world cancer report - iarc

prolonged use. Similar drugs, that is other
non-steroidal anti-inflammatory drugs,
appear to have this effect, and cancers at
sites apart from the bowel may be susceptible.
In respect of these and similar
agents, the IARC began a series of
Handbooks of Cancer Prevention in 1997
by considering the cancer-preventive activity
of non-steroidal anti-inflammatory
drugs [1]. Subsequent volumes have been
published on carotenoids [2], vitamin A [3],
retinoids [4] and use of sunscreens [5], the
latter being substances that reduce exposure
to a carcinogenic agent (in this case,
sunlight).
Relevant mechanisms
The appropriate use of a chemopreventive
agent may depend on an understanding of
the mechanism of action at all levels, in
animals and humans. Without this knowledge,
selection of preventive agents is
intuitive or the product of chance. The
trend in the field of chemoprevention has
therefore been to develop new agents
based on known mechanisms of action.
COX-2 inhibition
One aspect of tumour development is the
release of arachidonic acid and its metabolism
to eicosanoids, including prostaglandins.
Down-regulation of the cyclooxygenases
(COX-1 and COX-2) by pharmacological
means may result in reduced incidence
of cancer, because cyclooxygenases
catalyse the formation of prostaglandins,
which have multiple effects that
favour carcinogenesis [7] (Fig. 4.26). A
number of prostaglandin synthesis
inhibitors are effective in counteracting
tumorigenesis. Compounds such as antiinflammatory
steroids (i.e. glucocorticoids)
are potent inhibitors of experimental
skin carcinogenesis [8]. These compounds
are effective inhibitors of phospholipase
A 2, which may explain their abil-
Agent Humans Animals
Non-steroidal anti-inflammatory drugs
Aspirin Limited Sufficient
Sulindac Limited Sufficient
Piroxicam Inadequate Sufficient
Indomethacin Inadequate Sufficient
Carotenoids
β-Carotene (high dose supplements) Lack of activity Sufficient
β-Carotene (usual dietary levels) Inadequate Sufficient
Canthaxanthin Inadequate Sufficient
α-Carotene Inadequate Limited
Lycopene Inadequate Limited
Lutein Inadequate Limited
Fucoxanthin Inadequate Limited
Table 4.12 Evidence of cancer preventive activity: evaluations from the IARC Handbooks of Cancer Prevention series.
152 Prevention and screening
ity to decrease the amount of arachidonic
acid available for metabolism to proinflammatory
prostaglandins.
Aspirin and aspirin-like drugs can inhibit
colorectal tumorigenesis and are among
the few agents reported to be useful for
chemoprevention of neoplasia [1]. The
cyclooxygenase pathway is a major target
for prevention by non-steroidal antiinflammatory
drugs, primarily because
COX-2 plays a role in inflammation as well
as in apoptosis and angiogenesis. From
the perspective of chemoprevention, the
recent finding that overexpression of the
gene for COX-2, a key enzyme for the formation
of prostaglandins from arachidonic
acid, is an early and central event in
colon carcinogenesis provides an important
target for the development of chemopreventive
agents [9]. Overexpression of
COX-2 in epithelial cells inhibits apoptosis
and increases the invasiveness of tumour
cells [10]. Treatment of colon tumour cells
Retinoids
all-trans-Retinoic acid Inadequate Inadequate
13-cis-Retinoic acid Limited Limited
9-cis-Retinoic acid Inadequate Limited
Fenretinide (4-HPR) Inadequate Sufficient
Etretinate Inadequate Limited
Acitretin Inadequate Inadequate
N-Ethylretinamide Inadequate Lack of activity
Targretin Inadequate Inadequate
LGD 1550 Inadequate Inadequate
Preformed vitamin A Lack of activity Limited
Sunscreens Limited (squamous cell carcinoma) Sufficient
Inadequate (basal cell carcinoma) -
Inadequate (malignant melanoma) -