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

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.