The long-term goal of this research is to improve cancer therapy by combining mechanistic information about the cisplatin family of drugs with synthetic chemistry to produce new compounds and strategies for the selective destruction of tumors. Cisplatin, carboplatin, and oxaliplatin are leading anticancer agents and, for certain cancers, a paradigm for successful treatment. Detailed knowledge about how they function to target tumor tissue and trigger cellular pathways for destroying cancer cells will facilitate the design of more effective drugs and guide clinical protocols. A leading hypothesis is that the selective toxicity of platinum compounds for tumor versus normal cells and their efficacy for specific tissues are a consequence of the formation and survival of adducts on DNA, the acknowledged biological target. Early steps in this process are cancer cell entry, activation to form reactive species, DNA binding in the nucleus, and DNA damage-processing events. Plasma membrane receptors that internalize cisplatin and related compounds will be investigated. Knowledge of their identity will suggest cancer-cell targeting strategies and provide biomarkers for susceptible tumors. Platinum compounds with a tethered desthiobiotin unit will be used to capture plasma membrane and intracellular Pt-DNA- processing proteins. Carbon nanotubes and biodegradable nanoparticles are devised to deliver platinum prodrugs selectively to cancer cells, targeting specific receptors. Pt(IV) chemistry features prominently in this research, facilitating attachment of cell-targeting and gene-activating units at axial positions on the metal that dissociate upon reduction in the cell, affording a Pt(II) compound for DNA binding. Nucleosomes, the building blocks of chromosomes, will be constructed with site-specific Pt-DNA adducts and structurally characterized in solution by footprinting and in the solid state by X-ray crystallography. The major intrastrand 1,2-d(GpG) and 1,3-d(GpNpG) cross-links of cisplatin and oxaliplatin, as well as interstrand dG/dG cross-links, will be investigated. A biologically active monofunctional platinum compound bound to a single dG site will also be examined. Because cisplatin blocks RNA polymerase II, which triggers apoptosis and initiates nucleotide excision repair, transcription inhibition by Pt-DNA adducts will be studied with site-specifically modified nucleosomes in vitro and with platinated reporter plasmids in live cells following transfection. Repair shielding by high mobility group protein HMGB1 bound to Pt-DNA 1,2-intrastrand cross-links sensitizes cells to cisplatin. The dependence of this activity on cellular redox potential changes will be investigated, since the oxidation state of a pair of cysteines on HMGB1 modulates binding to platinated-DNA. Structure-function studies of RNA pol II on transcriptional elongation complexes will be performed to uncover details of the transcription inhibition process. Understanding the role of ligands on platinum in blocking transcription while eluding repair will guide the synthesis of new Pt drug candidates. Animal studies and a phase I clinical pilot trial will evaluate new compounds and strategies conceived in this project, with the ultimate aim of providing improved cancer treatment.
This research aims to improve cancer therapy by investigating the mechanism of action of the cisplatin family of drugs. The knowledge acquired will be used to design, synthesize, and evaluate new anticancer drug candidates for targeting and destroying tumors.
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