ABSTRACT
In this chapter, we will refer to some of the Ghemopre-where it is cytoprotective. It is also expressed in the early ventive ;;1gents th:1t h;;tve been or are being evai iJ<Jted ph::Jse of carcinogenesis in the l<lrge bowel 1 ° COX<) is clinically and could reach clinical application. induced during the inflammatory processes and during the
process of cellular hyperproli·feration and progression to neopl<>si<J_:-1 In order to reduce the production of
Pharmaceutic<•! drugs prostaglandins, aspirin, and the other commonly used non-NSAIDs, while aiming at the COX-2 (which was
Several drugs th<Jt h<Jve been investig<Jted or specifically induced by some infi<Jmm<Jtory or neoplastic: process). developed for their chemopreventive properties will now have a non-specific effec·: and inhibit both COX~1 and 2.2 •9 be consi<lered. 1 This non-specific inrdbition can result in the losf, of cyto-
Non-steroidal a111ti-inflam~matory drug;s Aspirin
protection <3nd ::JIIow ~~<Jm::,ge to occur to the gp.stroduoden::J I muco8a. Cyclooxygenase inhibition COX-2 inhibition studies have
The strongest epidemiologic evidence th•~t medic:;-ttion~: been performed with spec:ifiG COX-? inhibitors thought prevent colorectal cancer is for the NSAIDs family in gen-to act as promoters of apopt osis and inhibitors of invaeral and specifically for aspirin.1 :' The clinical evidence is sion and angiogenesis, which may prov1de a better for <l 50% reduction in incidence of large-bowel c:=tncer. complic:<Jtion-benefit ratio than th<Jt obt<Jined with However, this evidence is indirect, as a byproduct of epi-aspirin.11 New NSAIDs that are COX~1-sparing and are demiologic and follow-up studies in cl1ronic aspirin users COX-2-speGific inhibiting medications have been developed and users of other non-specific cyc;looxygen:1se :cOX! <Jnd rn<Jrketed. These include the less-specific nimesulide inhibitors. The aspirin effect is greater in those having a (Mesu lid, Helsinn Healthcare, Switzerland:!, which has high intake ol' vegetables and is influenced bl' having a been notecl to cause the side effect of llepatotoxiGity, and specific polymorphism of the ornithine dec•~rbo~yi<Jse n::JhiJmetone (HelifP.x Smith Kline Reech<Jm, UK). The gene.5•6 There is further supportive evidence for the highly specific COX-2 inhibitors include celecoxib (Celesignlficant efficacy of aspinn from intervention trials in brex), and valdecoxib (Bextra) Pfizer Inc., USA). So far, adenoma patients followed up for adenoma recurrence.v none of these have been approved for preventing sporadic
colorectal neoplasia, but trials had been initiated.1 •2•4 Oth~!r NSAIDs Their dose-dependent side effects includE• edema, a slight There are studies with newer and safer aspirin pre pararec!uction in rena! function, an<j elevation of b!oo<j pres-tion~; and other NSA!Ds. These include nitric oxide-aspirin sure. Bextra and Rofecoxib (Vioxx, Merck .s, Co., Inc., USA) (NO-aspinn). Shor-:-term human studies have demonhave b•3en withdrawn from th•3 market because of an strated tt1at, compared with aspirin, there is no gastric increased risk for cardiovascular and s~.in events. Ce!e-damage, and ex.pE~rimenta! studies have demonstrated coxib has been approved by the US Food and Drug Admin-inhibition of carcinogenesis. As yet, there are no pubistration (FDA) as an adjunct thE:rapy for FAP patients (see lished long-term human colorectal neoplasia prevention Chapter 6) as it has been den1onstrated to signi·ficant!y studles. 1l·,15 recluce their polyp sizes and numbers.1•2 .4 However, 5-aminosa/icylic acid (5-ASA) preparations are used for becaus•3 of the increased risk for cardiovascular events treating inflammatory bowel disease (ulcerative colitis and occurring \"lith COX-2 inhibitor drugs, it is not knov·Jn if they Crohn's diseases). They are given in the acute state, but will continue to be available for use even in young people also chronically, to reduce the frequency of disease with polyposis. relapses. There is epidemiologic evidence of less colorec-
There is good clinical evidence that NS~.IDs such as ta! neoplasia occurring in those persons v·J!lo ke!ep taking sui indac will inhibit the growth of adenomatous polyps in 5-ASA.16 This has been attributed to the transient COX-2 the retained rectum of FAP patientsY Sulindac and one of inhibition that occurs wt1ile taking therapyH its metabolites, su!indac sulfide, also int1ibit cellular proliferation and promote apoptosis. However, while reducing the number and siw of adenomatous polyps 1n FAP patients, they inhibit both COX-1 and COX-2. Unfortunately, this is an incomplete therapeutic effect and adenomatous tissue is still pmsent within the mucosa, and colorectal cancer can even occur \"'Jhile under treatrnent. 12
This is not unexpected, as experimental studies using a carcinogen clemonstrated that the magnitude of thmapeutlc response depende::t on hoV·! early su!indac \AJas administered in relationship to the carcinogen administration. So, in an ongoing genetic 1jisorder such as F.ll,P, it is very unlikely that NS,l\JDs can provide a complete therapeutic effect. COX-2 is also strongly expressed in other genetically dnven familial neoplasia syndromes, so that COX-2 int"1ibltors might a lso have a role in their rnanageme1t (see Chapter 6).
