Abstract 676: Dinitroazetidines are a novel class of anticancer agents and hypoxia-activated radiation sensitizers developed from highly energetic materials

Abstract

Abstract Here we report the first biologic studies of a unique class of potentially clinically useful compounds, derived from highly energetic materials. In an effort to develop unique targeted cancer therapies which maximize cytotoxicity to cancer cells while minimizing unwanted side effects to normal tissue, we have studied a series of novel, non-explosive compounds, based on the highly energetic dinitroazetidine scaffold. ABDNAZ, 1-acetylbromo-3,3-dinitroazetidine is a lead compound for clinical development both as a stand-alone chemotherapeutic drug and as a radiation sensitizer. In vitro studies demonstrated that ABDNAZ generated reactive oxygen species (ROS) in a concentration- and time-dependent manner. Modulation of intracellular redox status by buthionine-(S,R)-sulfoxime or N-acetylcysteine significantly affected ABDNAZ-induced apoptosis of tumor cells. ABDNAZ administered as a single agent was as cytotoxic to tumor cells as cisplatin with IC50s of 2.6 ± 1.6uM and 4.4 ± 2.2uM for ABDNAZ and cisplatin, respectively. ABDNAZ was more cytotoxic to tumor cells than cisplatin or tirapazamine under hypoxic conditions. ABDNAZ and cisplatin had similar effects on well established SCC VII tumors in mice, but unlike cisplatin, ABDNAZ at well-tolerated sub-maximum tolerated doses (MTD) significantly inhibited tumor growth without systemic toxicity. When combined with local tumor radiation therapy, ABDNAZ significantly enhanced the efficacy of the radiation and improved the therapeutic index of radiation therapy. Toxicity studies demonstrated that ABDNAZ was not myelosuppressive and had no apparent dose limiting toxicity when administered at sub-MTD dose daily for 14 days. These data demonstrate that ABDNAZ is a promising novel anticancer drug with a very favorable toxicity profile at therapeutic doses with activity in preclinical tumor models as both a stand-alone chemotherapeutic agent and as a radiosensitizer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 676. doi:10.1158/1538-7445.AM2011-676