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Posted on: 09/16/2002

Clinical Cancer Research Vol. 8, 3008-3018, September 2002
© 2002 American Association for Cancer Research
Experimental Therapeutics, Preclinical Pharmacology

The Apurinic/Apyrimidinic Endonuclease Activity of Ape1/Ref-1 Contributes to Human Glioma Cell Resistance to Alkylating Agents and Is Elevated by Oxidative Stress1

John R. Silber2, Michael S. Bobola, A. Blank, Kathryn D. Schoeler, Peter D. Haroldson, Mary B. Huynh and Douglas D. Kolstoe Departments of Neurological Surgery [J. R. S., M. S. B., K. D. S., M. B. H., D. D. K.] and Pathology [A. B., P. D. H.], University of Washington, Seattle, Washington 98195, and Division of Neurosurgery, Department of Surgery, Children’s Hospital and Regional Medical Center, Seattle, Washington 98105 [M. S. B.]

Alkylating agents are standard components of adjuvant chemotherapy for gliomas.We provide evidence here that Ape1/Ref-1, the major mammalian apurinic/apyrimidinic endonuclease (Ap endo), contributes to alkylating agent resistance in human glioma cells by incising DNA at abasic sites. We show that antisense oligonucleotides directed against Ape1/Ref-1 in SNB19, a human glioma cell line lacking O6-methylguanine-DNA-methyltransferase, mediate both reduction in Ape1/Ref-1 protein and Ap endo activity and concurrent reduction in resistance to methyl methanesulfonate and the clinical alkylators temozolomide and 1,3-(2-chloroethyl)-1-nitrosourea. An accompanying increase in the level of abasic sites indicates that the DNA repair activity of Ape1/Ref-1 contributes to resistance. Conversely, we also show that exposure of SNB19 cells to HOCl, a generator of reactive oxygen species (ROS), results in elevated Ape1/Ref-1 protein and Ap endo activity, enhanced alkylator resistance, and reduced levels of abasic sites. Given current evidence that heightened oxidative stress prevails within brain tumors, the finding that ROS increase resistance to clinical alkylators in glioma cells may have significance for the response of gliomas to alkylating agent-based chemotherapy. Our results may also be relevant to the design of therapeutic regimens using concurrent ionizing radiation (a generator of ROS) and alkylating agent-based chemotherapy.

[Editor's note: English translation: This may indicate the use of a drug such as Temodar, BCNU or CCNU might work better if given at the same time as radiation instead of after radiation. Also raises the possibility that drugs such as RSR13 may help the Temodar, BCNU or CCNU work better!]
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