world cancer report - iarc

with non-steroidal anti-inflammatory
drugs results in a dramatic increase in
arachidonic acid concentration, which, in
turn, stimulates the conversion of sphingomyelin
to ceramide, a known mediator
of apoptosis. The activity of non-steroidal
anti-inflammatory drugs to inhibit tumour
growth may also be related to their induction
of lipoxygenases [11].
New pharmacological agents, such as
celecoxib, have recently been developed
that are selective for inhibition of the
enzymatic activity of COX-2, while not
affecting the constitutive form of the
enzyme, COX-1. Celecoxib has been
shown to prevent colon carcinogenesis in
a rodent model. In 2000, celecoxib was
approved by the US Food and Drug
Administration as an adjunct to standard
care in patients with familial adenomatous
polyposis, in whom APC gene defects
result in a 100% chance of developing
colorectal cancer. It is now in clinical trials
in cohorts of patients at high risk of other
cancers apart from the colorectum.
Estrogen receptor modulation
Through clinical trials, tamoxifen has been
definitively shown to prevent contralateral
breast cancer in women previously diagnosed
with the disease [12], although an
effect on survival has yet to be confirmed.
Extensive trials are under way to determine
whether a preventive effect may be
achieved in women who have not had a
previous breast cancer. Although tamoxifen
and its derivatives have come into
clinical use recently, they were synthesized
well over 20 years ago, before the
estrogen receptors were cloned. The
mechanism of action of these drugs is
now understood on the basis of the receptors.
The demonstration of occurrence of
the estrogen receptor-β, as contrasted
with estrogen receptor-α, in the prostate,
colon and ovary suggests that it may be
useful to develop estrogen analogues that
will selectively bind to this isoform of the
receptor.
Retinoid receptors
Compounds related to vitamin A (retinoic
acid and similar substances termed
“retinoids”) were initially shown to modu-
Aspirin
COOH
OOCCH 3
Fig. 4.27 The ancient Greeks chewed the bark of willow trees to alleviate pain and fever, but it was not
until the last century that the active ingredient in willow bark, salicin, was isolated and commercially produced
as aspirin. Observational studies have shown that regular use of aspirin reduces the risk of cancer
of the colon and rectum.
late differentiation in many experimental
systems [13]. Retinoids that are selective
for binding to the three retinoid X receptors
(RXRs), while not binding to the three
retinoic acid receptors (RARs), may represent
a specific class of chemopreventive
agents. The retinoid X receptors are of
particular importance in the nuclear
receptor superfamily because of their ability
to heterodimerize with many other
members of this family, including retinoic
acid receptors, the vitamin D receptor, the
thyroid receptor, as well as with newly discovered
“orphan” receptors, such as peroxisome-proliferator-activated
receptor-γ.
Analytical epidemiology studies
Since 1970, the role of dietary fibre in
colorectal cancer has been explored in
many case-control studies, with relatively
consistent results suggesting a reduced
risk with higher consumption. A metaanalysis
of these studies showed both an
inverse association and a dose-response
relationship [14]. The results of the cohort
studies have been much less convincing.
In a recent prospective study of almost
90,000 female nurses who were followed
up for more than 16 years, colorectal cancer
developed in 787 women, and neither
total dietary fibre nor dietary fibre from
vegetables, fruit and cereals separately
was associated with the risk for distal
colonic or rectal adenomas. In fact,
greater consumption of vegetable fibre
was associated with a small increase in
risk [15].
Both case-control and cohort studies have
tended to show a reduced risk for
colorectal cancer after prolonged use of
aspirin [16]. Of 15 studies that specifically
addressed the association between regular
use of aspirin and/or other nonsteroidal
anti-inflammatory drugs and
colorectal cancer, nine case-control and
five out of six cohort studies recorded a
lower risk for colorectal cancer; one
cohort study showed an increased risk for
colorectal cancer among users of nonsteroidal
anti-inflammatory drugs [1]. As
observational epidemiological studies can
be subject to bias, chemoprevention with
Chemoprevention 153