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-ofconcept for ABDNAZ as a promising new anticancer agent with a favorable toxicity profile, either as a chemotherapeutic agent or a radiosensitizer. Cancer Res; 72(10); 2600-8. Ó2012 AACR.

RRx-001: a systemically non-toxic M2-to-M1 macrophage stimulating and prosensitizing agent in Phase II clinical trials

“…RRx-001-treated U87 xenograft (glioma) specimens analyzed immunohistochemically with anti-CD-31, a marker for vasculature, overexpressed in the neovascular tumor bed, and a fluorescent carbocyanine dye, DiOC7, that stains cells immediately adjacent to blood vessels and, thus, outlines perfused tumor vasculature, demonstrated increased vessel perfusion [29]. In a separate study of syngeneic SCCVII tumors, quantitative measurements of the flow of an ultrasound microbubble contrast agent demonstrated a significant enhancement of tumor perfusion following treatment with three different doses (3, 6, 12 mg/kg) of RRx-001 compared to control mice, reaching a peak at 6 h after treatment, and returning to baseline within 72 h [1].…”

“…Multiple lines of evidence indicate that metabolites of RRx-001 cross the blood-brain barrier: (1) in an ADME study with 14 C-labeled RRx-001, radioactivity was detected in the CNS [8]; (2) in an ongoing Phase I/II trial acronymed BRAINSTORM, a significant reduction in the Dynamic contrast-enhancedmagnetic resonance imaging (DCE-MRI)-derived volume transfer constant, K trans , has been demonstrated in multiple patients after one dose of single agent RRx-001, indicative of reduced vascular permeability; and (3) the combination of RRx-001 with artemisinin, in an experimental cerebral malaria model, synergistically decreased animal mortality, neurocognitive sequelae, cerebral vascular changes, and inflammatory cell accumulation in brain microvessels [10].…”

“…In addition to radiosensitization, RRx-001 demonstrated potent anticancer activity as a single agent [1]; significant cytotoxic enhancement was also present in combination with standard chemotherapy and immunotherapy through depletion of cancer stem cells (CSCs) and activation of p53 and Nrf2 pathways [1][2][3]. Moreover, RRx-001 has shown evidence of in vivo radio-and chemoprotection; in fact, the Armed Forces Radiobiology Research Institute is currently researching RRx-001 as a radioprotectant in case of a nuclear emergency.…”

Preclinical Evaluation of the Metabolism and Disposition of RRx-001, a Novel Investigative Anticancer Agent

“…RRx-001, a novel, nonexplosive molecule modified from a class of solid rocket propellants, has shown promise as a novel cancer therapeutic agent in a number of cell lines and tumor models (Bednarski et al, 2009;Ning et al, 2012). In mouse models, RRx-001 administered intravenously as a single agent was equipotent to cisplatin while better tolerated.…”

“…In mouse models, RRx-001 administered intravenously as a single agent was equipotent to cisplatin while better tolerated. RRx-001 also showed activity as a radiosensitizer in both in vitro and in vivo models (Ning et al, 2012). The activity of RRx-001 is thought to be associated with a nucleophilic substitution by circulating thiol compounds and covalent binding of RRx-001 to cysteinyl residues in Hb, followed by the generation of nitrogen oxides.…”