Chemopreventive Effect Of Aspirin Research Articles

Clinical Study of Aspirin and Zileuton on Biomarkers of Tobacco-Related Carcinogenesis in Current Smokers.

Simple SummaryAspirin and related drugs with anti-inflammatory effects have lung cancer prevention effects in laboratory studies and through their use in populations at risk for lung cancer. We studied aspirin plus zileuton compared to two placebo pills for 3 months in smokers. We studied genes associated with lung cancer, smoking, and lung disease. We used nasal swabs to collect nasal cells that were smoke exposed to look for changes in these genes. We found that most of the gene panels in the nasal cells related to smoking and lung cancer lung disease did not change in a favorable way, but we did see a favorable change in a gene panel representing abnormal squamous cells that may progress to lung cancer. We think this finding is of interest and can be studied further using deep lung biopsies to understand if this drug effect occurs where squamous cell lung cancer actually starts.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.

The efficacy of aspirin and metformin combination therapy in patients with rectal aberrant crypt foci: a double-blinded randomized controlled trial

BackgroundThe incidence and mortality rates of colorectal cancer (CRC) continue to increase worldwide. Therefore, new preventive strategies are needed to lower the burden of this disease. Previous studies reported that aspirin could suppress the development of sporadic colorectal adenoma. In addition, metformin is a biguanide derivative that is long widely used for the treatment of diabetes mellitus and has recently been suggested to have a suppressive effect on carcinogenesis and cancer cell growth. Both drugs exhibit a chemopreventive effect, but their efficacy is limited.Aberrant crypt foci (ACF), defined as lesions containing crypts that are larger in diameter and stain more darkly with methylene blue than normal crypts, are more prevalent in patients with cancer and adenomas, and considered a reliable surrogate biomarker of CRC. Thus, we designed a prospective trial as a preliminary study prior to a CRC chemoprevention trial to evaluate the chemopreventive effect of aspirin combined with metformin on colorectal ACF formation in patients scheduled for polypectomy.MethodsThis study is a double-blind randomized controlled trial that will be conducted in patients with both colorectal ACF and colorectal polyps scheduled for polypectomy. Eligible patients will be recruited for the study and the number of ACF in the rectum will be counted at the baseline colonoscopy. Then, the participants will be allocated to one of the following two groups; the aspirin plus placebo group or the aspirin plus metformin group. Patients in the aspirin plus placebo group will receive oral aspirin (100 mg) and placebo for 8 weeks, and those in the aspirin plus metformin group will receive oral aspirin (100 mg) and metformin (250 mg) for 8 weeks. After 8 weeks of administration, polypectomy will be performed to evaluate changes in the number of ACF, and the cell-proliferative activity in the normal colorectal mucosa and colorectal polyps.DiscussionThis is the first study proposed that will explore the effect of aspirin combined with metformin on the formation of colorectal ACF in humans.Trial registrationThis trial has been registered in the University Hospital Medical Information Network (UMIN) Clinical Trials Registry as UMIN000028259. Registered 17 July 2017.

The effect of aspirin on colorectal cancer incidence in African Americans.

4085 Background: From 2011 to 2016, the incidence and mortality rate of colorectal cancer(CRC) were highest among African Americans(AA), compared to other US racial/ethnic groups. Long-term aspirin use is recommended as a strategy to reduce the risk of CRC. Yet, there is scant information on the chemopreventive effect of aspirin among AA. It is imperative to assess whether the reported chemo-preventive effect also occurs in AA. Our central hypothesis is that aspirin use in AA is associated with a lower incidence of CRC, irrespective of race/ethnicity. Methods: We conducted a secondary analysis, using data from AA participants in the Atherosclerosis Risk in Communities(ARIC) longitudinal study, who did not have CRC at enrollment, from 1987 to 1998. We extracted demographic, clinical and mortality data to compare the incidence of CRC among participants taking aspirin compared to those who were not taking aspirin, stratified by age, tobacco use, and body mass index. All-cause mortality and CRC mortality will also be assessed, and we will use Cox proportional hazard regression to determine the relationship between aspirin use and CRC incidence, and mortality. Results: At baseline in 1987, 15,026 participants enrolled in the ARIC study, 25% of whom were AA, median age 54(range 44-66), including 46.7% who reported using aspirin. We analyzed follow-up data from 10,960 participants in 1996-1998, 20% of whom were AA, and 56.9% of whom were taking aspirin. Non-AA participants were more likely to report using aspirin at baseline and follow-up, compared to AA, 53% vs 30% and 59% vs 50% respectively. After 10years, the total incidence of CRC in AA participants was 1% compared with 1.1% in non-AA(p = 0.7). There was no difference in CRC incidence by aspirin use among all participants, and when stratified by race(among all participants p = 0.81, amongAA p = 0.68, among non-AA p = 0.94). Conclusions: We found no difference in the incidence of CRC among AA compared to Caucasians, by aspirin use. Investigation of consistency and/or dose of aspirin use by race may provide further insights on the relationship between aspirin use and CRC incidence, comparing AA to Caucasians.

Effects of low-dose aspirin on clinical outcome and disease progression in patients with gastroenteropancreatic neuroendocrine neoplasm

Objective: The chemopreventive effect of aspirin (ASA) has been observed in the setting of colorectal cancer and other solid neoplasms. Recently, ASA has demonstrated a promising anti-proliferative effect on GEP-NENs in vitro. However, the direct anti-neoplastic impact of ASA on GEP-NEN clinical outcome is yet to be clarified.Materials and methods: All the GEP-NEN patients followed up in three European Centers from January 2005 to September 2016 were retrospectively enrolled. Patients taking ASA in doses of 75–100 mg daily for cardiovascular prevention for at least six months were evaluated. The possible association between ASA and disease grading, staging, primary site, OS and PFS were evaluated.Results: Two hundred fifty one patients were included (117 males, median age 63 years). Of these, 64 patients were prescribed with ASA. No clear impact on OS or PFS was observed in GEP-NEN patients taking ASA compared to those not taking it. ASA intake was related with the patients' older age. At Cox multivariate analysis, stage IV and Ki-67 resulted independent predictors for OS and PFS. In the setting of intestinal NENs, a suggestive, but not statistically significant, protective role of ASA on PFS was observed [HR 0.41 (95% CI: 0.13–1.29)].Conclusions: Despite ASA showed promising anti-proliferative effects in vitro and a chemopreventive action in NENs has been reported, a clear impact of ASA on survival in NENs has not emerged from the present study. However, in the subgroup of patients with small-intestine NENs, ASA showed a trend toward a protective role.

Abstract 656: High resolution metabolomics of aspirin treatment in colon tissue and adenoma risk: Results from a randomized clinical trial

Abstract Although substantial evidence from cell and animal studies, epidemiological studies, and clinical trials supports the chemopreventive effects of aspirin, especially for colorectal cancer, the molecular mechanisms are uncertain. Aspirin incorporates two bioactive components in one molecule, a reactive acetyl moiety and a salicylate group, and is well known for its pleotropic effects. Its best-characterized pharmacologic activity is the irreversible acetylation of the cyclooxygenases (COX-1 and COX-2). However, there is evidence for numerous COX-independent mechanisms that could also modify colorectal carcinogenesis. This study applied an untargeted, discovery-based approach (metabolomics) to elucidate the effects of aspirin on low molecular weight molecules in human colon tissue and assess their impact on colorectal carcinogenesis. We utilized normal mucosal tissue biopsies collected at colonoscopy after about 3 years of treatment from a sub-set of N=325 participants in the Aspirin/Folate Polyp Prevention Study, a randomized, placebo-controlled trial of aspirin (81 or 325 mg/day) for the prevention of colorectal adenomas. The global metabolic effects of aspirin were assessed using a high-resolution Thermo Fusion mass spectrometer coupled with dual chromatography and dual ionization (HILIC positive and C18 negative electrospray ionization). Multivariable linear regression was used to identify metabolic features associated with aspirin treatment adjusting for age, sex and race. Multivariable Poisson regression was used to assess associations with adenoma outcomes of metabolic features associated with aspirin treatment. Products of aspirin metabolism (salicylate, salicyluric acid) were identified and statistically significantly increased in post treatment compared to baseline plasma samples confirming aspirin treatment status. After quality control exclusions, N=4,879 and N=5,390 features were included in analyses from the C18 and HILIC columns, respectively, of which N=244 and N=222 were associated with aspirin treatment at a raw P<0.05. At the pathway level, aspirin treatment was most strongly associated with perturbations in prostaglandin/arachidonic acid metabolism and the carnitine shuttle, which is involved in energy metabolism from fatty acids. At the metabolite level, only one feature (tentatively identified as a pterosin compound) was statistically significantly associated with aspirin treatment after FDR adjustment, but it was not associated with adenoma risk. Top features associated with aspirin treatment that were associated with adenoma outcomes included creatinine but are mostly of unknown identity at this time. In conclusion, a non-targeted high-resolution metabolomics approach has the potential to identify key downstream effects of aspirin involved in colorectal chemoprevention. Citation Format: Elizabeth L. Barry, Karan Uppal, Chunyu Ma, Dean P. Jones, John A. Baron, Veronika Fedirko. High resolution metabolomics of aspirin treatment in colon tissue and adenoma risk: Results from a randomized clinical trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 656.

Low-dose aspirin can reduce colorectal cancer mortality after surgery: A 10-year follow-up of 13528 colorectal cancer patients.

The chemopreventive effect of aspirin in colorectal cancer (CRC) is well studied, but its benefit in patients after CRC diagnosis and surgery is unclear. This study aims to investigate the effects of low-dose aspirin use in mortality among CRC patients after surgery. Patients were analyzed in two cohorts: (i) patients taking aspirin before CRC diagnosis and continued or discontinued aspirin after surgery and (ii) patients, who never used aspirin before CRC diagnosis, received or did not receive aspirin after surgery. CRC-related mortality and all-cause mortality were the primary and secondary outcomes. Sub-distribution hazard ratio (SHR) for competing-risk CRC mortality was fitted to adjust for other causes of death; hazard ratio (HR) was used to compare all-cause mortality. A total of 13528 CRC patients were included. Among 3292 patients with regular aspirin use before CRC diagnosis, 2658 (80.7%) continued aspirin and 634 (19.3%) discontinued aspirin after surgery. Continuous use of aspirin significantly reduced CRC-related mortality (SHR: 0.69, 95% confidence interval [CI]: 0.59-0.81) and all-cause mortality (HR: 0.61, 95% CI: 0.55-0.68). Among 10236 patients who did not use aspirin before CRC diagnosis, 1054 patients (10.3%) received aspirin after surgery and 9182 (89.7%) did not. Aspirin initiated after surgery reduced CRC-related mortality (SHR: 0.88, 95% CI: 0.80-0.98) and all-cause mortality (HR: 0.87, 95% CI: 0.81-0.94). Irrespective of aspirin use before surgery for CRC, low-dose aspirin after surgery lowers risk of both CRC-related mortality and overall mortality.

Aspirin associated with risk reduction of secondary primary cancer for patients with head and neck cancer: A population-based analysis.

As reported by the Taiwan Cancer Registry in 2013 squamous cell carcinoma of head and neck cancer (HNSCC) was the sixth most frequently diagnosed cancer and the 5th most common cause of cancer related death and its incidence and mortality rate is still rising. The co-occurrence of HNSCC and secondary primary cancer (SPC) and the chemopreventive effect of aspirin on certain malignancies had been reported. Therefore we conducted this national study to investigate the use of aspirin associated with risk reduction of secondary primary cancer for patients with head and neck cancer in Taiwan. We searched the Registry for Catastrophic Illness in the National Health Insurance Research Database (NHIRD) for 18,234 patients (3,576 aspirin users and 14,667 non-aspirin users) diagnosed with HNSCC during 2000–2005. The SPC incidence density during follow-up in 2000–2011 was compared between the groups. For HNSCC patients, aspirin use after diagnosis was significantly associated with SPC risk reduction by 25% (adjusted HR, 0.75; 95% CI, 0.63–0.89; p = 0.001) after multivariate analysis. In the subgroup analysis, we found that esophageal cancer and stomach cancer incidence were significantly reduced after aspirin use (adjusted HR, 0.60; 95% CI, 0.41–0.90; p = 0.01 for esophageal cancer; adjusted HR, 0.27; 95% CI, 0.08–0.87; p = 0.03 for stomach cancer). Aspirin use for 1–3 years was associated with SPC risk reduction by 35% (adjusted HR, 0.65; 95% CI, 0.49–0.87; p = 0.003). SPC risk reduction extended continuously for more than 3 years of follow up (adjusted HR, 0.72; 95% CI, 0.53–0.98; p = 0.030). Our data shows aspirin use was associated with reduced SPC incidence for HNSCC patients, attributed mainly to reduced risk of esophageal and stomach cancer.

Abstract 2308: Salicylic acid metabolites and derivatives inhibit CDK activity: Novel insights into aspirin's chemopreventive effects against colorectal cancer

Abstract Aspirin's potential as a drug continues to be evaluated for the prevention of colorectal cancer (CRC). Although multiple targets for aspirin and its metabolite, salicylic acid, have been identified, no unifying mechanism has been proposed to clearly explain its chemopreventive effects. Our goal here was to investigate the ability of salicylic acid metabolites, known to be generated through cytochrome P450 (CYP450) enzymes, and also its derivatives as cyclin dependent kinase (CDK) inhibitors to gain new insights into aspirin's chemopreventive actions. Using in vitro kinase assays, for the first time, we demonstrate that salicylic acid metabolites, 2,3-dihydroxybenzoic acid (2,3-DHBA) and 2,5-dihydroxybenzoic acid (2,5-DHBA), as well as derivatives 2,4-dihydroxybenzoic acid (2,4-DHBA), 2,6-dihydroxybenzoic acid (2,6-DHBA), inhibited CDK1 enzyme activity. 2,3-DHBA and 2,6-DHBA did not inhibit CDK2 and 4; however, both inhibited CDK-6 activity. Interestingly, another derivative, 2,4,6-trihydroxybenzoic acid (2,4,6-THBA) was highly effective in inhibiting CDK1, 2, 4 and 6 activity. Molecular docking studies showed that these compounds potentially interact with CDK1. Immunoblotting experiments showed that aspirin acetylated CDK1, and preincubation with salicylic acid and its derivatives prevented aspirin-mediated CDK1 acetylation, which supported the data obtained from molecular docking studies. We suggest that intracellularly generated salicylic acid metabolites through CYP450 enzymes within the colonic epithelial cells, or the salicylic acid metabolites generated by gut microflora may significantly contribute to the preferential chemopreventive effect of aspirin against CRC through inhibition of CDKs. This novel hypothesis and mechanism of action in aspirin's chemopreventive effects opens a new area for future research. In addition, structural modification to salicylic acid derivatives may prove useful in the development of novel CDK inhibitors in cancer prevention and treatment. Citation Format: Ranjini Sankaranarayanan, Rakesh Dachineni, D. Ramesh Kumar, Eduardo Callegari, Siddharth S. Kesharwani, Teresa Seefeldt, Hemachand Tummala, Jayarama B. Gunaje. Salicylic acid metabolites and derivatives inhibit CDK activity: Novel insights into aspirin's chemopreventive effects against colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2308.

Exploratory plasma proteomic analysis in a randomized crossover trial of aspirin among healthy men and women.

Long-term use of aspirin is associated with lower risk of colorectal cancer and other cancers; however, the mechanism of chemopreventive effect of aspirin is not fully understood. Animal studies suggest that COX-2, NFκB signaling and Wnt/β-catenin pathways may play a role, but no clinical trials have systematically evaluated the biological response to aspirin in healthy humans. Using a high-density antibody array, we assessed the difference in plasma protein levels after 60 days of regular dose aspirin (325 mg/day) compared to placebo in a randomized double-blinded crossover trial of 44 healthy non-smoking men and women, aged 21–45 years. The plasma proteome was analyzed on an antibody microarray with ~3,300 full-length antibodies, printed in triplicate. Moderated paired t-tests were performed on individual antibodies, and gene-set analyses were performed based on KEGG and GO pathways. Among the 3,000 antibodies analyzed, statistically significant differences in plasma protein levels were observed for nine antibodies after adjusting for false discoveries (FDR adjusted p-value<0.1). The most significant protein was succinate dehydrogenase subunit C (SDHC), a key enzyme complex of the mitochondrial tricarboxylic acid (TCA) cycle. The other statistically significant proteins (NR2F1, MSI1, MYH1, FOXO1, KHDRBS3, NFKBIE, LYZ and IKZF1) are involved in multiple pathways, including DNA base-pair repair, inflammation and oncogenic pathways. None of the 258 KEGG and 1,139 GO pathways was found to be statistically significant after FDR adjustment. This study suggests several chemopreventive mechanisms of aspirin in humans, which have previously been reported to play a role in anti- or pro-carcinogenesis in cell systems; however, larger, confirmatory studies are needed.

Regular Aspirin Use Associates With Lower Risk of Colorectal Cancers With Low Numbers of Tumor-Infiltrating Lymphocytes

Aspirin use reduces colorectal cancerrisk. Aspirin, a nonsteroidal anti-inflammatory drug, inhibits prostaglandin-endoperoxide synthase 2 (PTGS2 or cyclooxygenase-2); PTGS2 promotes inflammation and suppresses T-cell-mediated adaptive immunity. We investigated whether the inverse association of aspirin use with colorectal carcinoma risk was stronger for tumors with lower degrees of lymphocytic infiltrates than for tumors with higher degrees of lymphocytic infiltrates. We collected aspirin use data biennially from participants in the Nurses' Health Study and Health Professionals Follow-up Study. Participants were asked whether they took aspirin in most weeks, the number of tablets taken per week, and years of aspirin use. We collected available tumor specimens (n= 1458) from pathology laboratories in the United States. A pathologist confirmed the diagnosis of colorectal adenocarcinoma (excluding anal squamous cell carcinoma), and evaluated histopathology features, including patterns and degrees of lymphocytic infiltrates within and around tumor areas. Person-years of follow-up evaluation were accrued from the date of return of questionnaires until dates of colorectal cancer diagnosis, death, or the end of follow-up evaluation (June 2010). Duplication-method Cox proportional hazards regression was used to assess the association of aspirin with the incidence of colorectal carcinoma subgroups according to the degree of tumor-infiltrating lymphocytes (TILs), intratumoral periglandular reaction, peritumoral reaction, or Crohn's-like reaction. We documented 1458 rectal and colon cancers. The inverse association between regular aspirin use and colorectal cancer risk significantly differed by concentrations of TILs (Pheterogeneity= .007). Compared with nonregular use, regular aspirin use was associated with a lower risk of tumors that had low levels of TILs (relative risk, 0.72; 95% confidence interval, 0.63-0.81), and strength of the association depended on aspirin dose and duration (both Ptrend < .001). In contrast, aspirin use was not associated with a risk of tumors having intermediate or high levels of TILs. This differential association was consistent regardless of the status of tumor microsatellite instability, mutations in BRAF, or expression of PTGS2. Regular aspirin use was associated with a lower risk of tumors that contained low levels of CD3+ Tcells, CD8+ T cells, or CD45RO (PTPRC)+ T cells (measured by immunohistochemistry and computer-assisted image analysis). Based on data from the prospective cohort studies, regular use of aspirin is associated witha lower risk of colorectal carcinomas with low concentrations of TILs. These findings indicate that the immune response in thetumor microenvironment could be involved in the chemopreventive effects of aspirin.

Abstract 4284: Exploratory plasma proteomic analysis in a randomized cross-over trial of aspirin among healthy individuals

Abstract Background: Long-term use of aspirin is associated with lower colorectal cancer (CRC) incidence; however, the mechanism of the chemopreventive effect of aspirin is not fully understood. Animal studies suggest that COX-2, NFκB signaling and Wnt/β-catenin pathways may play a role, but no clinical trials have systematically evaluated the biological response to aspirin in healthy humans. Methods: We assessed the difference in plasma protein levels after 60 days of regular dose aspirin (325 mg/day) compared to placebo in a randomized, double-blinded, placebo-controlled, cross-over trial of 44 healthy non-smoking men and women, aged 21-45 years. Plasma proteomics was analyzed on an antibody microarray with ∼3,000 full-length antibodies, printed in triplicate. Moderated paired t-test was performed on individual antibodies, and gene set analyses were performed for KEGG and GO pathways. Results: Among the 3,387 antibodies, significant differences in plasma protein levels were observed for 267 antibodies (p&amp;lt;0.05), the most significant protein being a transcription-factor regulator belonging to a steroid receptor family and found to be differentially expressed in colon cancer cells. Other significant proteins are involved in multiple oncogenic pathways related to colon tumorigenesis. In the pathway analysis, 4 KEGG (among 138) and 69 GO (among 1,089) pathways were found to be significant (p&amp;lt;0.05), including natural killer (NK) cell-mediated cytotoxicity, butanoate metabolism and Wnt signaling pathways. Pathways that modulate cellular protein binding to steroid receptors were also significantly different between aspirin treatment and placebo (p&amp;lt;0.05). None of the results remained statistically significant after correction for multiple testing. Conclusion: Several proteins and pathways, which have previously been reported as playing a role in colorectal carcinogenesis in vitro were found to be differentially expressed after aspirin treatment vs. placebo in healthy human subjects. This study suggests several chemopreventive mechanisms of aspirin; however, larger, confirmatory studies are needed. Citation Format: Xiaoliang Wang, Yuzheng Zhang, Ali Shojaie, Paul D. Lampe, Lisa Levy, Ulrike Peters, John D. Potter, Emily White, Johanna W. Lampe. Exploratory plasma proteomic analysis in a randomized cross-over trial of aspirin among healthy individuals. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4284.

Can Tissue-Based Immune Markers be Used for Studying the Natural History of Cancer?

Aspirin use reduces colorectal cancer risk. Aspirin, a nonsteroidal anti-inflammatory drug, inhibits prostaglandin-endoperoxide synthase 2 (PTGS2 or cyclooxygenase-2); PTGS2 promotes inflammation and suppresses T-cell–mediated adaptive immunity. We investigated whether the inverse association of aspirin use with colorectal carcinoma risk was stronger for tumors with lower degrees of lymphocytic infiltrates than for tumors with higher degrees of lymphocytic infiltrates.We collected aspirin use data biennially from participants in the Nurses' Health Study and Health Professionals Follow-up Study. Participants were asked whether they took aspirin in most weeks, the number of tablets taken per week, and years of aspirin use. We collected available tumor specimens (n = 1458) from pathology laboratories in the United States. A pathologist confirmed the diagnosis of colorectal adenocarcinoma (excluding anal squamous cell carcinoma), and evaluated histopathology features, including patterns and degrees of lymphocytic infiltrates within and around tumor areas. Person-years of follow-up evaluation were accrued from the date of return of questionnaires until dates of colorectal cancer diagnosis, death, or the end of follow-up evaluation (June 2010). Duplication-method Cox proportional hazards regression was used to assess the association of aspirin with the incidence of colorectal carcinoma subgroups according to the degree of tumor-infiltrating lymphocytes (TILs), intratumoral periglandular reaction, peritumoral reaction, or Crohn's-like reaction.We documented 1458 rectal and colon cancers. The inverse association between regular aspirin use and colorectal cancer risk significantly differed by concentrations of TILs (Pheterogeneity = .007). Compared with nonregular use, regular aspirin use was associated with a lower risk of tumors that had low levels of TILs (relative risk, 0.72; 95% confidence interval, 0.63–0.81), and strength of the association depended on aspirin dose and duration (both Ptrend < .001). In contrast, aspirin use was not associated with a risk of tumors having intermediate or high levels of TILs. This differential association was consistent regardless of the status of tumor microsatellite instability, mutations in BRAF, or expression of PTGS2. Regular aspirin use was associated with a lower risk of tumors that contained low levels of CD3+ T cells, CD8+ T cells, or CD45RO (PTPRC)+ T cells (measured by immunohistochemistry and computer-assisted image analysis).Based on data from the prospective cohort studies, regular use of aspirin is associated with a lower risk of colorectal carcinomas with low concentrations of TILs. These findings indicate that the immune response in the tumor microenvironment could be involved in the chemopreventive effects of aspirin.

Daily aspirin reduces colorectal cancer incidence in patients with Lynch syndrome

Daily aspirin reduces colorectal cancer incidence in patients with Lynch syndrome

Is Low-Dose Aspirin Use Associated With a Reduced Risk of Colorectal Cancer? A Qresearch Primary Care Database Analysis

Introduction The chemopreventive effect of aspirin for colorectal cancer (CRC) is now well established. However, the dose and duration of aspirin use necessary for this effect is still unclear. Two very large US RCTs using low dose aspirin (325 and 100 mg alt. die) found no reduction in CRC incidence after 10 years follow-up, but a recent meta-analysis of five European aspirin trials suggested that aspirin in a dose of 75–300 mg daily resulted in a 24% reduction in CRC incidence.1 We have therefore examined the relationship between prescribed aspirin and CRC risk in QResearch, the largest primary care database in the United Kingdom. Methods A nested case-control study was conducted using data from 574 UK general practices in the QResearch database. Cases were all patients with >15 years of records and diagnosed with colorectal cancer between 1998 and 2008. Cases were matched to up to five controls. Prescriptions in the year before diagnosis were ignored. Association of aspirin use with risk of cancer was estimated in STATA using conditional logistic regression adjusted for comorbidities, smoking status, socio-economic status and use of non-steroidal anti-inflammatory drugs and statins. Results There were 6643 patients diagnosed with CRC with 15 years of records in the database. Of 24% CRC cases and their controls had been prescribed aspirin at some point, 77% in a dose of 75 mg, 93% as ≤150 mg and 98% as 300 mg or less. Table 1 shows a gradual reduction in CRC risk (odds ratios) with increasing total duration of aspirin use (p for trend = 0.012). In a larger cohort with only 10 years of database records, there were 9534 CRCs and the risk of CRC with 7–9 years of aspirin use was 0.82 (0.73–0.93, p Conclusion Use of low dose aspirin is associated with about a 20% reduction in CRC incidence but this reduction is only evident after over 7 years of use. Although this is a modest reduction aspirin, combined with other agents such as calcium could result in a more substantial effect.

Acetyl-11-Keto-Beta-Boswellic Acid Inhibits Cell Growth, Invasion, and Migration in Colon Cancer Cells by Modulating the Expression of MicroRNA Let-7 and the Mir-200 Family

Introduction: The chemopreventive effect of aspirin for colorectal cancer (CRC) is now well established. However the dose and duration of aspirin use necessary for this effect is still unclear. Two very large US RCTs using low dose aspirin (325mg and 100mg alt.die) found no reduction in CRC incidence after 10 years follow-up but a recent meta-analysis of 5 European aspirin trials suggested that aspirin in a dose of 75-300mg daily resulted in a 24% reduction in CRC incidence.1 We have therefore examined the relationship between prescribed aspirin and CRC risk in QResearch, the largest primary care database in the UK. Methods: A nested case-control study was conducted using data from 574 UK general practices in the Qresearch database. Cases were all patients with >15 years of records and diagnosed with colorectal cancer between 1998 and 2008. Cases were matched to up to 5 controls. Prescriptions in the year before diagnosis were ignored. Association of aspirin use with risk of cancer was estimated in STATA using conditional logistic regression adjusted for co-morbidities, smoking status, socio-economic status and use of non-steroidal antiinflammatory drugs and statins. Results: There were 6643 patients diagnosed with CRC with 15 years of records in the database. 24% of CRC cases and their controls had been prescribed aspirin at some point, 77% in a dose of 75mg, 93% as ≤150mg and 98% as 300mg or less. The Table shows a gradual reduction in CRC risk (odds ratios) with increasing total duration of aspirin use (p for trend=0.012). In a larger cohort with only 10 years of database records there were 9534 CRC's and the risk of CRC with 7-9 years of aspirin use was 0.82 (0.73-0.93, p<0.001) Conclusion: Use of low dose aspirin is associated with about a 20% reduction in CRC incidence but this reduction is only evident after over 7 years of use. Although this is a modest reduction aspirin combined with other agents such as calcium could result in a more substantial effect.

Aspirin may be more effective in preventing colorectal adenomas in patients with higher BMI (United States)

Obesity is a risk factor for colon cancer, possibly due to elevated levels of circulating cytokines derived from adipose tissue. Aspirin, which may affect the levels of these cytokines, has been shown in randomized controlled trials to decrease the risk of colorectal adenomas. We hypothesized that the chemopreventive effect of aspirin might be greater in individuals with higher body mass index (BMI). Data were available from the Aspirin/Folate Polyp Prevention Study, a randomized controlled trial of aspirin and folic acid to prevent recurrent colorectal adenomas. Obesity was defined as BMI > or = 30 (kg/m2), overweight as BMI of 25-29 (kg/m2) and normal weight as BMI <25 (kg/m2). For the analysis of the effect of aspirin on the recurrence of colorectal adenoma by BMI, we computed risk ratios for aspirin versus placebo within the three BMI strata using a modified Poisson model. Overall the risk reduction of adenomas with a daily dose of 325 mg aspirin was greater among subjects with higher BMI. Among obese subjects the risk ratio (RR) for advanced adenomas compared with placebo was 0.44 (95% CI 0.17-1.10), versus RR = 1.23 (95% CI 0.55-2.77) among those with normal weight. However, 81 mg aspirin daily did not interact with BMI to modify the risk of adenomas in such a fashion. The more pronounced effect of 325 mg aspirin in individuals with higher BMI suggests a possible protective role of anti-inflammatory aspirin against increased adipose-driven cytokines among obese subjects.

Aspirin and the prevention of colorectal neoplasia

Aspirin and the prevention of colorectal neoplasia

The role of eicosanoids, cyclooxygenases, and nonsteroidal anti-inflammatory drugs in colorectal tumorigenesis and chemoprevention.

There is mounting evidence from studies on experimental cancer in rodents, interventional studies in patients with familial adenomatous polyposis, and some, but not all, epidemiologic investigations, that suggests a chemopreventive effect of aspirin and nonaspirin nonsteroidal anti-inflammatory drugs (NSAIDs) against colorectal cancer. In addition, the mechanisms by which these agents modulate tumorigenesis are being elucidated in laboratory experiments. Currently available NSAIDs are unlikely to have an acceptable benefit-to-risk ratio for long-term use in an asymptomatic population. Once the discrete chemopreventive mechanisms are established and the genetic background and risk factor profile of individuals who will benefit from chemoprevention are clarified, a low-dose combination of NSAIDs with different targets may optimize efficacy and minimize toxicity. At present, however, colectomy is still the treatment of choice for patients with familial adenomatous polyposis, and early screening and regular surveillance colonoscopies are the choices for those at risk for hereditary nonpolyposis colorectal cancer. In the average-risk individual, endoscopic screening and surveillance will remain the core of efforts to prevent sporadic colorectal cancer.

Chemopreventive effect of aspirin on growth of aberrant crypt foci in rats.

Nonsteroidal anti-inflammatory drugs display a chemopreventive effect on polyps and cancer of the large bowel. This study evaluated the inhibitory effect of aspirin on the distribution and growth of aberrant crypt foci (ACF), the earliest putative preneoplastic and early neoplastic lesions in a rat model. For initiation of ACF, Sprague Dawley rats were injected with azoxymethane (30 mg/kg), a well-established rat carcinogen. After the second injection the rats were allocated to three groups, which received 0.2% or 0.6% aspirin or the solvent only (control group). After 6 weeks the animals were killed, and their colons removed, fixed in formalin, and screened for distribution and size of ACF, separately for middle and distal parts of the large intestine. The rats injected with azoxymethane showed a 100% incidence of ACF. Administration of 0.2% and 0.6% aspirin resulted in 55% and 54% reduction, respectively, in overall frequency of ACF. Aspirin significantly reduced the frequency of medium-sized (four to six crypts per focus) and large (three to six crypts per focus) but not the small (one to three crypts per focus) ACF. In the control group the ACF of the same multiplicity were larger than those in the aspirin-treated rats. No statistically significant difference in ACF-inhibiting effect was noted between 0.6% and 0.2% aspirin solution. Aspirin given at a concentration of either 0.2% of 0.6% thus has a chemopreventive effect on ACF, acting on postinitiation stage of azoxymethane-induced colonic carcinogenesis model in rats.

Effect of aspirin on incidence and growth of aberrant crypt foci induced in the rat colon by 1,2-dimethylhydrazine

The aim of this work was to investigate if the possible chemopreventive effect of aspirin (ASA) on rat colon carcinogenesis could be detected with a medium-term assay. The end-point chosen was the inhibition of incidence and growth of putative preneoplastic lesions, the aberrant crypt foci (ACF) induced in the rat colon by two administrations of 1,2-dimethylhydrazine (DMH, 25 mg/kg p.o.). At both 4 and 8 weeks after the starting of the carcinogenic treatment the incidence of total ACF was reduced of 60% in rats receiving ASA (10 mg/kg/day p.o.) for 12 consecutive days during the initiation treatment with DMH. Also the number of the larger foci (with 3 or more crypts) was significantly lower in ASA-treated rats at both time-points (about 70% reduction). Moreover, concomitant ASA treatment determined a significant decrease of the mean number of crypts per focus at week 8. These results indicate that the chemopreventive effect of ASA on chemically-induced rat colon carcinogenesis observed in long-term studies may be detected in this relatively short assay.