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Given the central role of DNA as radiobiological target, the design of radioprotectors which bind to DNA is an obvious strategy, however neither of the DNA binding radioprotectors discussed in this paper arose from such a deliberate design plan. WR1065 and amifostine emerged from an empirical drug development program, and the association between radioprotective efficacy and DNA binding only became evident in retrospect. In the case of methylproamine, derived from a minor groove DNA binding ligand developed for an entirely different purpose, and found to have a serendipitous radioprotective activity, incorporation electron-rich substituents has improved radioprotective activity compared to Hoechst 33342. No doubt this rational thread might be followed more explicitly in the design of future radioprotectors, but it remains to be seen whether it is possible to design DNA-binding radioprotectors that are devoid of any toxicity derived from the DNA-binding

This work was supported by licensing agreement between Sirtex Medical Inc and Peter MacCallum Cancer Centre and by the Intramural Research Program of the National Cancer

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**23** 

*USA* 

**DNA Damage Response and Repair: Insights** 

**into Strategies for Radiation Sensitization** 

Joshua D. Lawson1, Kristopher T. Kahle2, Kimberly Ng3,

*2Department of Neurosurgery, Massachusetts General Hospital and* 

*3Department of Radiation Oncology, Division of Genomic Stability and* 

*4Center for Theoretical and Applied Neuro-Oncology, Moores Cancer Center,* 

Glioblastoma is the most common form of primary brain tumors 1. About 10,000 new patients each year in the US are diagnosed with GBM. Despite its comparatively low incidence of about 2-3 new cases per 100,000 people per year (for comparison, the incidence of colon cancer in the US is approximately 1 new case per 1,800 people per year), the total number of deaths per year attributable to glioblastoma rivals that of other major cancers. This disparity reflects the lethal nature of the disease. If untreated, patients with glioblastoma generally die within 3 months of their diagnosis 2. Diffuse invasion into the surrounding normal cerebral parenchyma is a cardinal feature of glioblastoma, preventing surgical cure. In this context, it is not surprising that surgical resection alone does not significantly prolong patient survival 2. When maximal surgical resection is combined with radiation and the chemotherapeutic agent, temozolomide, the median survival of patients improved to 14.6 months 3. While this regimen achieves an approximate 10% five-year progression free survival 4, the majority of the afflicted patients succumb to the disease

within a year of diagnosis. Effective therapeutic strategies are desperately needed.

Despite the abundance of strategies and agents that have been tested over the last halfcentury for the treatment of GBM, the single most efficacious modality and significant advance has been the use of post-resection radiation therapy. In 1966, the Montreal Neurology Institute published the first large case series that suggested a survival advantage in patients who received an average total post-resection IR dose of 5,000–6,000 cGy 5. Over the next decade, other case series corroborated those data, suggesting an improvement in patient survival with post-resection IR 6-9. Although interpretation of these case series is

**1. Introduction** 

Bob Carter4, Santosh Kesari5 and Clark C. Chen3 *1Department of Radiation Oncology, Moores Cancer Center,* 

*DNA Repair, Dana-Farber Cancer Institute, Boston, MA* 

*University of California, San Diego, La Jolla, CA* 

*University of California, San Diego, La Jolla, CA 5Department of Neurosciences, Moores Cancer Center, University of California, San Diego, La Jolla, CA* 

*Harvard Medical School, Boston, MA* 

