Clinical study of the effect of combined treatment of aspirin and zileuton on biomarkers of tobacco-related carcinogenesis in current smokers
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PROVIDER: PRJNA733101 | ENA |
REPOSITORIES: ENA
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Project description:A chemopreventive effect of aspirin (ASA) on lung cancer risk is supported by epidemiologic and preclinical studies. Zileuton, a 5-LOX inhibitor has single agent activity and adds to the activity of NSAIDs in preclinical models of tobacco carcinogenesis We hypothesized that COX inhibitor + 5-LOX inhibitor may be more effective than placebo in modulating nasal epithelium gene signatures of tobacco exposure and lung cancer. We conducted a randomized, double-blinded study of low dose ASA plus zileuton vs. double placebo in current smokers to compare modulating effects on nasal epithelium gene expression and arachidonic acid (AA) metabolism. Sixty-three participants were randomized to combined treatment of ASA (81 mg QD) and zileuton (Zyflo CR) two 600 mg extended release tablets BID or placebo pills for 12 weeks. Combined ASA plus zileuton had minimal effects on nasal gene expression of nasal or bronchial gene expression signatures associated with smoking, lung cancer and chronic obstructive pulmonary disease but did favorably modulate a bronchial gene signature of squamous dysplasia. Combined ASA plus zileuton suppressed urinary leukotriene (LTE4) (change of 89.867±68.35 from baseline to 32.25±23.25, p <0.001), a surrogate of 5-LOX mediated AA metabolism but did not suppress urinary prostaglandin E2 metabolite (PGEM), a surrogate of cyclooxygenase-mediated AA metabolism. In conclusion, combined COX and 5-LOX inhibition by combined low dose ASA with zileuton in smokers favorably modulated a bronchial squamous dysplasia gene expression signature in the nasal epithelium of current smokers but had minimal effects on other carcinogenesis gene signatures. This combination decreased 5-LOX but not COX-2 mediated AA metabolism. Nasal gene expression signature determination is a novel approach to biomarker analysis, giving an approximation of the pulmonary milieu without having to perform invasive tissue sampling.
2022-06-29 | GSE175616 | GEO
Project description:A chemopreventive effect of aspirin (ASA) on lung cancer risk is supported by epidemiologic and preclinical studies. We conducted a randomized, double-blind, placebo controlled study in current heavy smokers to compare modulating effects of intermittent versus continuous low dose ASA on gene signatures of smoking and lung cancer from nasal brushings. Fifty-four participants were randomized to intermittent ASA (ASA 81 mg daily for one week alternating with placebo daily for one week) or continuous ASA (81 mg daily) for 12 weeks. The primary endpoint was modulation of a smoking gene signature in nasal brushings. Other [JB1] endpoints included modulation of nasal and bronchial gene signatures for smoking, lung cancer and chronic obstructive pulmonary disease (COPD) and changes in cyclooxygenase (COX)- and 5-lipoxygenase (LOX)-mediated arachidonic acid (ARA) metabolism. Low dose ASA intervention caused minimal changes in smoking and lung cancer gene signature scores in nasal epithelium of current heavy smokers. The small sample size of the intervention groups may have limited the ability to detect modulation of the gene signatures. Low dose ASA lowered urinary prostaglandin E metabolite, a marker of COX-mediated ARA metabolic pathway with no change in urinary leukotriene E4, a marker of 5-LOX-mediated pathway. Exploratory genomic analysis showed that ASA intervention induced wide-ranging genomic changes in the nasal epithelium, including modulation of the arachidonic acid pathway and wound healing. A companion study is underway using ASA plus zileuton to test dual suppression of COX- and 5-LOX-mediated pathways on these gene signature scores in current heavy smokers.
2019-12-24 | GSE124637 | GEO
Project description:The chemopreventive effect of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) on lung cancer risk is supported by epidemiologic and preclinical studies. Zileuton, a 5-lipoxygenase inhibitor, has additive activity with NSAIDs against tobacco carcinogenesis in preclinical models. We hypothesized that cyclooxygenase plus 5-lipoxygenase inhibition would be more effective than a placebo in modulating the nasal epithelium gene signatures of tobacco exposure and lung cancer. We conducted a randomized, double-blinded study of low-dose aspirin plus zileuton vs. double placebo in current smokers to compare the modulating effects on nasal gene expression and arachidonic acid metabolism. In total, 63 participants took aspirin 81 mg daily plus zileuton (Zyflo CR) 600 mg BID or the placebo for 12 weeks. Nasal brushes from the baseline, end-of-intervention, and one-week post intervention were profiled via microarray. Aspirin plus zilueton had minimal effects on the modulation of the nasal or bronchial gene expression signatures of smoking, lung cancer, and COPD but favorably modulated a bronchial gene expression signature of squamous dysplasia. Aspirin plus zileuton suppressed urinary leukotriene but not prostaglandin E2, suggesting shunting through the cyclooxygenase pathway when combined with 5-lipoxygenase inhibition. Continued investigation of leukotriene inhibitors is needed to confirm these findings, understand the long-term effects on the airway epithelium, and identify the safest, optimally dosed agents.
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Project description:Purpose: The purpose of this study was to describe transcriptomic changes between current and former smokers using differential gene expression and differential exon usage
2017-09-05 | GSE97531 | GEO
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2009-01-29 | GSE14633 | GEO
Project description:Comparison of gene and protein expression in the large airway epithelium of never and current smokers. Keywords: gene expression array-based (RNA / in situ oligonucleotide)
2009-04-10 | GSE4635 | GEO
Project description:MicroRNA expression was assayed from bronchial epithelial cells collected via bronchoscopy from healthy current and never smoker volunteers in order to determine the effect of cigarette smoke exposure on airway epithelial microRNA expression Keywords: Global microRNA expression profiling Bronchial epithelial cells were collected from current and never smokers via bronchoscopy. Low molecular weight RNA ( < 200 nucleotides) was isolated and hybridized to Invitrogen NCode microRNA microarrays to determine which microRNAs detected in bronchial epithelial cells were differentially expressed in the airways of smokers.
2009-01-28 | E-GEOD-14634 | biostudies-arrayexpress
Project description:The effect of intermittent versus continuous low dose aspirin on nasal epithelium gene expression in current smokers: a randomized, double-blinded clinical study
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Project description:Smoking is the leading cause of lung cancer death, although only a small percentage of smokers develop the disease. Cigarette smoke exposure is known to cause a field of injury in cells throughout the respiratory tract, and while these airway epithelial cells are morphologically normal, they can undergo genetic alterations in response to cigarette smoke exposure. We used microarrays to analyze the gene expression of epithelial cells in the extrathoracic epithelium, specifically nasal and buccal epithelium, to see if these cells underwent similar genetic alterations in response to tobacco exposure as seen in bronchial epithelial cells as has been previously reported. Experiment Overall Design: Buccal and nasal epithelial cell samples were collected from healthy current and never smokers. RNA was isolated from these samples and hybridized to Affymetrix microarrays. Gene expression from never smokers was compared to never smoker gene expression from bronchial epithelium as well as expression data from other tissues to determine commonalities in expression patterns in normal extra- and intra-thoracic samples. In addition, gene expression from smokers and nonsmokers was compared in bronchial, nasal, and buccal epithelium to determine similarities in gene expression in these tissues in response to cigarette smoker exposure.
2008-10-20 | E-GEOD-8987 | biostudies-arrayexpress
Project description:Aspirin use has been associated with reduced ovarian cancer risk. However, the underlying biological mechanisms are not fully understood We examined the association between gene expression profiles in ovarian tumors and current low and regular dose aspirin use in the 1-2 years prior to diagnosis
2023-10-03 | GSE230522 | GEO