This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bobola, M. S. Articles by Silber, J. R. Search for Related Content PubMed PubMed Citation Articles by Bobola, M. S. Articles by Silber, J. R.

Apurinic/Apyrimidinic Endonuclease Activity Is Associated with Response to Radiation and Chemotherapy in Medulloblastoma and Primitive Neuroectodermal Tumors

Authors' Affiliations: ¹ Division of Neurosurgery, Department of Surgery; ² Division of Hematology/Oncology; and ³ Department of Laboratories, Children's Hospital and Regional Medical Center; Departments of ⁴ Neurological Surgery, ⁵ Pathology and ⁶ Pediatrics, University of Washington, Seattle, Washington; and ⁷ Department of Neurological Surgery, University of California, San Francisco, California

Requests for reprints: Michael S. Bobola, Division of Neurosurgery, Department of Surgery, Children's Hospital and Regional Medical Center, Seattle, WA 98105. Phone: 206-987-2046; Fax: 206-527-3925; E-mail: michael.bobola{at}seattleschildren.org.

Purpose: Apurinic/apyrimidinic endonuclease (Ap endo) is a key DNA repair activity that confers resistance to radiation- and alkylator-induced cytotoxic abasic sites in human cells. We assayed apurinic/apyrimidinic endonuclease activity in medulloblastomas and primitive neuroectodermal tumors (PNET) to establish correlates with tumor and patient characteristics and with response to adjuvant radiation plus multiagent chemotherapy.

Experimental Design: Ap endo activity was assayed in 52 medulloblastomas and 10 PNETs from patients 0.4 to 21 years old. Ape1/Ref-1, the predominant human Ap endo activity, was measured in 42 medulloblastomas by immunostaining. Cox proportional hazards regression models were used to analyze the association of activity with time to tumor progression (TTP).

Results: Tumor Ap endo activity varied 180-fold and was significantly associated with age and gender. Tumor Ape1/Ref-1 was detected almost exclusively in nuclei. In a multivariate model, with Ap endo activity entered as a continuous variable, the hazard ratio for progression after adjuvant treatment in 46 medulloblastomas and four PNETs increased by a factor of 1.073 for every 0.01 unit increase in activity (P 0.001) and was independent of age and gender. Suppressing Ap endo activity in a human medulloblastoma cell line significantly increased sensitivity to 1,3-bis(2-chlororethyl)-1-nitrosourea and temozolomide, suggesting that the association of tumor activity with TTP reflected, at least in part, abasic site repair.

Conclusions: Our data (a) suggest that Ap endo activity promotes resistance to radiation plus chemotherapy in medulloblastomas/PNETs, (b) provide a potential marker of treatment outcome, and (c) suggest clinical use of Ap endo inhibitors to overcome resistance.

This article has been cited by other articles:

				D. R. McNeill and D. M. Wilson III A Dominant-Negative Form of the Major Human Abasic Endonuclease Enhances Cellular Sensitivity to Laboratory and Clinical DNA-Damaging Agents Mol. Cancer Res., January 1, 2007; 5(1): 61 - 70. [Abstract] [Full Text] [PDF]

				W. Lam, S.-Y. Park, C.-H. Leung, and Y.-C. Cheng Apurinic/Apyrimidinic Endonuclease-1 Protein Level Is Associated with the Cytotoxicity of L-Configuration Deoxycytidine Analogs (Troxacitabine and beta-L-2',3'-Dideoxy-2',3'-didehydro-5-fluorocytidine) but Not D-Configuration Deoxycytidine Analogs (Gemcitabine and beta-D-Arabinofuranosylcytosine) Mol. Pharmacol., May 1, 2006; 69(5): 1607 - 1614. [Abstract] [Full Text] [PDF]