Aspirin' aspirin

Graham Lampard reports on a seminar at The Great Hall, Bart's Hospital, London, that focused on the possible benefits of taking Aspirin to help cure cancer

When your doctor says go home and take two aspirins she may not be just dismissing you. For the medical uses of Aspirin are reaching much further than curing the common headache, and in a series of lectures given by the Aspirin Foundation at Bart's Hospital late last year, different aspects of its possible use in effective cancer treatments were discussed.

As if to highlight the importance of the seminar it was pointed out that the death rate from cancers for social class V is double that of social class I.

Professor Chris Paraskeva, from Bristol University spoke about the use of Aspirin in treating colorectal cancers. This cancer is the second most common cause of cancer deaths in the UK - and in much of the industrialised word - causing around 17,000 deaths every year in the UK, which demands an urgent need to develop new strategies for its prevention and treatment.

The incidence of colorectal cancer varies dramatically throughout the world and diet seems to play an important role. In recent years there has been considerable interest in the possible use of non-steroidal anti-inflammatory drugs (NSAIDs) in the prevention of bowel cancer. Clinical studies in the early eighties showed that the NSAID sulindac caused adenoma (benign tumours sometimes referred to as polyps) regression in patients with familial adenomatous polyposis (FAP). A number of epidemiological studies have shown that the regular intake of Aspirin (acetylsalicylic acid) can reduce the incidence of colorectal cancer by about 50%. High dose aspirin and prolonged use give the best protection.

The chemopreventive effects of NSAIDs such as aspirin are thought to occur, at least in part, through their well established ability to inhibit cyclooxygenase (COX), the rate limiting enzyme in prostaglandin biosynthesis (there are two isoforms, COX-1 and COX-2). COX-2 (and consequently prostaglandins) is over expressed in the majority of colorectal cancers and a significant proportion of adenomas. He said that although the precise mechanisms are unclear there is increasing evidence that the chemopreventive properties of NSAIDs is through a number of different pathways. These include their ability to inhibit tumour cell proliferation, induce apoptosis, inhibit tumour migration and invasion and a number of other important properties associated with tumorigenesis. The anti-neoplastic properties of NSAIDs suggest they may be of use not only in the prevention of bowel cancer but also in developing novel treatments.

In 1993, CAPP1, a European concerted action on Polyp Prevention was launched. Its co-ordinator, Professor John Burn, from the university of Newcstle, said that carriers of FAP were recruited to a randomised placebo controlled trial of 600mg aspirin and/or 30 grams of resistant starch. Substantial epidemiological evidence supports the view that these interventions might prevent the development of adenomatous polyps, the precursor of colorectal cancer. 206 FAP carriers received treatment. Completed data on 133 subjects followed for at least one year have been analysed. Neither intervention resulted in a significant reduction in polyp number as assessed either by the endoscopist or blinded review of rectal videos. The mean size of largest polyps was, however, significantly reduced in the aspirin only group (p=0.01). A secondary analysis used data from those who had stayed more than one year, suggesting higher compliance. Here, both aspirin alone and the combined aspirin/resistant starch group achieved significance (p=0.04 and p0.03).

Those treated with starch had significantly shorter crypts; those treated with aspirin had longer crypts and a 37% increase in crypt cell proliferation. These data suggest that aspirin and resistant starch are protective: 'against cancer but with different modes of action. Aspirin may act later, preventing progression of small adenomata. FAP carriers are an ideal study group since their molecular defect is shared with a majority of sporadic colorectal cancers and any FAP chemoprevention strategy is likely to have general relevance.'

CAPP2, a follow-up EU study, is testing aspirin and resistant starch in carriers of hereditary non-potyposis colon cancer. To date over 600 gene carriers of a target 1,000 have been randomised in thirty-eight centres worldwide. Such studies need sustained infrastructure investment as planned by the new International Society for Gastrointestinal Hereditary Tumours - InSIGHT.

Burn did point that to get CAPP2 up and running required 2m³ of paper submissions to the MHRA, who then came back and said the questionnaire from that submission was too complicated, largely because of the clauses they wanted added! He said that what frustrated him was that he could go on TV and tell viewers to GMTV, for instance, to take two Aspirins because it will do them good, and many would but if you wanted to do it statistically, the paperwork required by the MHRA made such trials extremely difficult.

The idea of COX inhibition introduced by Paraskeva was continued by Dr Henry Jabbour, from the University of Edinburgh Academic Centre. He discussed the effects of having sex in causing cervical cancer.

Dr Jabbour said that prostaglandins are bioactive lipids produced from arachidonic acid by cydooxygenase (COX) enzymes and specific terminal prostanoid synthase enzymes. Following biosynthesis, prostaglandins exert an autocrine/paracrine function by coupling to specific prostanoid-G protein-coupled receptors to activate intracellular signalling and gene transcription.

For many years prostaglandins have been recognised as key molecules in reproductive biology by regulating ovulation, endometrial physiology and cervical ripening. More recently a role for COX enzymes and prostaglandins has been ascertained in reproductive tract pathology, including carcinoma of the cervix.

Globally, cervical cancer is one of the leading causes of cancer-related deaths in women and has a major impact on morbidity and healthcare costs. It is particularly common in less developed countries, including south and central America, southeast Asia and sub Saharan Africa, where 80 % of the world's cervical cancers occur.

Dr Jobbour said that recent studies have confirmed a role for COX-1 and -2 enzymes and prostaglandin E (PGE) in cervical tumourigenesis. Moreover, expression and signalling of certain receptors are up-regulated in cervical carcinomas. Using a COX inducible expression system, his team have confirmed that COX-1 up-regulates the expression of COX-2, PGE synthase, cAMP linked EP receptors and synthesis of PGE.

'Thus, in cervical carcinomas COX enzymes may play a rote in tumoungenesis in an autocrine/paracrine manner by enhancing the synthesis of various prostaglandins, up-regulating the expression of target receptors and increasing signal transduction and transcription of target genes,' he said.

Target genes for the role of COX in cervical tumourigenesis include a host of pro-angiogenic factors that promote blood vessel formation and tumour development. Moreover, COX enzymes can regulate angiogenesis through inhibition of expression of anti-angiogenic factors. COX-2 expression results in an inhibition of expression of the Cathepsin-D gene and its subsequent effect on generation of anti-angiogenic factors such as angiostatin.

In addition to endogenous PGE, in sexually active women growth and invasiveness of neoplastic cervical epithelial cells may be regulated also by PGE present in seminal plasma. PGE concentrations are 10,000x in seminal plasma than that detected at the site of inflammation. 'Our studies confirm that seminal plasma up-regulates the expression of COX-2 and expression and signalling of EP receptors in cervical epithelial cells. Thus, in sexually active women endogenously synthesised and seminal plasma PGE may exacerbate cervical tumoungenesis by acting in concert to modulate the COX/PGE biosynthetic pathway in vivo.

These data outline the potential beneficial effect of COX enzyme inhibitors such as Aspirin in patients with cervical carcinoma. These inhibitors will block the activity of endogenously expressed COX enzymes and subsequent secretion of prostanoids that would activate the elevated receptors in an autocrine/paracrine manner. However, COX enzyme inhibitors alone may not be sufficient in women with cervical carcinoma who are sexually active. The elevated prostanoid receptors in cervical carcinomas may still be activated by seminal plasma prostaglandins in these women.

As if sexual activity wasn't enough for women, Professor Anthony Howell, from the University of Manchester, said that mammary cancers were also a problem.

'Use of aspirin and other NSAIDs is associated in several studies with reduced incidence of breast cancer and has stimulated interest in breast cancer prevention with such agents.' Again, the main target of NSAIDs is COX-1 & 2. The inducible isoform COX-2 is found in human mammary tumours. Its expression and subsequent prostaglandin products tend to be associated with poor prognosis. He said that the over-expression of COX-2 was sufficient to induce mammary tumours in transgenic mice and treatment with NSAIDs reduces tumour formation in many animal models. 'They may act by inhibiting angiogenesis and aromatase and increasing cell death.' A meta-analysis of six cohort and three case control studies of NSAIDs use in 2001 in relation to breast cancer reported a relative risk of 0.70 (95% CI 0.61-0.81) for the case control studies and 0.79 (95% CI 0.59-1.06) for the cohort studies.

He showed data from two important large cohort studies that reported results. An Iowa study of 27,616 women showed a significant reduction in risk of breast cancer with aspirin use but not with other NSAIDs. The Women's Health Initiative study of 80,741 women showed that regular use of NSAIDs for 10 or more years produced a 28% reduction in breast cancer. This study showed an effect for aspirin, ibuprofen and other NSAIDs. Prospective randomised studies are in progress to assess the value of aromatase and COX-2 inhibition for breast cancer prevention.

Moving further down the body, Professor Angus Dalgleish, from St George's Hospital Medical School, London, highlighted the role of Aspirin in bladder and prostate cancers. He said there was considerable evidence that aspirin can prevent bladder cancer, based on epidemiological studies as well as rat bladder cancer models where aspirin inhibits the formation of carcinogenic compounds; but that the role of aspirin in prostate cancer is more controversial, Where there are studies suggesting a clear protective role for aspirin in the development of prostate cancer there are also studies showing no statistical benefit.

'A number of variables have been looked at in these studies, such as a possible affect on metastatic disease, but not on chemoprevention,' he said. Other studies suggest that dose is critically important to inhibit prostate cancer progression. However, more recently a study has suggested that low dose aspirin (<75mg) may be more effective than anti inflammatory doses (>300 mg) of aspirin, thereby suggesting that there may be benefit through inhibiting the prostaglandin pathways and hence producing clotting potential.

He went on to show that there were a number of studies showing the benefit of anti coagulants, such as Heparin, in the treatment of cancer. Most of them have suggested benefit in preventing progression of disease in metastatic spread in patients given anti coagulant treatment. Unfortunately, the need to carefully manage these protocols in order to prevent serious bleeding has prevented widespread incorporation.

Gareth Morgan, secretary of the Welsh Aspirin Group, said that Aspirin had the potential to make a substantial beneficial contribution to cancer reduction programmes. 'However, the hypothesis that aspirin reduces cancer risk can only be properly demonstrated by appropriately designed randomised controlled trials (RCTs).' He said that more RCTs were therefore needed as a matter of urgency to test the aspirin and cancer hypothesis: 'The results of such trials may then be combined using meta-analyses methods to give estimates of the size of the cancer reduction effect.

'The practicalities of conducting RCTs are far-reaching. Substantial investments of time and money are required and results take many years to obtain. Yet, we now reach the point where such investments are required as there is a credible evidence base that needs to be tested experimentally.'

As well as the cancers described earlier, there is suggestive evidence that aspirin may reduce the risk of other cancers such as ovarian cancer and upper gastrointestinal tract cancer, so understanding the mechanism through which aspirin may reduce cancer risk is also an area requiring urgent investigation. It has been suggested that salicylate may contribute to the mechanism by inducing programmed cell death (apoptosis) in cancer cells. Humans consume salicylate ('natural aspirin') in fruits and vegetables. Due to changes in food production and consumption patterns, many individuals living in 'Western countries' are 'salicytate deficient'

Morgan said there is also a need for additional study on policy relating to the use of aspirin, It is known that aspirin has other benefits, namely reduction of cardiovascular disease risk, but also that it confers risks of undesirable effects, namely gastrointestinal irritation and bleeding. He said that Aspirin must only be used if benefits exceed risk: if RCT's confirm the cancer reduction properties of aspirin, this benefit versus risk equation changes. 'Potential policy responses to increased aspirin use should be considered NOW.'

He said that several other lines of research can be identified. They include health economic analyses and also 'risk communication' to ensure appropriate use of aspirin. Public health studies show that disease reduction interventions can increase health inequalities (something called the inverse care law effect), and there is danger of this occurring with aspirin given that it is inexpensive and easily available. In all situations aspirin must be used as a complement and not a competitor to other health improvement programmes. As a rider to that, one of the attendees, a prominent physician, took a regular anti-inflammatory dose of Aspirin each day - so perhaps it should be 'plink! Plink!' for us all.