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Adenovirus-Based Strategies Overcome Temozolomide Resistance by Silencing the O⁶-Methylguanine-DNA Methyltransferase Promoter

Departments of ¹ Neuro-Oncology and ² Biostatistics and Applied Mathematics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Marta M. Alonso, Department of Neuro-Oncology, Unit 1002, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-834-6251; Fax: 713-834-6230; E-mail: mmalonso{at}mdanderson.org.

Currently, the most efficacious treatment for malignant gliomas is temozolomide; however, gliomas expressing the DNA repair enzyme O⁶-methylguanine-DNA methyltransferase (MGMT) are resistant to this drug. Strong clinical evidence shows that gliomas with methylation and subsequent silencing of the MGMT promoter are sensitive to temozolomide. Based on the fact that adenoviral proteins directly target and inactivate key DNA repair genes, we hypothesized that the oncolytic adenovirus -24-RGD could be successfully combined with temozolomide to overcome the reported MGMT-mediated resistance. Our studies showed that the combination of -24-RGD and temozolomide induces a profound therapeutic synergy in glioma cells. We observed that -24-RGD treatment overrides the temozolomide-mediated G₂-M arrest. Furthermore, -24-RGD infection was followed by down-modulation of the RNA levels of MGMT. Chromatin immunoprecipitation assays showed that -24-RGD prevented the recruitment of p300 to the MGMT promoter. Importantly, using mutant adenoviruses and wild-type and dominant-negative forms of the p300 protein, we showed that -24-RGD interaction with p300 was required to induce silencing of the MGMT gene. Of further clinical relevance, the combination of -24-RGD and temozolomide significantly improved the survival of glioma-bearing mice. Collectively, our data provide a strong mechanistic rationale for the combination of oncolytic adenoviruses and temozolomide, and should propel the clinical testing of this therapy approach in patients with malignant gliomas. [Cancer Res 2007;67(24):11499–504]