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have a poor prognosis.7 In addition, recurrence and metastasis of CRC also carry a very high mortality rate. Therefore,
there is a need for improvement in the diagnosis of CRC as
well as identification of newer therapeutic targets that can
be specifically drugged to improve the management of
these cancers.8
An important key survival molecule that is currently
being investigated as a molecular marker and a potential
therapeutic target is cyclooxygenase-2 (Cox-2) in various
cancers. The main function of Cox is to synthesize prostaglandins (PGs) from arachidonic acid (AA). There are 2 isoforms of Cox: Cox-1 that is found to be expressed in normal
cells and Cox-2 that is preferentially expressed in cancer
cells and its expression is enhanced by pro-inflammatory
cytokines and carcinogens.9 COX-1 and COX-2 catalyze the
rate-limiting step in the metabolic conversion of AA to PGs.
Prostaglandins are involved in a variety of pathologic processes. Specifically, prostaglandin E2 (PGE2) has been shown
to mediate the pro-inflammatory and tumor-promoting
effects of COX-2 in CRC.10 Cox-2 has been found to be
overexpressed in a variety of cancers including breast, ovary,
colorectal, thyroid, and lung.11 COX-2 overexpression is
seen in precancerous and cancerous lesions in the colon and
is associated with decreased colon cancer cell apoptosis and
increased production of angiogenesis-promoting factors.12
Up to 50% of colorectal adenomas and 85% of sporadic
colon carcinomas have elevated levels of COX-2, and
COX-2 overexpression in CRC is associated with a worse
survival. COX-2 appears to play a role in polyp formation,
and COX-2 inhibition suppresses polyp growth, restores
apoptosis, and decreases expression of proangiogenic factors. Inhibition of COX-2 also downregulates the phosphatidylinositol 3-kinase (PI3K) signaling pathway, which plays
an important role in carcinogenesis and cancer cell resistance
to apoptosis.13 Strong COX-2 expression was associated
with high incidence and recurrence of CRC than weak or
absent COX-2 expression.14
Aspirin and other nonsteroidal anti-inflammatory drugs
(NSAIDs) have been tested in randomized clinical trials
and have been successful in reducing the risk of CRC.
Unfortunately, by inhibiting COX enzymes, they tend to
inhibit physiologically important PGs that could ultimately
lead to potentially fatal toxicities that exclude their longterm use for cancer chemoprevention. COX-2 inhibitors
and NSAIDs are associated with an increased risk for cardiovascular events, gastrointestinal ulcerations, and bleeding. As for aspirin, even though it has a more favorable
cardiovascular profile, hemorrhagic stroke and gastrointestinal bleeding are a concern particularly with prolonged
use of the drug.10
Evidence for the anticancer effects of aspirin has
emerged from in vitro and animal models, epidemiologic
studies, and randomized data, with the most extensive evidence pertaining to CRC. Identifying biomarkers or clinical characteristics which predict benefit from aspirin use

Hospital Pharmacy 55(3)
could lead to a more targeted intervention and protect some
individuals from unnecessary treatment and possible side
effects. A number of potential clinical, molecular, and
genetic biomarkers have been evaluated including the following: genes mutated in CRC (PIK3CA and BRAF), molecules proposed to have a role in the mechanism through
which aspirin exerts its anticancer effects (cyclo-oxygenase [COX] enzymes and human leukocyte antigen (HLA)
class I expression), and key genetic polymorphisms that
may influence the actions of aspirin.15
COX inhibitory activity of celecoxib and other NSAIDs
and their promising chemopreventive activity have led
investigators to study COX-independent mechanisms for
the purpose of developing derivatives that lack COX inhibitory activity but retain or have improved anticancer
activity.16
Although there were a lot of studies done, some of them
were associated with side effects that hinder the use and
others were associated with nonsignificant results. A study
that compares aspirin and placebo stated that no differences between groups in the rate of recurrence (odds ratio
[OR] 0.95; 95% confidence interval [CI] = 0.61-1.48),
adverse effects, or secondary outcomes.17 Extended follow-up of women in the Women's Health Initiative (WHI)
Dietary Modification (WHI DM) trial did not confirm
combined protective effects of aspirin and low-fat diet on
CRC risk among the postmenopausal women. In one study,
it was found that CRC incidence was not different in the
DM from the comparison group among any type of NSAID
users. None of the interactions with any category of NSAID
use was statistically significant; however, there was most
modest evidence for an interaction (P = .07) with aspirin
use at baseline (hazard ratio [HR] = 0.81, 95% CI = 0.601.11 for users; HR = 1.12, 95% CI = 0.97-1.30 for nonusers). Strength and duration of aspirin use at baseline did
not alter the associations.18 Therefore, it is important to
review many studies to arrive at net effect of the using
NSAIDs in the treatment of CRC.

Methods
Data Source and Search Strategy
A systemic literature search of MEDLINE, PubMed, NEJM,
Google Scholar, and Google for identification of articles
published between August 2006 and June 2017 was performed. We applied the same search strategy to the all databases using the appropriate controlled vocabulary with
restriction on language (using only English language) and
without restriction on publication status (published, in press,
or in progress). The reference lists of the identified publications were reviewed for identification of additional studies. A
total of 94 journal articles were downloaded of which 40
were excluded due to nonrelevance and a year of publication
before 10 years.
Hospital Pharmacy - June 2020

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