Abstract LB-166: Characterization of a novel class of carbazole based radiation sensitizers

Abstract

Abstract Technological advances in radiation therapy have greatly improved our ability to deliver a precise dose of radiation to a defined volumetric target with high accuracy. However, local recurrence of cancer, especially that in the previously irradiated area continues to be a significant cause of morbidity and mortality in patients who initially receive radiation therapy. It has been known for some time that certain agents, mostly chemotherapeutic drugs, are capable of enhancing the effects of radiation when given in conjunction with radiation therapy. Concurrent use of these agents (including cis-platinum and 5-fluorouracil, to name a few) with radiation has been shown to result in improved disease control in a wide variety of cancers. Even though these agents are highly beneficial to many patients who receive them, their use is often limited due to their inherent toxicities as well as their ability to enhance radiation induced normal tissue reactions. Previously, we have reported that quinacrine, an old antimalarial drug known to induce p53 activity and suppress NF-κB activity in cells, are capable of radiation sensitization in vitro. Since that time, we have been studying a group of compounds we named Curaxins for its radiation sensitizing qualities. Curaxins are carbazole compounds that were selected for their ability to induce p53 activity and reduce NF-κB activity in a variety of human cancer cell lines. These compounds are known to have much higher potency than quinacrine. Though they were originally developed as single-agent anticancer agents, our recent investigations have shown that many of these Curaxins are also very potent radiation sentizers in vitro and in vivo. We have recently completed a preliminary screen of our existing Curaxins for their ability to enhance cytotoxicity of ionizing radiation, utilizing B16 murine melanoma cell line as our model system. Clonogenic survival assays were peformed in presence of various doses of Curaxins ranging from 2 nM to 200 nM. Of twelve Curaxins screened for this purpose, nine were found to be very potent sensitizers at either 2 nM and/or 20 nM. We also studied the effect of two of the Curaxins for their radiosensitizing activities in vivo, using a B16 lung metastasis model in C57BL/6 mice. Combination of Curaxins to thoracic irradiation resulted in greater tumor control (indicated by reduced lung weight) and longer mean survival compred to irradiation alone or Curaxins alone. It is notable that in vitro radiosensitization by these two Curaxins occurs at concentrations not known to cause p53 induction in B16 cells, suggesting that this effect may not be entirely dependent on the p53 pathway. We are currently in the process of further characterizing the radiosensitizing qualities of the remaining seven radiosensitizing Curaxins both in vitro and in vivo. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-166.