Modification of the Radiation Response

My research is directed toward the discovery of ways to modify the radiation response of both normal and tumor tissue. Such modification can be important for the improvement of cancer treatment using ionizing radiation either by protecting normal tissues or enhancing the sensitivity of tumor. Further, identifying means to protect normal tissues, particularly against radiation-induced late effects such as carcinogenesis, is important for countermeasure considerations of large populations exposed to radiation or in patients at risk for second malignancies following successful radiotherapy.

With respect to enhancing the effects of radiation damage to tumors, a number of approaches are being evaluated including molecularly targeted agents and cytotoxic chemotherapeutic agents. The overall objective here is to obtain a therapeutic gain by providing selective radiosensitization in tumors as compared to normal tissues. Admittedly, this has been and continues to be a difficult goal to achieve. We are presently evaluating in human tumor cell lines and xenografts treated with inhibitors such as KRAS mutation inhibitors, vasculogenesis inhibitors, and OxpPhos inhibitors. Studies include the effects of the agent combined with radiation on cell survival, DNA damage repair, and cell cycle perturbations coupled with the effects of the combination on specific signal transduction pathways.

Our laboratory was first to identify nitroxides (lead compound Tempol) as catalytic antioxidants and radiation protectors providing protection against oxidative- and radiation-induced damage. Extensive pre-clinical studies are directed to normal tissue radioprotection using systemically or topically applied Tempol to protect against oral mucositis and salivary gland damage resulting from cisplatin-based chemoradiation in mice without interfering with tumor response. Studies are also directed to better define the mechanism of Tempol-mediated reduction in weight gain in mice. Preliminary findings indicate that chronic supplementation of Tempol in the diet of mice over their life span can reduce body weight without toxicity, decrease cancer, and extend survival when administered immediately after non-lethal total body radiation (TBI). Delaying administration of the Tempol diet 1 month after TBI also enhanced survival and decreased carcinogenesis, suggesting that there may be a considerable "progression" phase of TBI-induced cancer induction that is amenable to modification and/or intervention. We are also studying the effects of Tempol on mice gut microflora.

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