent: Uptake, structure, function, and prospects
Author(s) -
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
Publication year - 2008
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.0803441105
Subject(s) - chemistry , stereochemistry , adduct , guanosine , cisplatin , dna , oxaliplatin , nucleotide excision repair , nucleotide , platinum , dna adduct , pyridine , dna repair , biochemistry , medicinal chemistry , cancer , biology , colorectal cancer , gene , organic chemistry , chemotherapy , genetics , catalysis
We have identified unique chemical and biological properties of a cationic monofunctional platinum(II) complex,cis -diammine(pyridine)chloroplatinum(II),cis -[Pt(NH3 )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 ofcis -{Pt(NH3 )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.