title: Dinitroazetidines are a novel class of anticancer agents and hypoxia-activated radiation sensitizers developed from highly energetic materials.
abstract: In an effort to develop cancer therapies that maximize cytotoxicity, while minimizing unwanted side effects, we studied a series of novel compounds based on the highly energetic heterocyclic scaffold, dinitroazetidine. In this study, we report the preclinical validation of 1-bromoacetyl-3,3-dinitroazetidine (ABDNAZ), a representative lead compound currently in a phase I clinical trial in patients with cancer. In tumor cell culture, ABDNAZ generated reactive free radicals in a concentration- and time-dependent manner, modulating intracellular redox status and triggering apoptosis. When administered to mice as a single agent, ABDNAZ exhibited greater cytotoxicity than cisplatin or tirapazamine under hypoxic conditions. However, compared with cisplatin, ABDNAZ was better tolerated at submaximal doses, yielding significant tumor growth inhibition in the absence of systemic toxicity. Similarly, when combined with radiation, ABDNAZ accentuated antitumor efficacy along with the therapeutic index. Toxicity studies indicated that ABDNAZ was not myelosuppressive and no dose-limiting toxicity was apparent following daily administration for 14 days. Taken together, our findings offer preclinical proof-of-concept for ABDNAZ as a promising new anticancer agent with a favorable toxicity profile, either as a chemotherapeutic agent or a radiosensitizer.
authors.affiliation: Department of Radiation Oncology, Stanford University Medical Center, Stanford, CA 94305, USA.
authors.forename: Shoucheng
authors.initials: S
authors.lastname: Ning
authors.forename: Mark
authors.initials: M
authors.lastname: Bednarski
authors.forename: Bryan
authors.initials: B
authors.lastname: Oronsky
authors.forename: Jan
authors.initials: J
authors.lastname: Scicinski
authors.forename: Gordon
authors.initials: G
authors.lastname: Saul
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Knox
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001384:Azetidines / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000378:metabolism; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005609:Free Radicals / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D009369:Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D009574:Nitro Compounds / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*
chemical_list: C573948:1-bromoacetyl-3,3-dinitroazetidine; D000970:Antineoplastic Agents; D001384:Azetidines; D005609:Free Radicals; D009574:Nitro Compounds; D011838:Radiation-Sensitizing Agents