DNA Replication Arrest and DNA Damage Response Induced by Alkylating Minor Groove Binders

Abstract

In this report, we study the cellular mechanism of adozelesin-induced DNA replication arrest. Adozelesin is an analog of CC-1065, a cyclopropylpyrroloindole (CPI) isolated from Streptomyces zelensis. Several CPI compounds have entered clinical studies for solid tumors, including breast cancer. Adozelesin is capable of binding to the minor groove of A/T-rich DNA sequences and alkylating the N3 of adenine at 3'-end of the binding sites (1, 21). These two activities contribute to its anti- cancer ability. Binding of adozelesin does not distort the duplex structure of targeted DNA (1) or cause any DNA strand break (2). Although nucleotide excision repair might be involved in the removal of CPI-induced lesions (4, 6), CC-1065:DNA adducts persist in BSC-1 green monkey cells (22). It is possible that these DNA adducts are been repaired inefficiently in treated cells.

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Document Details

Document Type
Technical Report
Publication Date
May 01, 2002
Accession Number
ADA406157

Entities

People

  • Shu-ru Kuo
  • Thomas Melendy

Organizations

  • University at Buffalo

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  • Air Platforms
  • Biomedical

DTIC Thesaurus Topics

  • Alkaloids
  • Antibodies
  • Biochemistry
  • Biomedical Research
  • Breast Cancer
  • Cell Line
  • Cell Physiological Processes
  • Cells
  • Chemical Compounds
  • Chemistry
  • Chemotherapeutic Agents
  • Inhibitors
  • Neoplasms
  • New York
  • Nucleotides
  • Phosphorylation
  • Proteins

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  • Biology
  • Chemistry

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  • Geochemistry
  • Molecular Genetics