This Article Full Text Full Text (PDF) Supplementary Data 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 Trivedi, R. N. Articles by Sobol, R. W. Search for Related Content PubMed PubMed Citation Articles by Trivedi, R. N. Articles by Sobol, R. W.

The Role of Base Excision Repair in the Sensitivity and Resistance to Temozolomide-Mediated Cell Death

Hillman Cancer Center, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania

Requests for reprints: Robert W. Sobol, Hillman Cancer Center, University of Pittsburgh Cancer Institute, Research Pavilion, Suite 2.6, 5117 Centre Avenue, Pittsburgh, PA 15213-1863. Phone: 412-623-7764; Fax: 412-623-7761; E-mail: rws9{at}pitt.edu.

DNA-alkylating agents have a central role in the curative therapy of many human tumors; yet, resistance to these agents limits their effectiveness. The efficacy of the alkylating agent temozolomide has been attributed to the induction of O⁶-MeG, a DNA lesion repaired by the protein O⁶-methylguanine-DNA methyltransferase (MGMT). Resistance to temozolomide has been ascribed to elevated levels of MGMT and/or reduced mismatch repair. However, >80% of the DNA lesions induced by temozolomide are N-methylated bases that are recognized by DNA glycosylases and not by MGMT, and so resistance to temozolomide may also be due, in part, to robust base excision repair (BER). We used isogenic cells deficient in the BER enzymes DNA polymerase-ß (pol-ß) and alkyladenine DNA glycosylase (Aag) to determine the role of BER in the cytotoxic effect of temozolomide. Pol-ß–deficient cells were significantly more susceptible to killing by temozolomide than wild-type or Aag-deficient cells, a hypersensitivity likely caused by accumulation of BER intermediates. RNA interference–mediated pol-ß suppression was sufficient to increase temozolomide efficacy, whereas a deficiency in pol- or pol- did not increase temozolomide-mediated cytotoxicity. Overexpression of Aag (the initiating BER enzyme) triggered a further increase in temozolomide-induced cytotoxicity. Enhanced Aag expression, coupled with pol-ß knockdown, increased temozolomide efficacy up to 4-fold. Furthermore, loss of pol-ß coupled with temozolomide treatment triggered the phosphorylation of H2AX, indicating the activation of the DNA damage response pathway as a result of unrepaired lesions. Thus, the BER pathway is a major contributor to cellular resistance to temozolomide and its efficacy depends on specific BER gene expression and activity.

This article has been cited by other articles:

				D. R. McNeill, W. Lam, T. L. DeWeese, Y.-C. Cheng, and D. M. Wilson III Impairment of APE1 Function Enhances Cellular Sensitivity to Clinically Relevant Alkylators and Antimetabolites Mol. Cancer Res., June 1, 2009; 7(6): 897 - 906. [Abstract] [Full Text] [PDF]

				C. K. Augustine, J. S. Yoo, A. Potti, Y. Yoshimoto, P. A. Zipfel, H. S. Friedman, J. R. Nevins, F. Ali-Osman, and D. S. Tyler Genomic and Molecular Profiling Predicts Response to Temozolomide in Melanoma Clin. Cancer Res., January 15, 2009; 15(2): 502 - 510. [Abstract] [Full Text] [PDF]

				W. Wick, M. Platten, and M. Weller New (alternative) temozolomide regimens for the treatment of glioma Neuro-oncol, January 1, 2009; 11(1): 69 - 79. [Abstract] [Full Text] [PDF]

				M. H. Kulke, J. L. Hornick, C. Frauenhoffer, S. Hooshmand, D. P. Ryan, P. C. Enzinger, J. A. Meyerhardt, J. W. Clark, K. Stuart, C. S. Fuchs, et al. O6-Methylguanine DNA Methyltransferase Deficiency and Response to Temozolomide-Based Therapy in Patients with Neuroendocrine Tumors Clin. Cancer Res., January 1, 2009; 15(1): 338 - 345. [Abstract] [Full Text] [PDF]

				M. Zheng, D. Bocangel, R. Ramesh, S. Ekmekcioglu, N. Poindexter, E. A. Grimm, and S. Chada Interleukin-24 overcomes temozolomide resistance and enhances cell death by down-regulation of O6-methylguanine-DNA methyltransferase in human melanoma cells Mol. Cancer Ther., December 1, 2008; 7(12): 3842 - 3851. [Abstract] [Full Text] [PDF]

				D. Allen, D. C. Herbert, C. A. McMahan, V. Rotrekl, R. W. Sobol, S. H. Wilson, and C. A. Walter Mutagenesis Is Elevated in Male Germ Cells Obtained from DNA Polymerase-beta Heterozygous Mice Biol Reprod, November 1, 2008; 79(5): 824 - 831. [Abstract] [Full Text] [PDF]

				M. E. Hegi, L. Liu, J. G. Herman, R. Stupp, W. Wick, M. Weller, M. P. Mehta, and M. R. Gilbert Correlation of O6-Methylguanine Methyltransferase (MGMT) Promoter Methylation With Clinical Outcomes in Glioblastoma and Clinical Strategies to Modulate MGMT Activity J. Clin. Oncol., September 1, 2008; 26(25): 4189 - 4199. [Abstract] [Full Text] [PDF]

				R. N. Trivedi, X.-h. Wang, E. Jelezcova, E. M. Goellner, J.-b. Tang, and R. W. Sobol Human Methyl Purine DNA Glycosylase and DNA Polymerase {beta} Expression Collectively Predict Sensitivity to Temozolomide Mol. Pharmacol., August 1, 2008; 74(2): 505 - 516. [Abstract] [Full Text] [PDF]

				P. Rietschel, J. D. Wolchok, S. Krown, S. Gerst, A. A. Jungbluth, K. Busam, K. Smith, I. Orlow, K. Panageas, and P. B. Chapman Phase II Study of Extended-Dose Temozolomide in Patients With Melanoma J. Clin. Oncol., May 10, 2008; 26(14): 2299 - 2304. [Abstract] [Full Text] [PDF]

				M. Sanada, M. Hidaka, Y. Takagi, T. Y. Takano, Y. Nakatsu, T. Tsuzuki, and M. Sekiguchi Modes of actions of two types of anti-neoplastic drugs, dacarbazine and ACNU, to induce apoptosis Carcinogenesis, December 1, 2007; 28(12): 2657 - 2663. [Abstract] [Full Text] [PDF]

				C. N. Kundu, R. Balusu, A. S. Jaiswal, and S. Narayan Adenomatous polyposis coli-mediated hypersensitivity of mouse embryonic fibroblast cell lines to methylmethane sulfonate treatment: implication of base excision repair pathways Carcinogenesis, October 1, 2007; 28(10): 2089 - 2095. [Abstract] [Full Text] [PDF]

				Y. Yoshimoto, C. K. Augustine, J. S. Yoo, P. A. Zipfel, M. A. Selim, S. K. Pruitt, H. S. Friedman, F. Ali-Osman, and D. S. Tyler Defining regional infusion treatment strategies for extremity melanoma: comparative analysis of melphalan and temozolomide as regional chemotherapeutic agents Mol. Cancer Ther., May 1, 2007; 6(5): 1492 - 1500. [Abstract] [Full Text] [PDF]

				Q. Zhou, P. Guo, X. Wang, S. Nuthalapati, and J. M. Gallo Preclinical Pharmacokinetic and Pharmacodynamic Evaluation of Metronomic and Conventional Temozolomide Dosing Regimens J. Pharmacol. Exp. Ther., April 1, 2007; 321(1): 265 - 275. [Abstract] [Full Text] [PDF]

				D. P. Cahill, K. K. Levine, R. A. Betensky, P. J. Codd, C. A. Romany, L. B. Reavie, T. T. Batchelor, P. A. Futreal, M. R. Stratton, W. T. Curry, et al. Loss of the Mismatch Repair Protein MSH6 in Human Glioblastomas Is Associated with Tumor Progression during Temozolomide Treatment Clin. Cancer Res., April 1, 2007; 13(7): 2038 - 2045. [Abstract] [Full Text] [PDF]

				N. Auger, J. Thillet, K. Wanherdrick, A. Idbaih, M.-E. Legrier, B. Dutrillaux, M. Sanson, and M.-F. Poupon Genetic alterations associated with acquired temozolomide resistance in SNB-19, a human glioma cell line. Mol. Cancer Ther., September 1, 2006; 5(9): 2182 - 2192. [Abstract] [Full Text] [PDF]

				R. D. Kennedy and A. D. D'Andrea DNA Repair Pathways in Clinical Practice: Lessons From Pediatric Cancer Susceptibility Syndromes J. Clin. Oncol., August 10, 2006; 24(23): 3799 - 3808. [Abstract] [Full Text] [PDF]

				L. Tentori, C. Leonetti, M. Scarsella, A. Muzi, E. Mazzon, M. Vergati, O. Forini, R. Lapidus, W. Xu, A. S. Dorio, et al. Inhibition of poly(ADP-ribose) polymerase prevents irinotecan-induced intestinal damage and enhances irinotecan/temozolomide efficacy against colon carcinoma FASEB J, August 1, 2006; 20(10): 1709 - 1711. [Abstract] [Full Text] [PDF]

				A. Mookerjee, J. Mookerjee Basu, P. Dutta, S. Majumder, S. Bhattacharyya, J. Biswas, S. Pal, P. Mukherjee, S. Raha, R. N. Baral, et al. Overcoming Drug-Resistant Cancer by a Newly Developed Copper Chelate through Host-Protective Cytokine-Mediated Apoptosis. Clin. Cancer Res., July 15, 2006; 12(14): 4339 - 4349. [Abstract] [Full Text] [PDF]

				J.-P. Capp, F. Boudsocq, P. Bertrand, A. Laroche-Clary, P. Pourquier, B. S. Lopez, C. Cazaux, J.-S. Hoffmann, and Y. Canitrot The DNA polymerase {lambda} is required for the repair of non-compatible DNA double strand breaks by NHEJ in mammalian cells Nucleic Acids Res., May 31, 2006; 34(10): 2998 - 3007. [Abstract] [Full Text] [PDF]

				L. Liu and S. L. Gerson Targeted Modulation of MGMT: Clinical Implications Clin. Cancer Res., January 15, 2006; 12(2): 328 - 331. [Abstract] [Full Text] [PDF]