We know pretty well how aspirin works in reducing cardiovascular risk and this is through its unique properties of permanently inactivating a platelet enzyme called cyclooxygenase 1. There are some distinct features of aspirin pharmacodynamics on platelets which are the fact that you can achieve a full effect with a once daily dosing, that is a dosing interval of 24 hours, despite aspirin’s short half-life in the human circulation. This is due to the permanent nature of platelet COX1 inactivation by aspirin.
The second feature is that you achieve the maximal effect at low doses, doses between 75-100mg. Higher doses will not give you any greater benefit and, in fact, they may give you more side effects. It’s interesting because when you look at the evidence for the chemopreventive effective of aspirin against, for example, colorectal cancer, it looks as if the same fingerprints are apparent of aspirin action being detectable at low doses, 75-100mg given once daily, and the effect being saturable at low doses, so higher doses will not produce greater benefits in terms of preventing cancer incidence and mortality which may help us to understand the mechanism through which aspirin works as a potential chemopreventive agent. All these indirect lines of evidence point to the platelet as a potential target for aspirin pharmacodynamics. Platelet activation at sites of intestinal mucosal lesions may lead to the release of platelet mediators which are both lipid and protein in nature and these platelet derived mediators could then impact on adjacent nucleated cells of the intestinal mucosal-like stromal cells to induce COX2 expression. We know from a lot of preclinical data that COX2 induction is then proliferative and pro-angiogenic. This might explain why in certain clinical models, for example the sporadic colorectal adenoma recurrence, you have a similar effect with low dose aspirin acting upstream on platelet activation and with selective COX2 inhibitors working downstream on COX2 activity of nucleated cells. This is, of course, a working hypothesis and is something that we are currently trying to test directly.
Do you think it will be difficult for aspirin to be approved in Europe for colorectal cancer?
I think understanding the mechanism of action and defining the optimal dose are important aspects, not only for the scientific community but in particular for the regulatory community. So I’m sure that this is an area where we need further studies in order to pave the way to a new regulatory approval. In terms of primary prevention it would be the very first example of a potential chemopreventive strategy with relatively limited toxicity, or at least a toxicity that we know pretty well what it is for which there are potential measures that can reduce toxicity in terms, for example, of GI bleeding. There were presentations at this meeting suggesting that H. pylori eradication may substantially reduce the risk of ulcer formation and therefore bleeding from pre-existing ulcers due to aspirin.
