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An Aspirin a day keeps the cancer at bay?

An Aspirin a day keeps the cancer at bay?

Despite significant advances, cancer remains one of the major causes of morbidity and mortality in the world. It is estimated that half of us will develop one form of cancer or another in our lifetime [1]. Though cancer therapy has improved immeasurably in recent decades, cancer treatment remains unpleasant for the patient, is expensive to implement and remains frustratingly ineffective in some circumstances. Therefore, preventing the cancer from manifesting in the first place is a major target of modern cancer research.

The non-steroidal anti-inflammatory drugs (NSAIDs) contain some of the most commonly prescribed drugs in the world. Prescribed for common ailments, such as chronic inflammatory disorders, pain and fever, it is likely that most family medicine cabinets will contain a pack of aspirin or its related drugs. It is thought that 30 million aspirin prescriptions were written in England in 2007 [2], cementing this drug in particular as a staple of our everyday lives. Since its trademark in the late 19th century by the German pharmaceutical giant Bayer AG, aspirin has been frequently been championed as a cure-all strategy. The message was simple: no matter the ailment, reach for an aspirin. Indeed, who hasn’t heard the old adage, ‘an Aspirin a day keeps the doctor away’?

Image from: http://www.trendhunter.com/trends/dinosaurs-make-great-pets-aspirin-ad-show-us-why-the-dinosaur-became-extinc
Aspirin has been marketed as wonder drug for well over a century, with its benefical effects the subject of some suggestive advertising campaigns. Image from Trendhunter

While it is always difficult to separate pharmaceutical spin from absolute truth, the evidence for Aspirin’s wonder-drug title is substantial. In addition to its use as an effective anti-inflammatory, it has been shown in recent decades that Aspirin may significantly decrease the risk of cardiovascular disease. It has been suggested in recent clinical trials that regular use of Aspirin may decrease the risk of myocardial infarction by up to 32% and stroke by around 15% [3]. As a result, Aspirin has evolved for many people from a commonly used drug to treat maladies into a regularly taken, prophylactic strategy to prevent them.

If that weren’t enough, there is now substantial evidence to suggest that similar regular use of Aspirin may provide protection against certain forms of cancer. In large analyses of data taken from trials designed to test the drug’s ability to prevent cardiovascular disorders, it is becoming clear that regular use of Aspirin drastically reduces the risk of developing cancer, particularly cancers of the colon and the stomach. These analyses, undertaken by Rothwell and colleagues [4, 5], suggest that the risk of developing colorectal cancer may be reduced by up to 40%. It is worth remembering that these are relative, not absolute decreases. The lifetime risk of colorectal cancer is around 4 in 100. Therefore, a 40% decrease in risk shifts this risk to around 2.4 in 100. Of course, additional risk factors can shift this lifetime risk, but it is clear that aspirin is extremely beneficial. The consensus that has largely been reached regarding it use is that daily use for around 5 years provides lasting protection, albeit after a ‘lag’ period of around 10 years.

Investigations into just how these drugs have their protective effect have yielded fascinating findings. Over the past

Aspirin works by inhibiting the cyclooxygenase enzymes. It recognises the active sites of the enzymes, the sections that extend at the bottom of this image. It then adds molecules called acetyl groups at these regions, preventing the enzyme from having its action and preventing the production of the prostanoids. Image from RSCB.

few decades, researched as honed in on Aspirin’s anti-inflammatory activity as an explanation. The active ingredient of Aspirin, salicylate, works by modifying and inactivating enzymes called cyclooxygenases, commonly referred to as COX enzymes. These enzymes are responsible for the production of a group of lipids known as the prostanoids, some of which play important roles in inflammation. However, it is thought that these prostanoids, particularly a molecule called Prostaglandin E2, may also play crucial roles in the development of numerous cancers. Hence, chronic inflammation and constantly high levels of these inflammatory mediators, is now considered to be a risk factor for developing cancers and inhibiting their production may provide significant protection.

However, while an aspirin a day may keep the cancer at bay, it may not keep the doctor away in some people. A significant obstacle to the regular use of Aspirin to prevent cancer and cardiovascular disease is the substantial toxicity associated with daily ingestion. While the prostanoids produced by the COX enzymes do play roles in the development of numerous diseases, they also play important roles in healthy tissues. Prostanoids are tasked with protection of the lining of the colon and the stomach, as well as other tissues, and regulate the formation of blood clots. Therefore, constant suppression of their protection can result in breakdown these protection layers, resulting in gastric ulcers and bleeding, and a substantially increased risk of cardiovascular disease, such as myocardial infarction. With this in mind, there has to be a crucial balancing act set up to determine whether an individual will benefit from regularly taking Aspirin and other NSAIDs. If a person has an inherently high risk of developing gastric bleeding, the benefit derived from preventing the potential onset of colorectal cancer will probably be outweighed by the risk of these bleeding complications.

But what can help us to determine whether these drugs are advisable for people on a individualised basis? Family history can provide some degree of advice. For example, an individual with a family history of heart attacks or strokes will not benefit from using an NSAID that inhibits the COX enzymes in a way that puts them at risk from such events. Instead, they will be directed to a different drug that decreases the levels of Prostaglandin E2 in a way that may prevent colorectal cancer, but doesn’t increase their risk of heart attacks any further; or they may simply be told to avoid regular NSAID use. However, improving access to advanced medical technologies may provide a far more accurate prediction of benefit.

Genome sequencing has been heavily publicised in its ability to predict an individual’s risk of developing certain diseases, including cancer, but recent studies have suggested it may also predict whether people will respond to certain therapies or preventative strategies. Within the past year, numerous papers have been published that report such risk factors and predictive markers. For example, intrinsically low levels of an enzyme called 15-PGDH, which breaks down Prostaglandin E2 and can hence be seen as protective against bowel cancer, can predict both an increased risk of colon cancer and a varying response to certain NSAIDs: patients will not benefit from taking Aspirin, but are protected with regular use of a similar drug, Sulindac [6, 7]. Even more excitingly, tiny changes at certain points in the genome can also exquisitely predict a positive or negative response from regular use of these drugs [8]. These advances in medical technology provide an exciting prospect, whereby individual genome sequencing can both predict the risk of developing certain cancers and determine the most appropriate strategy to safely prevent these cancers from ever arising.

It really does seem like Aspirin is the drug that keeps on giving. Now, through the addition of its potential prevention of numerous cancers to its armoury, it may gain a new lease of life as a staple of the measures that we routinely undertake to stave of cancer. Undoubtedly, increasing our understanding about how cancer arises and how differences in our genomes reflect the way we respond to drugs will lead to greater fine-tuning of both this and other preventative strategies.

‘Til next time…

Joe


 

Further Reading…

[1] – http://www.cancerresearchuk.org/cancer-info/cancerstats/incidence/risk/statistics-on-the-risk-of-developing-cancer
[2] – National Health Service Information Centre. Prescription cost analysis for England 2007. Available from: http://www.ic.nhs. uk/webfiles/publications/PCA publication/PCA 2007 complete V2.pdf
[3] – http://www.ahrq.gov/professionals/clinicians-providers/resources/aspprovider.html 
[4] – http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)61543-7/abstract
[5] – http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)61720-0/abstract
[6] – http://carcin.oxfordjournals.org/content/36/2/291.abstract
[7] – http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4030641/
[8] – http://jama.jamanetwork.com/article.aspx?articleid=2203800

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