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Novel Chemical Enhancers of Heat Shock Increase Thermal Radiosensitization through a Mitotic Catastrophe Pathway

¹ Department of Radiation Oncology/Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee; ² Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky; ³ Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri; ⁴ Princess Margaret Hospital (University Health Network) and Departments of Radiation Oncology and Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; and ⁵ Department of Radiology, University of Arkansas for Medical Sciences, Little Rock, Arkansas

Requests for reprints: Michael L. Freeman, Department of Radiation Oncology, Vanderbilt School of Medicine, B 902 TVC, Nashville, TN 37232. Phone: 615-322-3606; Fax: 615-343-3061; E-mail: michael.freeman{at}vanderbilt.edu.

Radiation therapy combined with adjuvant hyperthermia has the potential to provide outstanding local-regional control for refractory disease. However, achieving therapeutic thermal dose can be problematic. In the current investigation, we used a chemistry-driven approach with the goal of designing and synthesizing novel small molecules that could function as thermal radiosensitizers. (Z)-(±)-2-(1-Benzenesulfonylindol-3-ylmethylene)-1-azabicyclo[2.2.2]octan-3-ol was identified as a compound that could lower the threshold for Hsf1 activation and thermal sensitivity. Enhanced thermal sensitivity was associated with significant thermal radiosensitization. We established the structural requirements for activity: the presence of an N-benzenesulfonylindole or N-benzylindole moiety linked at the indolic 3-position to a 2-(1-azabicyclo[2.2.2]octan-3-ol) or 2-(1-azabicyclo[2.2.2]octan-3-one) moiety. These small molecules functioned by exploiting the underlying biophysical events responsible for thermal sensitization. Thermal radiosensitization was characterized biochemically and found to include loss of mitochondrial membrane potential, followed by mitotic catastrophe. These studies identified a novel series of small molecules that represent a promising tool for the treatment of recurrent tumors by ionizing radiation. [Cancer Res 2007;67(2):695–701]

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