Covalent Modification of DNA and Protein by Bioactivated Antitumor Acylfulvenes

Information

  • Research Project
  • 8101215
  • ApplicationId
    8101215
  • Core Project Number
    R01CA123007
  • Full Project Number
    5R01CA123007-05
  • Serial Number
    123007
  • FOA Number
  • Sub Project Id
  • Project Start Date
    4/23/2007 - 17 years ago
  • Project End Date
    2/28/2013 - 11 years ago
  • Program Officer Name
    LEES, ROBERT G.
  • Budget Start Date
    3/1/2011 - 13 years ago
  • Budget End Date
    2/28/2013 - 11 years ago
  • Fiscal Year
    2011
  • Support Year
    5
  • Suffix
  • Award Notice Date
    2/28/2011 - 13 years ago
Organizations

Covalent Modification of DNA and Protein by Bioactivated Antitumor Acylfulvenes

DESCRIPTION (provided by applicant): Acylfulvenes, derivatives of illudin natural products, are a promising class of drugs for cancer treatment. They are notable for high therapeutic indices and selectivities for tumor cells, and clinical trials are underway. Acylfulvenes are alkylating agents, but the detailed chemical mechanisms of DNA and protein-adduct formation, and how this relates to tumor-cell selectivity is not known. The long-term goals of this project are to define a mechanistic paradigm accounting for the selective toxicities of acylfulvenes that will lead to the development of combined-agent and tailored therapies designed to site-specifically tune acylfulvene toxicity. The objectives of this application are to establish a link from acylfulvene bioactivation to biomolecular target modification and cytotoxicity. The specific aims are to (1) Characterize in vitro patterns of DNA alkylation by acylfulvenes and distinguish adducts that result from direct modification of DNA from those of bioactivation-coupled reactions;(2) Characterize the mechanism of inhibition of cellular redox proteins by acylfulvenes;(3) Determine the influence of a bioactivating reductase on acylfulvene alkylation reactions and toxicity in cells. The research approach for aim 1 involves the synthesis of chemically activated molecular probes that will be used to identify products of DNA alkylation by bioactivated acylfulvenes. We will use chemical characterization methods to identify the structures of acylfulvene DNA adducts. In aim 2, we will use enzyme-inhibition studies combined with a mass-spectrometry-based approach to structurally map protein covalent modification. In aim 3, we will use reductase-overexpressing cells and stable tumor cell lines to test the impact of adduct formation in the complex environment of the cell. Acylfulvenes are a new class of drugs that kill cancer cells by becoming covalently linked to biomolecules in the cell and initiating a sequence of biological events that result in cell death. The initial chemical transformations that govern this process and how they differ in cells that are sensitive to acylfulvenes versus those that are not are unknown. The ability to selectively target tumor cells is a central problem in cancer therapy and consequently understanding this mechanism is important for designing safer cancer therapy strategies.

IC Name
NATIONAL CANCER INSTITUTE
  • Activity
    R01
  • Administering IC
    CA
  • Application Type
    5
  • Direct Cost Amount
  • Indirect Cost Amount
  • Total Cost
    178096
  • Sub Project Total Cost
  • ARRA Funded
    False
  • CFDA Code
    395
  • Ed Inst. Type
  • Funding ICs
    NCI:178096\
  • Funding Mechanism
    Research Projects
  • Study Section
    SBCA
  • Study Section Name
    Synthetic and Biological Chemistry A Study Section
  • Organization Name
    SWISS FEDERAL INST OF TECH (ETH ZURICH)
  • Organization Department
  • Organization DUNS
    481907673
  • Organization City
    ZURICH
  • Organization State
  • Organization Country
    SWITZERLAND
  • Organization Zip Code
    8092
  • Organization District
    SWITZERLAND