Structural and Mechanistic Studies of Anticancer Platinum Drugs: Uptake, Activation, and the Cellular Response to DNA Binding

  • Shanta Dhar
  • Stephen J. Lippard
Part of the Cancer Drug Discovery and Development book series (CDD&D)

Abstract

The action of platinum anticancer drugs is a multistep process involving uptake, activation, DNA binding, and cellular responses. Our research investigates these early stages of action of platinum complexes. We demonstrated that the effectiveness of oxaliplatin and cis-diammine(pyridine)chloroplatinum(II) (cDPCP) is a consequence of their selective delivery to cells containing organic cation transporters OCT1 and OCT2. This work inspired us to devise strategies for novel cell-targeting modalities, which include tethering receptor-binding moieties like estrogen or conjugated peptide motifs to a cis-diammineplatinum(II) unit, and the use of single walled carbon nanotubes as “longboat” delivery systems. Structural studies of DNA containing bound platinum complexes resulted in two significant findings. First, an X-ray structure of a site-specific monofunctional platinum-DNA dodecamer duplex containing a guanosine modified by cis-{Pt(NH3)2(py)}2+ resembles that of B-DNA, differing from structures containing a 1,2- or 1,3- intrastrand cross-link. Nevertheless, certain features resemble that of the 1,2-cross-link. Second, 1,3-GTG-intrastrand cis-diammineplatinum(II) cross-links determine and override the natural positioning of DNA on the nucleo-some core particle. Close examination of cellular responses associated with cis-[Pt(NH3)2(py)Cl]Cl, cDPCP, revealed the potency of this compound to be a consequence of a competition between transcription inhibition and excision repair. Photo-cross-linking studies of platinated DNA to proteins in cancer cell nuclear extracts reveal the panoply of factors that process the platinum adducts at the early stage of recognition.

Keywords

Cisplatin Uptake Platinum(IV) compounds Receptors DNA binding Cellular responses 

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Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Shanta Dhar
    • 1
  • Stephen J. Lippard
    • 1
  1. 1.Department of Chemistry, Massachusetts Institute of TechnologyCambridgeUSA

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