pulmicort and Precancerous-Conditions

Chronicles in Drug Discovery features special interest reports on advances in drug discovery and development. This month we focus on the progress of the ongoing search for safe and effective chemopreventive agents. Chemoprevention is a strategy to decrease the risk of developing cancer by using agents that prevent or abrogate carcinogenic processes. Bowman- Birk inhibitor concentrate, budesonide, NCX-4016 and statins are all undergoing investigation in the clinical setting as potential chemopreventive agents for head and neck, lung, colon and breast cancers, respectively.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Anticarcinogenic Agents; Aspirin; Budesonide; Cell Transformation, Neoplastic; Chemoprevention; Clinical Trials as Topic; Drug Evaluation, Preclinical; Glucocorticoids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Neoplasms; Precancerous Conditions; Trypsin Inhibitor, Bowman-Birk Soybean; Trypsin Inhibitors

Preclinical studies suggest that inhaled budesonide may be an effective chemopreventive agent for lung cancer. We conducted a phase IIb study to determine the effects of inhaled budesonide in smokers with bronchial dysplasia.. A total of 112 smokers with more than or equal to one site of bronchial dysplasia > 1.2 mm in size identified by autofluorescence bronchoscopy-directed biopsy was randomly assigned to receive placebo or budesonide (Pulmicort Turbuhaler) 800 microg twice daily inhalation for 6 months. The primary end point was change in the histopathologic grade on repeat biopsy of the same sites at the end of 6 months.. There were no significant differences in the regression or progression rates of bronchial dysplasia between the two groups. There was a statistically significant but modest decrease in p53 and BclII expression in the bronchial biopsies after 6 months of Pulmicort Turbuhaler versus placebo (P = 0.01 and P = 0.001, respectively). There was a small but statistically significant decrease in the proportion of computed tomography-detected lung nodules after Pulmicort Turbuhaler compared with placebo (P = 0.024).. Our results suggest that in smokers, inhaled budesonide in the dose of 1600 microg daily for 6 months had no effect in regression of bronchial dysplastic lesions or prevention of new lesions. Budesonide treatment resulted in a modest decrease in p53 and BclII protein expression in bronchial biopsies and a slightly higher rate of resolution of computed tomography-detected lung nodules. Whether budesonide truly has an effect in preneoplastic lesions in the peripheral airways and alveoli requires additional investigation.

Topics: Administration, Inhalation; Adult; Aged; Biopsy; Bronchi; Bronchodilator Agents; Budesonide; Cough; Double-Blind Method; Fatigue; Female; Headache; Humans; Immunohistochemistry; Ki-67 Antigen; Logistic Models; Male; Middle Aged; Pharynx; Precancerous Conditions; Proto-Oncogene Proteins c-bcl-2; Respiratory Mucosa; Treatment Outcome; Tumor Suppressor Protein p53

Complete endoscopic resection (CER) of short-segment Barrett's esophagus with high grade dysplasia (HGD) and early esophageal adenocarcinoma (EEA) is a precise staging tool and achieves durable disease control. The major drawback is development of post-endoscopic resection esophageal stricture (PERES). No effective therapy to prevent PERES has been described. Viscous budesonide slurry (VBS) may have a role in the prevention of PERES by suppressing the post-CER inflammatory process. The study aim was to evaluate the efficacy of VBS for the prevention of PERES.. Prospective data were collected on patients referred for CER of HGD or EEA. After January 2012, patients routinely received VBS (two 0.5-mg/2-mL budesonide respules mixed with sucralose) twice daily for 6 weeks following each stage of the CER schedule. All patients received high dose proton pump inhibitor therapy for the duration of CER and the following 3 months. Patients had no other intervention to prevent PERES. A validated dysphagia score was used (0 - 4, no dysphagia to aphagia). Endoscopic dilation was performed for dysphagia. Patients receiving VBS were compared with historical controls. The primary endpoint was the need for dilation.. Between January 2008 and January 2015, 104 of 116 eligible patients completed CER. The VBS group (n = 29) and non-VBS group (n = 75) had similar patient, disease, and procedural characteristics. Dilations were needed in 13.8 % vs. 37.3 % (P = 0.03), with a median of one vs. two procedures (P = 0.01), and median dysphagia score during CER of 0 vs. 1 (P = 0.02) in the VBS and non-VBS groups, respectively. No VBS-related adverse events were noted.. In this pilot study VBS significantly reduced PERES and shortened the dilation program after CER.

Topics: Adenocarcinoma; Adult; Aged; Anti-Inflammatory Agents; Barrett Esophagus; Budesonide; Drug Administration Schedule; Esophageal Neoplasms; Esophageal Stenosis; Esophagoscopy; Female; Follow-Up Studies; Humans; Male; Middle Aged; Pilot Projects; Postoperative Complications; Precancerous Conditions; Prospective Studies; Treatment Outcome; Viscosity

A previously carried out randomized phase IIb, placebo-controlled trial of 1 year of inhaled budesonide, which was nested in a lung cancer screening study, showed that non-solid and partially solid lung nodules detected by low-dose computed tomography (LDCT), and not immediately suspicious for lung cancer, tended to regress. Because some of these nodules may be slow-growing adenocarcinoma precursors, we evaluated long-term outcomes (after stopping the 1-year intervention) by annual LDCT.. We analyzed the evolution of target and non-target trial nodules detected by LDCT in the budesonide and placebo arms up to 5 years after randomization. The numbers and characteristics of lung cancers diagnosed during follow-up were also analyzed.. The mean maximum diameter of non-solid nodules reduced significantly (from 5.03 mm at baseline to 2.61 mm after 5 years) in the budesonide arm; there was no significant size change in the placebo arm. The mean diameter of partially solid lesions also decreased significantly, but only by 0.69 mm. The size of solid nodules did not change. Neither the number of new lesions nor the number of lung cancers differed in the two arms.. Inhaled budesonide given for 1 year significantly decreased the size of non-solid nodules detected by screening LDCT after 5 years. This is of potential importance since some of these nodules may progress slowly to adenocarcinoma. However, further studies are required to assess clinical implications.. NCT01540552.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Administration, Inhalation; Antineoplastic Agents; Budesonide; Clinical Trials, Phase II as Topic; Early Detection of Cancer; Humans; Lung Neoplasms; Multidetector Computed Tomography; Multiple Pulmonary Nodules; Precancerous Conditions; Predictive Value of Tests; Randomized Controlled Trials as Topic; Retrospective Studies; Risk Factors; Solitary Pulmonary Nodule; Time Factors; Treatment Outcome

Our discovery that the perinatal period involves nucleotide modifications and gene overexpression in mouse lung prompted us to evaluate whether mice may become more susceptible to cigarette smoke when exposure starts immediately after birth. We previously showed that mainstream cigarette smoke is a quite potent carcinogen in neonatal mice. Further on, we showed that exposure of mice to environmental cigarette smoke (ECS), starting at birth, results in alterations of a variety of intermediate biomarkers. However, after 4 months of exposure to ECS followed by 7 months of recovery in filtered air, the lung tumor yield was rather low. In the present study, we evaluated the protective effects of the glucocorticoid budesonide and of the dietary agent phenethyl isothiocyanate in mice exposed to ECS for 9 months followed by 2 months of recovery. After weanling, the mice exposed to ECS since birth underwent a variety of alterations of molecular and cytogenetical end points, and 11 months after birth, they exhibited significant histopathologic changes, such as pulmonary anthracosis, emphysema, hemorrhagic areas, alveolar bronchiolarization, bronchial hyperplasia, and tumors, both benign and malignant. The carcinogenic response was less evident in dams exposed to ECS under identical conditions. Both phenethyl isothiocyanate and budesonide, administered daily with the diet after weanling, attenuated several alterations of ECS-related biomarkers and moderately protected the lungs from histopathologic alterations, including tumors. Thus, although not as efficiently as the bioassay in mainstream cigarette smoke-exposed mice, the model in neonatal mice is suitable to evaluate both ECS carcinogenicity and its modulation by chemopreventive agents.

Topics: Adenoma; Age Factors; Animals; Animals, Newborn; Anticarcinogenic Agents; Apoptosis; Bone Marrow Cells; Budesonide; Carcinoma; DNA Adducts; Drug Screening Assays, Antitumor; Epithelial Cells; Female; Isothiocyanates; Lung; Lung Diseases; Lung Neoplasms; Male; Mice; Precancerous Conditions; Pregnancy; Time Factors; Tobacco Smoke Pollution

CC10, the secretory product of bronchiolar Clara cells, is infrequently expressed in non-small cell lung cancer (NSCLC), and its overexpression in NSCLC cell lines results in a less malignant phenotype. CC10 levels in bronchoalveolar lavage fluid (BAL) and serum are significantly lower in current smokers than healthy nonsmokers, but the effect of long-term smoking cessation on CC10 is unknown. We measured CC10 in baseline BAL and plasma collected from current (n = 81) and former (n = 23) smokers participating in a chemoprevention trial. Former smokers had significantly higher plasma CC10 levels compared with current smokers [mean, 62.1 ng/mL (95% CI, 43.0-81.2); range, 23.0-175.0 ng/mL for former smokers; and mean, 37.1 ng/mL (95% CI, 29.8-44.4); range, 5.0-171.0 ng/mL for current smokers; P < 0.001]. BAL CC10 levels also trended in the same direction. A significant positive correlation was found between CC10 plasma and BAL levels. After adjustment for age, sex, and pack-years of cigarette consumption, former smokers had 1.70 (95% CI, 1.23-2.36) times higher plasma CC10 levels than current smokers (P < 0.01), whereas former smokers also had nonsignificantly higher baseline BAL CC10 levels compared with current smokers [adjusted mean ratio (95% CI), 1.60 (0.92-2.80), P = 0.094 and 1.35 (0.86-2.10), P = 0.193 for the absolute and normalized BAL CC10, respectively]. These results show that sustained smoking cessation is associated with higher plasma CC10 levels, suggesting that at least some of the damage associated with tobacco smoke may be repaired by long-term smoking cessation.

Topics: Blood Proteins; Bronchi; Bronchoalveolar Lavage Fluid; Bronchodilator Agents; Budesonide; Chi-Square Distribution; Enzyme-Linked Immunosorbent Assay; Female; Humans; Linear Models; Lung; Male; Middle Aged; Precancerous Conditions; Smoking; Smoking Cessation; Uteroglobin