© The Author 2006. Published by Oxford University Press.
ARTICLE |
Effect of Chemotherapy-Induced DNA Repair on Oncolytic Herpes Simplex Viral Replication
Affiliation of authors: Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA
Correspondence to: Manish Aghi, MD, PhD, Brain Tumor Research Center, Massachusetts General Hospital–Simches Research Bldg., 185 Cambridge St., CPZN-3800, Boston, MA 02114 (e-mail: maghi{at}partners.org).
Background: Gliomas treated with the alkylating agent temozolomide have incomplete responses in part because of tumoral repair of chemotherapy-induced DNA damage. Data from phase I trials suggest that G207, an oncolytic herpes simplex virus (HSV) with mutated ribonucleotide reductase (RR) and 
34.5 genes, is safe but needs greater viral oncolysis to be effective. We hypothesized that temozolomide and G207 treatment limitations could be jointly addressed using temozolomide-induced tumor-protective DNA repair pathways to enhance viral replication. Methods: Human glioblastoma cells (U87, T98, and U373) and U87 cells transfected with the gene for the DNA repair enzyme O6-methylguanine DNA methyltransferase (MGMT) were treated with G207 and/or temozolomide. Drug interactions, expression of the growth arrest DNA damage 34 (GADD34) and RR transcripts before and after their knockdown with short interfering RNAs, DNA strand breaks, and apoptosis were measured using Chou–Talalay analysis, real-time reverse transcription–polymerase chain reaction, the comet assay, and flow cytometry, respectively. Survival of mice (groups of ten) with intracranial U87 xenograft tumors treated with temozolomide and/or G207 was analyzed using Kaplan–Meier analysis. Results: Temozolomide exhibited strong synergy with G207 in both MGMT-negative and the MGMT inhibitor O6-benzylguanine–treated MGMT-expressing gliomas (Chou–Talalay combination indices = 0.005 to 0.39) and induced GADD34 expression primarily in nonapoptotic MGMT-negative U87 glioma cells (fold difference = 16, 95% confidence interval [CI] = 12.6 to 20.4, compared with untreated cells). MGMT-expressing T98 and U87/MGMT cells treated with temozolomide plus O6-benzylguanine had higher RR expression than untreated cells (fold difference =14.9, 95% CI = 10.1 to 22.0 [T98]; 9.9, 95% CI = 7.0 to 13.8 [U87/MGMT]). GADD34 and RR knockdown increased temozolomide-induced DNA damage and inhibited the synergy of G207 and temozolomide in U87 and O6-benzylguanine–treated U87/MGMT cells. Mice bearing intracranial U87 tumors survived longer after combination therapy (100% survival at 90 days) than after single-agent therapy (median survival = 46 and 48 days with G207 and temozolomide treatment, respectively). Conclusions: Temozolomide-induced DNA repair pathways vary with MGMT expression and enhance HSV-mediated oncolysis in glioma cells. These findings unveil the potential of HSV to target cells surviving temozolomide treatment.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  H. Wakimoto, S. Kesari, C. J. Farrell, W. T. Curry Jr., C. Zaupa, M. Aghi, T. Kuroda, A. Stemmer-Rachamimov, K. Shah, T.-C. Liu, et al. Human Glioblastoma-Derived Cancer Stem Cells: Establishment of Invasive Glioma Models and Treatment with Oncolytic Herpes Simplex Virus Vectors Cancer Res., April 15, 2009; 69(8): 3472 - 3481. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Nagano, J. Y. Perentes, R. K. Jain, and Y. Boucher Cancer Cell Death Enhances the Penetration and Efficacy of Oncolytic Herpes Simplex Virus in Tumors Cancer Res., May 15, 2008; 68(10): 3795 - 3802. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S.-F. Lin, S. P. Gao, D. L. Price, S. Li, T.-C. Chou, P. Singh, Y.-Y. Huang, Y. Fong, and R. J. Wong Synergy of a Herpes Oncolytic Virus and Paclitaxel for Anaplastic Thyroid Cancer Clin. Cancer Res., March 1, 2008; 14(5): 1519 - 1528. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. M. Alonso, C. Gomez-Manzano, B. N. Bekele, W.K. A. Yung, and J. Fueyo Adenovirus-Based Strategies Overcome Temozolomide Resistance by Silencing the O6-Methylguanine-DNA Methyltransferase Promoter Cancer Res., December 15, 2007; 67(24): 11499 - 11504. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Kurozumi, J. Hardcastle, R. Thakur, M. Yang, G. Christoforidis, G. Fulci, F. H. Hochberg, R. Weissleder, W. Carson, E. A. Chiocca, et al. Effect of Tumor Microenvironment Modulation on the Efficacy of Oncolytic Virus Therapy J Natl Cancer Inst, December 5, 2007; 99(23): 1768 - 1781. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T.-C. Liu, H. Wakimoto, R. L. Martuza, and S. D. Rabkin Herpes Simplex Virus Us3( ) Mutant as Oncolytic Strategy and Synergizes with Phosphatidylinositol 3-Kinase-Akt Targeting Molecular Therapeutics Clin. Cancer Res., October 1, 2007; 13(19): 5897 - 5902. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Li, Z. Zeng, X. Fu, and X. Zhang Coadministration of a Herpes Simplex Virus-2 Based Oncolytic Virus and Cyclophosphamide Produces a Synergistic Antitumor Effect and Enhances Tumor-Specific Immune Responses Cancer Res., August 15, 2007; 67(16): 7850 - 7855. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. S. Adusumilli, M.-K. Chan, M. Hezel, Z. Yu, B. M. Stiles, T.-C. Chou, V. W. Rusch, and Y. Fong Radiation-Induced Cellular DNA Damage Repair Response Enhances Viral Gene Therapy Efficacy in the Treatment of Malignant Pleural Mesothelioma Ann. Surg. Oncol., January 1, 2007; 14(1): 258 - 269. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T.-C. Liu, T. Zhang, H. Fukuhara, T. Kuroda, T. Todo, X. Canron, A. Bikfalvi, R. L. Martuza, A. Kurtz, and S. D. Rabkin Dominant-Negative Fibroblast Growth Factor Receptor Expression Enhances Antitumoral Potency of Oncolytic Herpes Simplex Virus in Neural Tumors. Clin. Cancer Res., November 15, 2006; 12(22): 6791 - 6799. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T.-C. Chou Theoretical Basis, Experimental Design, and Computerized Simulation of Synergism and Antagonism in Drug Combination Studies Pharmacol. Rev., September 1, 2006; 58(3): 621 - 681. [Abstract] [Full Text] [PDF]
|
|