N‐methylnitrosourea–induced carcinoma as a model for laryngeal carcinogenesis

Caicedo-Granados, Emiro; Galbraith, Arthur R.; Schachern, Monika G.; Hartle, Donna E.; Wattenberg, Lee W.; Wuertz, Beverly R.; Keel, Suzanne B.; Yueh, Bevan; Ondrey, Frank G.

doi:10.1002/hed.23536

Cited by 5 publications

(8 citation statements)

References 20 publications

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“…Six‐week‐old female Jackson A/J mice (Jackson Laboratory, Bar Harbor, ME) were fed D‐62 powdered Wattenberg diet, 2 g/mouse/day 95 and allowed to acclimate for 1 week upon arrival prior to experiments. In accord with previously established methods for modeling aerodigestive tract damage attributed to GERD and LPR, 1,95–99 mechanical injury applied during the first 2 weeks of a four‐week treatment course was used to predispose the laryngeal mucosa to chemical injury by pepsin/acid applied throughout the 4 weeks. When performed in this manner, mechanical injury increases mucosal susceptibility to subsequent chemical injury while leaving little detectable injury at the conclusion of a four‐week treatment course 95 .…”

Section: Methodsmentioning

confidence: 99%

“…In accord with previously established methods for modeling aerodigestive tract damage attributed to GERD and LPR, 1,95–99 mechanical injury applied during the first 2 weeks of a four‐week treatment course was used to predispose the laryngeal mucosa to chemical injury by pepsin/acid applied throughout the 4 weeks. When performed in this manner, mechanical injury increases mucosal susceptibility to subsequent chemical injury while leaving little detectable injury at the conclusion of a four‐week treatment course 95 . Mechanical injury was performed on all animals (including control) once weekly during the first 2 weeks of treatment as described (see experimental schema, Fig.…”

Section: Methodsmentioning

confidence: 99%

“…When performed in this manner, mechanical injury increases mucosal susceptibility to subsequent chemical injury while leaving little detectable injury at the conclusion of a four-week treatment course. 95 Mechanical injury was performed on all animals (including control) once weekly during the first 2 weeks of treatment as described (see experimental schema, Fig. 1).…”

Section: In Vivo Mouse Modelmentioning

confidence: 99%

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Oral and Inhaled Fosamprenavir Reverses Pepsin‐Induced Damage in a Laryngopharyngeal Reflux Mouse Model

et al. 2022

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Objective More than 20% of the US population suffers from laryngopharyngeal reflux. Although dietary/lifestyle modifications and alginates provide benefit to some, there is no gold standard medical therapy. Increasing evidence suggests that pepsin is partly, if not wholly, responsible for damage and inflammation caused by laryngopharyngeal reflux. A treatment specifically targeting pepsin would be amenable to local, inhaled delivery, and could prove effective for endoscopic signs and symptoms associated with nonacid reflux. The aim herein was to identify small molecule inhibitors of pepsin and test their efficacy to prevent pepsin‐mediated laryngeal damage in vivo. Methods Drug and pepsin binding and inhibition were screened by high‐throughput assays and crystallography. A mouse model of laryngopharyngeal reflux (mechanical laryngeal injury once weekly for 2 weeks and pH 7 solvent/pepsin instillation 3 days/week for 4 weeks) was provided inhibitor by gavage or aerosol (fosamprenavir or darunavir; 5 days/week for 4 weeks; n = 3). Larynges were collected for histopathologic analysis. Results HIV protease inhibitors amprenavir, ritonavir, saquinavir, and darunavir bound and inhibited pepsin with IC50 in the low micromolar range. Gavage and aerosol fosamprenavir prevented pepsin‐mediated laryngeal damage (i.e., reactive epithelia, increased intraepithelial inflammatory cells, and cell apoptosis). Darunavir gavage elicited mild reactivity and no discernable protection; aerosol protected against apoptosis. Conclusions Fosamprenavir and darunavir, FDA‐approved therapies for HIV/AIDS, bind and inhibit pepsin, abrogating pepsin‐mediated laryngeal damage in a laryngopharyngeal reflux mouse model. These drugs target a foreign virus, making them ideal to repurpose. Reformulation for local inhaled delivery could further improve outcomes and limit side effects. Level of evidence NA. Laryngoscope, 133:S1–S11, 2023

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: In Vivo Mouse Modelmentioning

confidence: 99%

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Oral and Inhaled Fosamprenavir Reverses Pepsin‐Induced Damage in a Laryngopharyngeal Reflux Mouse Model

et al. 2022

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“…Ondrey's group developed both hamster and mouse models of laryngeal carcinogenesis with direct laryngoscopy techniques. Both can be used to study carcinogenesis, inflammation, and proximal airway cancer chemoprevention …”

Section: Rodent Models To Investigate Laryngeal Carcinogenesismentioning

confidence: 99%

“…Both can be used to study carcinogenesis, inflammation, and proximal airway cancer chemoprevention. [38][39][40] Clinical relevance of regional agent delivery techniques for inflammation and carcinogenesis…”

Section: Rodent Models To Investigate Laryngeal Carcinogenesismentioning

confidence: 99%

Airway reflux

Johnston

Ondrey

Rosen

et al. 2016

Annals of the New York Academy of Sciences

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An ever-increasing number of adult and pediatric disorders have been shown to be influenced or caused by airway reflux. This has become a controversial and complicated aspect of medicine that requires a multidisciplinary approach. Evidence indicates that it is not only the acidic components of gastric refluxate that injure extraesophageal tissues but also the nonacidic components, such as pepsin and bile. There is a realization that proton pump inhibitors will not be effective when nonacidic components of refluxate are causing the problem. New in vitro and in vivo models for the study of airway reflux and new therapeutic and surgical approaches are discussed in this review article.

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Inhaled fosamprenavir for laryngopharyngeal reflux: Toxicology and fluid dynamics modeling

Lesnick,

Samuels,

Seabloom

et al. 2024

Laryngoscope Investig Oto

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ObjectivesApproximately 25% of Americans suffer from laryngopharyngeal reflux (LPR), a disease for which no effective medical therapy exists. Pepsin is a predominant source of damage during LPR and a key therapeutic target. Fosamprenavir (FOS) inhibits pepsin and prevents damage in an LPR mouse model. Inhaled FOS protects at a lower dose than oral; however, the safety of inhaled FOS is unknown and there are no inhalers for laryngopharyngeal delivery. A pre‐Good Lab Practice (GLP) study of inhaled FOS was performed to assess safety and computational fluid dynamics (CFD) modeling used to predict the optimal particle size for a laryngopharyngeal dry powder inhaler (DPI).MethodsAerosolized FOS, amprenavir (APR), or air (control) were provided 5 days/week for 4 weeks (n = 6) in an LPR mouse model. Organs (nasal cavity, larynx, esophagus, trachea, lung, liver, heart, and kidney) were assessed by a pathologist and bronchoalveolar lavage cytokines and plasma cardiotoxicity markers were assessed by Luminex assay. CFD simulations were conducted in a model of a healthy 49‐year‐old female.ResultsNo significant increase was observed in histologic lesions, cytokines, or cardiotoxicity markers in FOS or APR groups relative to the control. CFD predicted that laryngopharyngeal deposition was maximized with aerodynamic diameters of 8.1–11.5 μm for inhalation rates of 30–60 L/min.ConclusionsA 4‐week pre‐GLP study supports the safety of inhaled FOS. A formal GLP assessment is underway to support a phase I clinical trial of an FOS DPI for LPR.Level of EvidenceNA.

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N‐methylnitrosourea–induced carcinoma as a model for laryngeal carcinogenesis

Cited by 5 publications

References 20 publications

Oral and Inhaled Fosamprenavir Reverses Pepsin‐Induced Damage in a Laryngopharyngeal Reflux Mouse Model

Oral and Inhaled Fosamprenavir Reverses Pepsin‐Induced Damage in a Laryngopharyngeal Reflux Mouse Model

Airway reflux

Inhaled fosamprenavir for laryngopharyngeal reflux: Toxicology and fluid dynamics modeling

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