Oxidative DNA base damage by the antitumor agent 3-amino-1,2,4-benzotriazine 1,4-Dioxide (Tirapazamine)

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Abstract

Tirapazamine is a bioreductively activated DNA-damaging agent that selectively kills the hypoxic cells found in solid tumors. In this work, base excision repair enzymes were used to provide evidence that tirapazamine causes significant amounts of damage to both purine and pyrimidine residues in double-stranded DNA.

In this work, base excision repair enzymes that remove oxidatively damaged DNA bases, leaving behind easily detected strand breaks, were used to provide evidence that tirapazamine causes significant amount of damage to both purine and pyrimidine residues in double-stranded DNA.

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Acknowledgements

This work was generously supported by American Cancer Society Grant RPG-00–028–01.

References (37)

  • K.L. Laderoute et al.

    Biochem. Pharmacol.

    (1988)
  • L.H. Patterson et al.

    Biochem. Pharmacol.

    (2000)
  • A.P. Breen et al.

    Free Rad. Biol. Med.

    (1995)
  • G. Scholes et al.

    J. Mol. Biol.

    (1960)
  • B. Epe et al.

    Methods Enzymol.

    (1994)
  • D.I. Edwards et al.

    Int. J. Radiat. Biol. Phys.

    (1992)
  • B. Ganley et al.

    Bioorg. Med. Chem.

    (2001)
  • W.A. Denny

    Wilson Expert Opin. Invest. Drugs

    (2000)
  • J.M. Brown

    Cancer Res.

    (1999)
  • R.V. Lloyd et al.

    Mol. Pharmacol.

    (1991)
  • P. Wardman et al.

    Br. J. Cancer

    (1996)
  • S.A. Fitzsimmons et al.

    Carcinogenesis

    (1994)
  • J.S. Daniels et al.

    J. Am. Chem. Soc.

    (1996)
  • K.A. Biedermann et al.

    Br. J. Cancer

    (1991)
  • B.G. Siim et al.

    Br. J. Cancer

    (1996)
  • J.-T. Hwang et al.

    Biochemistry

    (1999)
  • J.S. Daniels et al.

    Chem. Res. Toxicol.

    (1998)
  • G.D.D. Jones et al.

    Cancer Res.

    (1996)
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