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      Mechanistic and Pharmacological Issues of Aspirin as an Anticancer Agent

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          Abstract

          Recent findings have shown that aspirin, taken for several years, reduces the long-term risk of some cancers, particularly colorectal cancer. The result that aspirin benefit is detectable at daily low-doses (at least 75mg), the same used for the prevention of cardiovascular disease, positions the antiplatelet action of aspirin at the center of its antitumor efficacy. At low-doses given every 24 h, aspirin is acting by a complete and persistent inhibition of cyclooxygenase (COX)-1 in platelets (in the pre-systemic circulation) while causing a limited and rapidly reversible inhibitory effect on COX-2 and/or COX-1 expressed in nucleated cells. Aspirin has a short half-life in human circulation (approximately 20 min); nucleated cells have the ability to resynthesize the acetylated COX-isozymes within a few hours, while platelets do not. COX-independent mechanisms of aspirin, such as the inhibition of Wnt/ β-catenin and NF-kB signaling and the acetylation of extra-COX proteins, have been suggested to play a role in its chemo-preventive effects, but their relevance remains to be demonstrated in vivo at clinical doses. In conclusion, the results of clinical pharmacology and the analysis of randomized and epidemiological studies suggest that colorectal cancer and atherothrombosis share a common mechanism of disease, i.e. enhanced platelet activation in response to injury at distinct sites.

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          Most cited references103

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          Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients.

          (2002)
          To determine the effects of antiplatelet therapy among patients at high risk of occlusive vascular events. Collaborative meta-analyses (systematic overviews). Randomised trials of an antiplatelet regimen versus control or of one antiplatelet regimen versus another in high risk patients (with acute or previous vascular disease or some other predisposing condition) from which results were available before September 1997. Trials had to use a method of randomisation that precluded prior knowledge of the next treatment to be allocated and comparisons had to be unconfounded-that is, have study groups that differed only in terms of antiplatelet regimen. 287 studies involving 135 000 patients in comparisons of antiplatelet therapy versus control and 77 000 in comparisons of different antiplatelet regimens. "Serious vascular event": non-fatal myocardial infarction, non-fatal stroke, or vascular death. Overall, among these high risk patients, allocation to antiplatelet therapy reduced the combined outcome of any serious vascular event by about one quarter; non-fatal myocardial infarction was reduced by one third, non-fatal stroke by one quarter, and vascular mortality by one sixth (with no apparent adverse effect on other deaths). Absolute reductions in the risk of having a serious vascular event were 36 (SE 5) per 1000 treated for two years among patients with previous myocardial infarction; 38 (5) per 1000 patients treated for one month among patients with acute myocardial infarction; 36 (6) per 1000 treated for two years among those with previous stroke or transient ischaemic attack; 9 (3) per 1000 treated for three weeks among those with acute stroke; and 22 (3) per 1000 treated for two years among other high risk patients (with separately significant results for those with stable angina (P=0.0005), peripheral arterial disease (P=0.004), and atrial fibrillation (P=0.01)). In each of these high risk categories, the absolute benefits substantially outweighed the absolute risks of major extracranial bleeding. Aspirin was the most widely studied antiplatelet drug, with doses of 75-150 mg daily at least as effective as higher daily doses. The effects of doses lower than 75 mg daily were less certain. Clopidogrel reduced serious vascular events by 10% (4%) compared with aspirin, which was similar to the 12% (7%) reduction observed with its analogue ticlopidine. Addition of dipyridamole to aspirin produced no significant further reduction in vascular events compared with aspirin alone. Among patients at high risk of immediate coronary occlusion, short term addition of an intravenous glycoprotein IIb/IIIa antagonist to aspirin prevented a further 20 (4) vascular events per 1000 (P<0.0001) but caused 23 major (but rarely fatal) extracranial bleeds per 1000. Aspirin (or another oral antiplatelet drug) is protective in most types of patient at increased risk of occlusive vascular events, including those with an acute myocardial infarction or ischaemic stroke, unstable or stable angina, previous myocardial infarction, stroke or cerebral ischaemia, peripheral arterial disease, or atrial fibrillation. Low dose aspirin (75-150 mg daily) is an effective antiplatelet regimen for long term use, but in acute settings an initial loading dose of at least 150 mg aspirin may be required. Adding a second antiplatelet drug to aspirin may produce additional benefits in some clinical circumstances, but more research into this strategy is needed.
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            The MAPK signaling cascade.

            The transmission of extracellular signals into their intracellular targets is mediated by a network of interacting proteins that regulate a large number of cellular processes. Cumulative efforts from many laboratories over the past decade have allowed the elucidation of one such signaling mechanism, which involves activations of several membranal signaling molecules followed by a sequential stimulation of several cytoplasmic protein kinases collectively known as mitogen-activated protein kinase (MAPK) signaling cascade. Up to six tiers in this cascade contribute to the amplification and specificity of the transmitted signals that eventually activate several regulatory molecules in the cytoplasm and in the nucleus to initiate cellular processes such as proliferation, differentiation, and development. Moreover, because many oncogenes have been shown to encode proteins that transmit mitogenic signals upstream of this cascade, the MAPK pathway provides a simple unifying explanation for the mechanism of action of most, if not all, nonnuclear oncogenes. The pattern of MAPK cascade is not restricted to growth factor signaling and it is now known that signaling pathways initiated by phorbol esters, ionophors, heat shock, and ligands for seven transmembrane receptors use distinct MAPK cascades with little or no cross-reactivity between them. In this review we emphasize primarily the first MAPK cascade to be discovered that uses the MEK and ERK isoforms and describe their involvement in different cellular processes.
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              Screening for colorectal cancer: U.S. Preventive Services Task Force recommendation statement.

              (2008)
              Update of the 2002 U.S. Preventive Services Task Force (USPSTF) recommendation statement on screening for colorectal cancer. To update its recommendation, the USPSTF commissioned 2 studies: 1) a targeted systematic evidence review on 4 selected questions relating to test characteristics and benefits and harms of screening technologies, and 2) a decision analytic modeling analysis using population modeling techniques to compare the expected health outcomes and resource requirements of available screening modalities when used in a programmatic way over time. The USPSTF recommends screening for colorectal cancer using fecal occult blood testing, sigmoidoscopy, or colonoscopy in adults, beginning at age 50 years and continuing until age 75 years. The risks and benefits of these screening methods vary. (A recommendation). The USPSTF recommends against routine screening for colorectal cancer in adults 76 to 85 years of age. There may be considerations that support colorectal cancer screening in an individual patient. (C recommendation). The USPSTF recommends against screening for colorectal cancer in adults older than age 85 years. (D recommendation). The USPSTF concludes that the evidence is insufficient to assess the benefits and harms of computed tomographic colonography and fecal DNA testing as screening modalities for colorectal cancer. (I statement).
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                Author and article information

                Journal
                Pharmaceuticals (Basel)
                Pharmaceuticals (Basel)
                pharmaceuticals
                Pharmaceuticals
                MDPI
                1424-8247
                05 December 2012
                December 2012
                : 5
                : 12
                : 1346-1371
                Affiliations
                [1 ] Department of Neuroscience and Imaging, Center of Excellence on Aging (CeSI), “G. d’Annunzio” University, Via dei Vestini 31, 66100 Chieti, Italy; E-Mail: m.dovizio@ 123456unich.it (M.D.); s.tacconelli@ 123456unich.it (S.T.); ppatrignani@ 123456unich.it (P.P.)
                [2 ] University of Zaragoza School of Medicine, University Hospital Lozano Blesa, IIS Aragón. CIBERehd, 50009 Zaragoza, Spain; E-Mail: carlossostres@ 123456gmail.com (C.S.)
                [3 ] Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, PA 19104, USA; E-Mail: emanuela@ 123456mail.med.upenn.edu (E.R)
                Author notes
                [* ] Author to whom correspondence should be addressed; E-Mail: ppatrignani@ 123456unich.it ; Tel.: +39-0871-541473; Fax: +39-0871-3556718.
                Article
                pharmaceuticals-05-01346
                10.3390/ph5121346
                3816673
                24281340
                f1a3de05-8d88-438d-9511-0ec7a23657f2
                © 2012 by the authors; licensee MDPI, Basel, Switzerland.

                This article is an open-access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/3.0/).

                History
                : 06 November 2012
                : 16 November 2012
                : 30 November 2012
                Categories
                Review

                aspirin,colorectal cancer,platelet,cycloooxygenase-1
                aspirin, colorectal cancer, platelet, cycloooxygenase-1

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