title: NO to cancer: The complex and multifaceted role of nitric oxide and the epigenetic nitric oxide donor, RRx-001.
abstract: The endogenous mediator of vasodilation, nitric oxide (NO), has been shown to be a potent radiosensitizer. However, the underlying mode of action for its role as a radiosensitizer - while not entirely understood - is believed to arise from increased tumor blood flow, effects on cellular respiration, on cell signaling, and on the production of reactive oxygen and nitrogen species (RONS), that can act as radiosensitizers in their own right. NO activity is surprisingly long-lived and more potent in comparison to oxygen. Reports of the effects of NO with radiation have often been contradictory leading to confusion about the true radiosensitizing nature of NO. Whether increasing or decreasing tumor blood flow, acting as radiosensitizer or radioprotector, the effects of NO have been controversial. Key to understanding the role of NO as a radiosensitizer is to recognize the importance of biological context. With a very short half-life and potent activity, the local effects of NO need to be carefully considered and understood when using NO as a radiosensitizer. The systemic effects of NO donors can cause extensive side effects, and also affect the local tumor microenvironment, both directly and indirectly. To minimize systemic effects and maximize effects on tumors, agents that deliver NO on demand selectively to tumors using hypoxia as a trigger may be of greater interest as radiosensitizers. Herein we discuss the multiple effects of NO and focus on the clinical molecule RRx-001, a hypoxia-activated NO donor currently being investigated as a radiosensitizer in the clinic.
authors.affiliation: EpicentRx, Inc., 800 W El Camino Real, Suite 180, Mountain View, CA 94040, United States. Electronic address: jscicinski@epicentrx.com.
authors.forename: Jan
authors.initials: J
authors.lastname: Scicinski
authors.affiliation: EpicentRx, Inc., 800 W El Camino Real, Suite 180, Mountain View, CA 94040, United States.
authors.forename: Bryan
authors.initials: B
authors.lastname: Oronsky
authors.affiliation: Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, United States.
authors.forename: Shoucheng
authors.initials: S
authors.lastname: Ning
authors.affiliation: Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, United States.
authors.forename: Susan
authors.initials: S
authors.lastname: Knox
authors.affiliation: Department of Urology, Stanford University, Stanford, CA, United States.
authors.forename: Donna
authors.initials: D
authors.lastname: Peehl
authors.affiliation: University of Michigan, Radiation Oncology, Ann Arbor, MI, United States.
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Kim
authors.affiliation: Los Gatos Pharmaceuticals, Los Gatos, CA, United States.
authors.forename: Peter
authors.initials: P
authors.lastname: Langecker
authors.affiliation: EpicentRx, Inc., 800 W El Camino Real, Suite 180, Mountain View, CA 94040, United States.
authors.forename: Gary
authors.initials: G
authors.lastname: Fanger
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001384:Azetidines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D044127:Epigenesis, Genetic; D005720:Gamma Rays / Q000627:therapeutic use; D006454:Hemoglobins / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D051379:Mice; D008958:Models, Molecular; D009369:Neoplasms / Q000098:blood supply / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D009569:Nitric Oxide / Q000378:metabolism / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D009574:Nitro Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism; D011485:Protein Binding; D011838:Radiation-Sensitizing Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D001384:Azetidines; D006454:Hemoglobins; D020030:Nitric Oxide Donors; D009574:Nitro Compounds; C577469:RRx-001; D011838:Radiation-Sensitizing Agents; D009569:Nitric Oxide; C100003:deoxyhemoglobin; D052247:Nitric Oxide Synthase Type II; D010100:Oxygen
keywords: Cancer; Hypoxia; Nitric oxide; Radiosensitization; Radiotherapy