Experimental and Clinical Therapeutics

Monday, October 17, 2005 3:00 PM-5:00 PM Exhibit Hall

(PP110) Development of enhancers of thermal radiosensitization.

Freeman, Michael *,1, Sekhar, Konjeti1, Rogers, Buck2, Crooks, Peter3, Xu, Mai2, Moros, Eduardo2, Roti Roti, Joseph2, 1 Vanderbilt University, Nashville, TN, United States2 Washington University School of Medicine, St. Louis, MO, United States3 University of Kentucky, Lexington, KY, United States

ABSTRACT- Purpose/Objective: The objective of this investigation was to develop enhancers of thermal radiosensitization. Effective radiation sensitizers should differentially sensitize tumor cells following administration of clinically relevant doses without causing significant cytotoxicity by themselves. Mechanisms of action include increased formation of frank DNA damage, inhibition of DNA repair, and/or altering apoptotic signaling. Heat shock is an example of an effective radiation sensitizer, increasing sensitivity to low LET irradiation by factors of 2 to 3. While the mechanism by which heat shock sensitizes involves inhibition of DNA repair, it is not well understood. Furthermore, the problems associated with clinical application of hyperthermia are well documented. Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit radiation-mediated anti-apoptotic signaling. NSAIDs also active NADPH oxidase, generating significant oxidative stress. Heat shock-mediated damage is augmented by oxidative stress. Thus, in cell culture models NSAIDs are potent enhancers of thermal radiosensitization and may be used as a basis for enhancer development. Materials/Methods: To extend the cell culture models to mouse models, mice were implanted with HT29 xenographic flank tumors and administered indomethacin by oral gavage followed by a 42 C/1hr heat shock and 4 Gy of X-rays. Survival of HT29 tumor cells was determined using an in vivo/in vitro assay. Novel indole analogs were synthesized based on indomethacin structure/activity profiles. Cell survival curves were used to measure analog enhancer activity. SiRNA approaches were used to test mechanistic pathways. Results: By itself, a 42 C heat shock did not affect HT29 tumor response. Addition of indomethacin to the heat shock increased radiation-mediated cell death by a factor of 3 compared to irradiation alone or heat shock plus irradiation. These results support a proof of principle. The indole analogs did not inhibit COX-2 activity nor were they cytotoxic by themselves when tested in cell culture models. The indole analogs significantly enhanced thermal radiation sensitization of HT29 cells produced by a 41 C/1 hr heat shock, which by itself did not affect radio-sensitization. Radiation sensitization was found to be associated with de-localization of MRE11, as determined by siRNA experimentation. Conclusions: Potentially, the indole analogs may be used to produce significant thermal radiosensitizion from clinically feasible hyperthermic treatments.

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2005 RRS