Non-Steroidal Anti-Inflammatory Drug Use and Colorectal Polyps in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial
ABSTRACT Non-steroidal anti-inflammatory drugs (NSAIDs) have been documented in animal and human studies to reduce risk for colorectal cancer and adenomatous polyps, but risk modification for subgroups of the population and effects on hyperplastic polyps have been less studied.
Data on recent use of two frequently ingested NSAIDs, aspirin and ibuprofen, were collected at baseline from participants aged 55-74 years in the 10 centers of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO). Participants randomized to the intervention arm of the trial received a flexible sigmoidoscopy during a baseline examination. Follow-up of detected polyps was accomplished outside the Trial setting and relevant records were sought and abstracted. Cases (n=4,017) included subjects with a biopsy-proven polyp in the left side of the colon (descending colon, sigmoid, and rectum) detected as a consequence of PLCO screening; controls (n=38,396) were subjects with no left-sided colon polyp.
Regular use of aspirin (≥ 4 times/month) in the past year was inversely associated with hyperplastic polyps (odds ratios (OR)=0.8, 95% confidence interval (CI)=0.7-0.9), adenomatous polyps (OR=0.8, 95% CI=0.8-0.9), and advanced adenomas (OR=0.8, 95% CI=0.7-0.9). As frequency of aspirin use increased, the prevalence of polyps decreased significantly for each histological classification (P for trend ≤ 0.0004). Similar patterns were found for adenomas and ibuprofen. Overall protection was consistent in both the descending colon or sigmoid and the rectum, but more evident in males. In males, the OR for heavy use of combined aspirin and ibuprofen (≥ 2 times/day) was 0.6 (95% CI=0.5-0.8), as opposed to 0.9 (95% CI=0.8-1.1) in females. The protective effects of NSAIDs for females were apparent only among those with body mass index (BMI) <25 (OR=0.8, 95% CI=0.7-1.0 for regular use of NSAIDs; P interaction=0.04). We also found a slightly stronger protection of NSAIDs in the 70-74 years age group compared with those aged 55-69 years.
This study of a large general risk population supports previous work that recent use of aspirin and ibuprofen is associated with a decreased risk of colorectal adenomas and demonstrates that this protective effect may be stronger in certain population subgroups and is also evident for aspirin and hyperplastic polyps.
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ABSTRACT: Esterase hydrolysis of drugs can accelerate their elimination thereby limiting their efficacy. Poly-ethylene glycol covalently attached on drugs (pegylation) is known to improve the efficiency of many drugs. Using as a test agent the novel phospho-ibuprofen (PI), we examined whether pegylation of PI could abrogate its hydrolytic degradation by esterases; PI, known to inhibit colon cancer growth, has a carboxylic ester hydrolysable by carboxylesterases (CES). We covalently attached PEG-2000 to PI (PI-PEG) and studied its stability by exposing it to cells overexpressing CES and by administering it to mice. We also evaluated PI-PEG's anticancer efficacy in human colon cancer xenografts and in Apcmin/+ mice. PI-PEG was stable in the presence of cells overexpressing CES1 or CES2, while PI was extensively hydrolyzed (90.2 ± 0.7 %, 14.3 ± 1.1 %, mean ± SEM). In mice, PI was nearly completely hydrolyzed. Intraveous administration of PI-PEG resulted in significant levels in blood and in colon cancer xenografts (xenograft values in parentheses): AUC0-24h = 2,351 (2,621) (nmole/g)xh; Cmax = 1,965 (886) nmole/g; Tmax = 0.08 (2) h. The blood levels of ibuprofen, its main hydrolytic product, were minimal. Compared to controls, PI-PEG inhibited the growth of the xenografts by 74.8% (p<0.01), and reduced intestinal tumor multiplicity in Apcmin/+ mice by 73.1% (p<0.01) prolonging their survival (100% vs. 55.1% of controls; p=0.013).Pegylation protects PI from esterase hydrolysis and improves its pharmacokinetics. In preclinical models of colon cancer, PI-PEG is a safe and efficacious agent that merits further evaluation.Journal of Pharmacology and Experimental Therapeutics 07/2014; 351(1). DOI:10.1124/jpet.114.217208 · 3.86 Impact Factor
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ABSTRACT: The discovery of ibuprofen’s anti-inflammatory activity by Dr (now Professor) Stewart Adams and colleagues (Boots Pure Chemical Company Ltd, Nottingham, UK) 50 years ago represented a milestone in the development of anti-inflammatory analgesics. Subsequent clinical studies were the basis for ibuprofen being widely accepted for treating painful conditions at high anti-rheumatic doses (≤ 2400 mg/d), with lower doses (≤ 1200 mg/d for ≤ 10 days) for mild–moderate acute pain (e.g. dental pain, headache, dysmenorrhoea, respiratory symptoms and acute injury). The early observations have since been verified in studies comparing ibuprofen with newer cyclo-oxygenase-2 selective inhibitors (‘coxibs’), paracetamol and other non-steroidal anti-inflammatory drugs (NSAIDs). The use of the low-dose, non-prescription, over-the-counter (OTC) drug was based on marketing approval in 1983 (UK) and 1984 (USA); and it is now available in over 80 countries. The relative safety of OTC ibuprofen has been supported by large-scale controlled studies. It has the same low gastro-intestinal (GI) effects as paracetamol (acetaminophen) and fewer GI effects than aspirin. Ibuprofen is a racemate. Its physicochemical properties and the short plasma-elimination half-life of the R(-) isomer, together with its limited ability to inhibit cyclo-oxygenase-1 (COX-1) and thus prostaglandin (PG) synthesis, compared with that of S(+)-ibuprofen, are responsible for the relatively low GI toxicity. The R(-) isomer is then converted in the body to the S(+) isomer after absorption in the GI tract. Ex vivo inhibition of COX-1 (thromboxane A2) and COX-2 (PGE2) at the plasma concentrations of S(+)-ibuprofen corresponding to those found in the plasma following ingestion of 400 mg ibuprofen in dental and other inflammatory pain models provides evidence of the anti-inflammatory mechanism at OTC dosages. R(-)-ibuprofen has effects on leucocytes, suggesting that ibuprofen has anti-leucocyte effects, which underlie its anti-inflammatory actions. Future developments include novel gastro-tolerant forms for ‘at risk’ patients, and uses in the prevention of neuro-inflammatory states and cancers.International Journal of Clinical Practice 01/2013; 67(s178). DOI:10.1111/ijcp.12055 · 2.54 Impact Factor
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ABSTRACT: Polyphenol-rich plants are known to possess benefits to human health. Recent studies have revealed that many Traditional Chinese Medicines (TCMs) are rich sources of polyphenols and exhibit antioxidant and anti-inflammatory activities, and these TCMs have been shown experimentally to overcome some chronic diseases, including cancer. Longan flowers and seeds, two TCMs traditionally used for relieving pain and urinary diseases, have been revealed in our recent reports and other studies to possess rich amounts of polyphenolic species and exhibit strong anti-oxidant activity, and these could be applied for the treatment of diabetes and cancer. Herein, we review the recent findings regarding the benefits of these two TCMs in the treatment of human cancer and the possible cellular and molecular mechanisms of both substances.08/2012; 2(4):78-85. DOI:10.5493/wjem.v2.i4.78