AERD patients usually suffer from moderate or severe forms of asthma requiring chronic treatment with moderate to high doses of inhaled glucocorticosteroids; oral glucocorticoids are necessary to control asthma in many of these patients (2). In addition, the majority of aspirin-intolerant asthmatics have nasal and sinus symptoms. The incidence of rhinosinusitis, as demonstrated by CT scans, is up to 100%, and the frequency of nasal polyps may be as high as 90% (6). Rhinosinusitis is protracted and the nasal polyps tend to recur following polypectomy: the recurrence rate for nasal polyps in AERD patients is several times higher than in aspirin-tolerant asthmatics after standard polypectomy but also after Functional Endoscopic Sinus Surgery (FEES). Polypoid hypertrophy of the mucosa is not just limited to the nasal cavity; it usually involves all sinuses and is more extensive in ASA-intolerant compared to Acetylsalicylic Acid (ASA) - tolerant patients with nasal polyposis. There is also clinical evidence that uncontrolled chronic rhinosinusitis often aggravates the course of asthma in these patients.
The mechanism of aspirin-hypersensitivity in asthmatic patients is not immunological but is related to pharmacological properties of ASA and other NSAIDs. As originally documented in 1975 by Andrew Szczeklik et al (7), only NSAIDs that are strong or at least moderate inhibitors of prostaglandins (more specifically, inhibitors of COX-1, an enzyme that converts arachidonic acid into prostaglandins, thromboxanes and prostacycline), can cause reactions in ASA-intolerant patients. It is postulated that inhibition of COX-1 by aspirin or other NSAIDs triggers a biochemical cascade which causes asthma. In fact, a local deficiency in prostaglandin E2 synthesis was found in nasal polyps, epithelial cells and bronchial fibroblasts from ASA-hypersensitive patients, suggesting a basal defect in this regulatory mechanism which may be further exacerbated by aspirin (8, 9).
Liu Y, Ju J, Xiao H, et al: Effects ofcombination of calcium and aspirin on azoxymethane-induced aberrantcrypt foci formation in the colons of mice and rats. Nutr Cancer.60:660–665. 2008. : :
Drugs administered during treatment periods of the study were: paracetamol (po), lincomycin (po), ibuprofen (po), acetylsalicylic acid (po) and dexpanthenol ointment (topical).
Din FV, Theodoratou E, Farrington SM, etal: Effect of aspirin and NSAIDs on risk and survival fromcolorectal cancer. Gut. 59:1670–1679. 2010. : :
Logan RF, Little J, Hawtin PG andHardcastle JD: Effect of aspirin and non-steroidalanti-inflammatory drugs on colorectal adenomas: case-control studyof subjects participating in the Nottingham faecal occult bloodscreening programme. BMJ. 307:285–289. 1993. :
The phenotypic studies indicated that the diaspirincompounds were capable of inducing apoptosis (). On analysis of the mechanismsunderlying this apoptosis, we found that similar to aspirin, thediaspirin compounds sequentially induced depletion of cyclin D1,degradation of IκB, nuclear translocation of NF-κB/RelA complexesand repression of NF-κB activity. However, in contrast to aspirin,the aspirin analogues did not induce nucleolar translocation ofRelA or cell cycle arrest. Aspirin consists of acetyl andsalicylate moieties, both of which have their own individualtargets (). The aspirinanalogues we generated retained the salicylate part of the moleculebut lost the acetyl component. Indeed, western blot analysis withantibodies against acetylated lysine indicated that aspirin induceda dose-dependent increase in protein acetylation, but this was notobserved in response to DiA and F-DiA (data not shown). Therefore,one possibility is that the ability of aspirin to stimulate NF-κBsignalling is associated with the salicylate component of thecompound while nucleolar translocation of RelA and cell cyclearrest are associated with its acetylating potential. In keepingwith this suggestion, salicylate has previously been shown toactivate p38 kinase activity (),which we have previously shown lies upstream of aspirin effects oncyclin D1 and the NF-κB pathway ().
Bousserouel S, Gosse F, Bouhadjar M, SolerL, Marescaux J and Raul F: Long-term administration of aspirininhibits tumour formation and triggers anti-neoplastic molecularchanges in a pre-clinical model of colon carcinogenesis. Oncol Rep.23:511–517. 2010.
Paracetamol has since been used increasingly as a substitute for other analgesics such as aspirin and phenacetin, and in the United Kingdom its sales have exceeded those of aspirin for more than a decade.
Effect of diaspirin and fumaryldiaspirin on an implantable colorectal mouse tumour model. MAC13cells were implanted subcutaneously into the flank of three groups(N=6) of NMRI mice. Twelve days after implantation, mice wereintravenously administered 1 mg/kg DiA or F-DiA daily, while thecontrol group received PBS. The results demonstrate a robustinhibition of growth in the drug-treated groups, which weresignificantly different from the control group(*P
Sansom OJ, Stark LA, Dunlop MG and ClarkeAR: Suppression of intestinal and mammary neoplasia by lifetimeadministration of aspirin in Apc(Min/+) and Apc(Min/+), Msh2(−/−)mice. Cancer Res. 61:7060–7064. 2001.
Taken together, the above data suggest that thediaspirin compounds, particularly F-Dia, have potent activityagainst CRC cells. To determine whether these effects translateinto potency, we utilised the well characterisedMAC13 syngeneic mouse model of CRC (). In the cytotoxicity assays MAC13cells cultured were more sensitive to DiA and F-DiAthan aspirin (data not shown); , the mouse coloncarcinoma cells were implanted subcutaneously into NMRI mice andtreatment commenced 12 days after implantation. Low dose (1 mg/kg)DiA or F-DiA was administered every day for 10 days by intravenousinjection. No overt side-effect was observed between the treatmentand vehicle-treated control group, and food and water intake wasunaffected. As shown in ,treatment with DiA and F-DiA significantly inhibited the growth ofthe tumours, and almost complete suppression of growth was apparentin the mice treated with F-DiA.