773
Views
40
CrossRef citations to date
0
Altmetric
Drug Evaluation

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

, , , , , , , , , , , , , , , , , , , & show all
Pages 109-119 | Received 17 Aug 2016, Accepted 01 Dec 2016, Published online: 21 Dec 2016

References

  • Ning S, Bednarski M, Oronsky B, et al. Dinitroazetidines are a novel class of anticancer agents and hypoxia-activated radiation sensitizers developed from highly energetic materials. Cancer Res. 2012;72:2600–2608.
  • Ning S, Sekar TV, Scicinski J, et al. Nrf2 activity as a potential biomarker for the pan-epigenetic anticancer agent, RRx-001. Oncotarget. 2015;6:21547–21556.
  • Scicinski J, Oronsky B, Ning S, et al. NO to cancer: the complex and multifaceted role of nitric oxide and the epigenetic nitric oxide donor, RRx-001. Redox Biol. 2015;6:1–8.
  • Reid T, Oronsky B, Scicinski J, et al. Safety and activity of RRx-001 in patients with advanced cancer: a first-in-human, open-label, dose-escalation phase 1 study. Lancet Oncol. 2015;16:1133–1142.
  • Wilcox C, Zhang Y-X, Bauer S. The thermochemistry of TNAZ (1,3,3-trinitroazetidine) and related species: models for calculating heats of formation. J Mol Struct (Theochem). 2000;528:95–109.
  • Straessler NA, Lesley MW, Cannizzo LF. Development of a safe and efficient two-step synthesis for preparing 1-bromoacetyl-3,3-dinitroazetidine, a novel clinical anticancer candidate. Org Process Res Dev. 2012;16:512–517.
  • Oronsky BT, Reid T, Knox SJ, et al. The scarlet letter of alkylation: a mini review of selective alkylating agents. Transl Oncol. 2012;5:226–229.
  • Scicinski J, Oronsky B, Taylor M, et al. Preclinical evaluation of the metabolism and disposition of RRx-001, a novel investigative anticancer agent. Drug Metab Dispos. 2012;40:1810–1816.
  • Scicinski J, Oronsky B, Ning S, et al. Discovery and development of RRx-001, a novel nitric oxide and ROS mediated epigenetic modulator. In: Bonavida B, editor. Nitric oxide and cancer: pathogenesis and therapy. Springer; 2015.
  • Yalcin O, Oronsky B, Carvalho LJ, et al. From METS to malaria: RRx-001, a multi-faceted anticancer agent with activity in cerebral malaria. Malar J. 2015;14:218.
  • Fens MHAM, Larkin SK, Morris CR, et al. NO or no NO, increased reduction of nitrite to nitric oxide by modified red blood cells. ASH Annu Meet Abstr. 2011;118:2125.
  • Brouse C, Ortiz D, Su Y, et al. Impact of hemoglobin nitrite to nitric oxide reductase on blood transfusion for resuscitation from hemorrhagic shock. Asian J Transfus Sci. 2015;9:55–60.
  • Fens MH, Larkin SK, Oronsky B, et al. The capacity of red blood cells to reduce nitrite determines nitric oxide generation under hypoxic conditions. Plos One. 2014;9:e101626.
  • Scicinski J, Oronsky B, Cooper V, et al. Development of methods for the bioanalysis of RRx-001 and metabolites. Bioanalysis. 2014;6:947–956.
  • Reid T, Oronsky B, Infante J, et al. A phase 1 trial and pharmacokinetic study of RRx-001, a novel ROS-mediated pan-epigenetic agent. J Clin Oncol. 2014;32(suppl):abstr 2578.
  • Ostuni R, Kratochvill F, Murray PJ, et al. Macrophages and cancer: from mechanisms to therapeutic implications. Trends Immunol. 2015;36:1–11.
  • Reid T, Dad S, Korn R, et al. Two case reports of resensitization to previous chemotherapy with the novel hypoxia-activated hypomethylating anticancer agent RRx-001 in metastatic colorectal cancer patients. Case Rep Oncol. 2014;7:79–85.
  • Cabrales P, Oronsky B, Scicinski J. Abstract 1420: rRx-001 inhibits glucose erythrocyte and tumor glucose 6-phosphate dehydrogenase. Cancer Res. 2014;74:1420.
  • Cabrales P, Reid T, Oronsky B, et al. RRx-001 an EXO-based epigenetic anti-cancer agent in phase 2 clinical trials. ISEV2014 Educational Event; 2014; San Diego (CA).
  • Fens MH, van Wijk R, Andringa G, et al. A role for activated endothelial cells in red blood cell clearance: implications for vasopathology. Haematologica. 2012;97:500–508.
  • Oronsky B, Oronsky N, Knox S, et al. Episensitization: therapeutic tumor resensitization by epigenetic agents: a review and reassessment. Anticancer Agents Med Chem. 2014;14:1121–1127.
  • Das DS, Ray A, Das A, et al. A novel hypoxia-selective epigenetic agent RRx-001 triggers apoptosis and overcomes drug resistance in multiple myeloma cells. Leukemia. 2016;30:2187–2197.
  • Raghunand N, Scicinski J, Oronsky B, et al. RRx-001 oxidation of redox sensitive protein thiols in tumors measured by Gd-LC7-SH enhanced MRI in preclinical tumor models. Proceedings: AACR 105th Annual Meeting 2014; 2014 Apr 5–9; San Diego (CA), Abstract 2068.
  • Schulze A, Harris A. How cancer metabolism is tuned for proliferation and vulnerable to disruption. Nature. 2012;491:364–373.
  • van der Vliet A, Eiserich JP, Cross CE. Nitric oxide: a pro-inflammatory mediator in lung disease? Respir Res. 2000;1:67–72.
  • Wang J-Y, Wen L-L, Huang Y-N, et al. Dual effects of antioxidants in neurodegeneration: direct neuroprotection against oxidative stress and indirect protection via suppression of glia-mediated inflammation. Curr Pharm Des. 2006;12:3521–3533.
  • Meng Z, Yan C, Deng Q, et al. Oxidized low-density lipoprotein induces inflammatory responses in cultured human mast cells via Toll-like receptor 4. Cell Physiol Biochem. 2013;31:842–853.
  • Setty BN, Betal SG. Microvascular endothelial cells express a phosphatidylserine receptor: a functionally active receptor for phosphatidylserine-positive erythrocytes. Blood. 2008;111:905–914.
  • Scicinski J, Oronsky B, Ning S, et al. Abstract 4371: rRx-001 modulates intratumor blood flow in SCCVII and U87 tumors. Cancer Res. 2012;72:4371.
  • Zhao H, Ning S, Scicinski J, et al. Abstract 3515: rRx-001: a double action systemically non-toxic epigenetic agent for cancer therapy. Cancer Res. 2015;75:3515.
  • Das DS, Tian Z, Ray A, et al. Anti-myeloma activity of a novel free radical inducer Rrx-001. Blood. 2014;124:4712.
  • Carter C, Reid T, Fisher G, et al. O3.8 early results: “ROCKET” a phase II study of RRx-001, a novel triple epigenetic inhibitor, resensitization to irinotecan in colorectal cancer. Ann Oncol. 2015;26:ii4–ii5.
  • Swinney DC, Anthony J. How were new medicines discovered? Nat Rev Drug Discov. 2011;10:507–519.
  • Dy GK, Adjei AA. Understanding, recognizing, and managing toxicities of targeted anticancer therapies. CA Cancer J Clin. 2013;63:249–279.
  • Barouch-Bentov R, Sauer K. Mechanisms of drug resistance in kinases. Expert Opin Investig Drugs. 2011;20:153–208.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.