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

Proc Natl Acad Sci U S A. 2008 Jul 1;105(26):8902-7. doi: 10.1073/pnas.0803441105. Epub 2008 Jun 25.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

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

Substances

  • Antineoplastic Agents
  • DNA Adducts
  • Organic Cation Transporter 1
  • Organoplatinum Compounds
  • Solutions
  • cis-diammine(pyridine)chloroplatinum(II)
  • Oxaliplatin
  • DNA
  • RNA Polymerase II
  • Cisplatin

Associated data

  • PDB/3CO3