title: Chemoprevention by N-acetylcysteine of low-dose CT-induced murine lung tumorigenesis.
abstract: Data from the National Lung Screening Trial suggested that annual computed tomography (CT) screening of at-risk patients decreases lung cancer mortality by 20%. We assessed the effects of low-dose CT radiation in mice exposed to 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone (NNK) to mimic the effects of annual CT screening in heavy smokers and ex-smokers. A/J mice were treated at 8 weeks with NNK followed 1 week later by 4 weekly doses of 0, 10, 30 or 50 mGy of whole-body CT and euthanized 8 months later. Irradiated mice exhibited significant 1.8- to 2-fold increases in tumor multiplicity in males (16.1 ± 0.8 versus 9.1 ± 1.5 tumors per mouse; P < 0.0001) and females (21.6 ± 0.8 versus 10.5 ± 1.4 tumors per mouse; P < 0.0001), respectively, compared with unirradiated mice with no dose effect observed; female mice exhibited higher sensitivity to radiation exposure than did males (P < 0.0001). Similar results were obtained when tumor area was determined. To assess if the deleterious effects of radiation could be prevented by antioxidants, female mice were fed a diet containing 0.7% N-acetylcysteine (NAC) starting 3 days prior to the first CT exposure and continuing for a total of 5 weeks. NAC prevented CT induced increases in tumor multiplicity (10.5 ± 1.2 versus 20.7 ± 1.5 tumors per mouse; P < 0.0001) back to levels seen in NNK/unirradiated mice (10.5 ± 1.2). Our data suggest that exposure of sensitive populations to CT radiation increases the risk of tumorigenesis, and that antioxidants may prevent the long-term carcinogenic effects of low-dose radiation exposure. This would allow annual screening with CT while preventing the potential long-term toxicity of radiation exposure.
authors.affiliation: Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA. msmiller@wakehealth.edu
authors.forename: Mark Steven
authors.initials: MS
authors.lastname: Miller
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Moore
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Walb
authors.forename: Nancy D
authors.initials: ND
authors.lastname: Kock
authors.forename: Albert
authors.initials: A
authors.lastname: Attia
authors.forename: Scott
authors.initials: S
authors.lastname: Isom
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: McBride
authors.forename: Michael T
authors.initials: MT
authors.lastname: Munley
mesh_terms: D000111:Acetylcysteine / Q000627:therapeutic use*; D000818:Animals; D002273:Carcinogens / Q000633:toxicity; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000528:radiation effects; D005260:Female; D016166:Free Radical Scavengers / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000209:etiology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008805:Mice, Inbred A; D009381:Neoplasms, Radiation-Induced / Q000209:etiology / Q000517:prevention & control*; D009602:Nitrosamines / Q000633:toxicity; D014057:Tomography, X-Ray Computed / Q000009:adverse effects*
chemical_list: D002273:Carcinogens; D016166:Free Radical Scavengers; D009602:Nitrosamines; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D000111:Acetylcysteine