Aspirin helps more than just aches and pains--its properties go far beyond that. Rod Flower explains

Ask any medical student and he or she will tell you that aspirin reduces fever, pain, and inflammation but may cause ulcers. If prompted, students may also recollect that it prolongs bleeding and may prevent strokes and heart attacks, but they are unlikely to know of aspirin's use in treating cancer or Alzheimer's disease.

A defining point in the history of aspirin was the discovery that it inhibited prostaglandin forming cyclo-oxygenase (COX 1).1 Prostaglandins cause inflammation, fever, and pain; have gastric cytoprotective actions; and may play a part when platelets aggregate, so this discovery provided a unified explanation for the effects of aspirin--and most other non-steroidal anti-inflammatory drugs.

Events took an even more interesting turn when scientists found another isoform of cyclo-oxygenase--cyclo-oxygenase-2 (COX 2).2 Although both enzymes are similar in many ways, they differ in important ways--for eample, COX 2 was induced in cells by inflammatory insults. COX 2 therefore seemed to be the most relevant target in inflammation, which led to the notion that the constitutive COX 1 generated prostaglandins required to maintain physiological functions (such as protection of the gastric mucosa, aggregation of platelets) whereas COX 2 generated pro-inflammatory mediators.3 Aspirin inhibited both isoforms, as did most non-steroidal anti-inflammatory drugs, perhaps explaining why these compounds were not only effective treatment but also had characteristic side effects.

Current interest

The ensuing search by the pharmaceutical industry for selective COX 2 inhibitors culminated in the recent introduction of new, safer, anti-inflammatory drugs as well as the rediscovery of older drugs that had COX 2 selective actions. But, as aspirin is a drug that inhibits both isoforms, one may ask why it continues to be used and why there is a continuing interest in its pharmacology?

The answer to the first part of this question is complex, but it is partly down to aspirin's unique mechanism of action that inhibits both COX 1 and COX 2 irreversibly. The effects of this are evident in platelets where cyclo-oxygenase cannot be replaced, explaining why a single aspirin can depress aggregation of platelets for many days. The half life of aspirin in plasma is short; esterases remove the acetyl group leaving free salicylate, which may have a secondary pharmacological effect, through cyclo-oxygenase inhibition or other mechanism, adding to the complexity of aspirin's action.

Cancers

The current interest in aspirin stems from the fact that many animal experiments and human epidemiological studies now link treatment with aspirin (and other non-steroidal anti-inflammatory drugs) with beneficial effects in a variety of cancers, including breast cancer, ovarian cancers, oesophageal cancer, and colorectal cancer. Recent meta-analyses supported that idea that the overall relative risk of colorectal cancer is reduced in people taking long term aspirin.4 Another meta-analysis of observational data confirmed a protective effect in oesophageal cancer and gave evidence of a relation with dose and duration of treatment, and other studies showed a beneficial effect in the case of ovarian cancer.4 5 How aspirin or other non-steroidal anti-inflammatory drugs produce this effect is not entirely clear, but the synthesis or activity of COX 2 is increased in many tumours, and inhibition could activate apoptotic mechanisms or suppress angiogenesis.6 The link between diet and the prevention of colorectal cancer has never been suggested to be attributable to salicylic acid in plant and vegetable foodstuffs.7

Alzheimer's disease

It was evidence from longitudinal studies of patients taking chronic non-steroidal anti-inflammatory drugs that originally pointed to a reduced risk in Alzheimer's disease,8 and these findings are borne out by other more recent data,9 which showed an inverse relationship between taking aspirin (and other non-steroidal anti-inflammatory drugs) and Alzheimer's disease but not other forms of dementia. Once again, the mechanism is uncertain--Alzheimer's undoubtedly has an inflammatory component and therefore COX 2 may be the target, although other mechanisms have been suggested.10

Two questions bedevil what is otherwise an exciting prospect for treatment. What is the minimum dose required to achieve these effects, and how do we asses the relative risk and benefit of a preventive treatment that will entail treating healthy people for many years with a drug known to have gastric and other side effects? Here, aspirin's grandchildren may have a role. COX 2 seems to be the main culprit in both cancer and Alzheimer's disease, so the selective COX 2 inhibitors, which have reduced gastric side effects, are natural choices for such long term prophylactic treatment.

The future

What of the future of aspirin itself? Because of its profound effects on platelets, aspirin is unlikely to be supplanted as a cheap and effective prophylactic treatment for patients at risk of excessive aggregation of platelets, but in view of its venerable history, it is surprising that aspirin is still the subject of ongoing medicinal chemistry effort. Attaching a nitric oxide donor to the molecule seems to ameliorate the side effects of the drug while boosting its therapeutic effects.11 The discovery of a third form of cyclo-oxygenase,12 mainly confined to the central nervous system and heart, which is also inhibited by aspirin, will no doubt provide yet another twist to the continuing story of this fascinating but simple drug.

1. Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat New Biol 1971;231:232-5.
2. Xie WL, Chipman JG, Robertson DL, Erikson RL, Simmons DL. Expression of a mitogen-responsive gene encoding prostaglandin synthase is regulated by mRNA splicing. Proc Natl Acad Sci USA 1991;88:2692-6.
3. Mitchell JA, Akarasereenont P, Thiemermann C, Flower RJ, Vane JR. Selectivity of nonsteroidal antiinflammatory drugs as inhibitors of constitutive and inducible cyclooxygenase. Proc Natl Acad Sci USA 1993;90:11 693-7.
4. Bosetti C, Gallus S, La Vecchia C. Aspirin and cancer risk: an update to 2001. Eur J Cancer Prev 2002;11:535-42.
5. Corley DA, Kerlikowske K, Verma R, Buffler P. Protective association of aspirin/NSAIDs and esophageal cancer: a systematic review and meta-analysis. Gastroenterology 2003;124:47-56.
6. Thun MJ, Henley SJ, Patrono C. Nonsteroidal anti-inflammatory drugs as anticancer agents: mechanistic, pharmacologic, and clinical issues. J Natl Cancer Inst 2002;94:252-66.
7. Paterson JR, Lawrence JR. Salicylic acid: a link between aspirin, diet and the prevention of colorectal cancer. QJM 2001;94:445-8.
8. Stewart WF, Kawas C, Corrada M, Metter EJ. Risk of Alzheimer's disease and duration of NSAID use. Neurology 1997;48:626-32.
9. Broe GA, Grayson DA, Creasey HM, Waite LM, Casey BJ, Bennett HP, et al. Anti-inflammatory drugs protect against Alzheimer disease at low doses. Arch Neurol 2000;57:1586-91.
10. Gao F, Bales KR, Dodel RC, Liu J, Chen X, Hample H, et al. NF-kappaB mediates IL-1beta-induced synthesis/release of alpha2-macroglobulin in a human glial cell line. Brain Res Mol Brain Res 2002;105:108-14.
11. Burgaud JL, Ongini E, Del Soldato P. Nitric oxide-releasing drugs: a novel class of effective and safe therapeutic agents. Ann N Y Acad Sci 2002;962:360-71.
12. Chandrasekharan NV, Dai H, Roos KL, Evanson NK, Tomsik J, Elton TS, et al. COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure, and expression. Proc Natl Acad Sci USA 2002;99:13 926-31.

Guidelines: We intend publishing within 24 hours all responses that contribute substantially to the topic under discussion. To avoid points that have already been made please read other people's responses before posting your own. All responses will be eligible for publication in the paper studentBMJ, providing that current appointment and place of work are given. Name and email address are required to send a response and will be published with the response.

Please note: When writing a respnse to a response, please enter the original title of the article and the author of the response you are responding to.