Combined Actions and Interactions of Chemicals in Mixtures

Several inhibitors of tumour promotion are described in the literature but their
mechanisms of action are not always understood. Many antioxidants may both
enhance or inhibit promotion, but they seem most often to be inhibitors. Nonsteroidal
anti-inflammatory agents (NSAIDs) have an antagonistic action on colon
carcinogenesis by inhibiting cyclooxygenase which forms cell-growth stimulating
prostaglandins (Reddy et al., 1996; Thun et al., 1991), and certain terpenoids may
inhibit carcinogenesis by inhibiting farnesyl transferase so that the ras protein can
not be inserted correctly in the membrane of malignant cells (Gelb et al., 1995).
Some early defined anticarcinogens were inhibitors of ornithine decarboxylase
which is important for the formation of polyamine cytoskeleton components
needed during cell division, and many others had hormonal actions (Slaga et al.,
1980; Yuspa et al., 1976).
Some anticarcinogens have been shown to have an effect very late in
carcinogenesis, even after the appearance of tumours, notably beta-carotene on oral
cancers in hamsters (Schwartz and Shklar, 1987) and also on the appearance of oral
plaques in human smokers (Sankaranarayanan et al., 1997; Garewal, 1995).
However, the anticarcinogenic action of beta-carotene against a minor cancer in
smokers cannot be outweighed by its negative actions on their major cancer of the
lung. Similarly, are potentiating actions known for several anticarcinogens, and
much more research is necessary in order to sort out why. In some cases it may
simply be a question of dose, with lower doses being protective, and higher doses
leading to damage. In others it may be that anticarcinogens act by provoking
natural defence mechanisms in the body, in other words, some toxicity is necessary
for the beneficial effects to appear.
In conclusion many anticarcinogens are known in the scientific literature, but we
are only beginning to understand their mechanisms. The only anticarcinogens for
which there is some international consensus on their beneficial effect are the
NSAIDs, for which the conclusions of an international work group under IARC are
positive (IARC working group, 1997). For other compounds, including carotenoids
and retinol, IARC has not been able to conclude that there is evidence for a positive
effect in humans (IARC working group, 1998a; IARC working group, 1998b).
7.3.6 Conclusions: Over-all effects and complex mixtures
Carcinogenesis is often described as a multi-step process. The fact that we know
that different chemical, physical or biological agents may affect either step makes
it clear that cancer is most often the result of combined toxic effects. The
interaction of carcinogens affecting different steps in carcinogenesis has been
known for half a decade to cause synergistic effects, strongly increasing the tumour
response. Thus, initiators, promoters, converters, and co-carcinogens all act in
concert to potentiate the final tumour outcome. Anticarcinogens may prevent or
inhibit cancer at either step, and are also known to potentiate each other in some
cases. What is clear from the review above is that potentiation can also be caused
by compounds affecting the same step by different mechanisms. The possibilities
for combinational effects in carcinogenesis are therefore many, and new models for
short-term induction of tumours in animals are developed all the time leading to
more and more reduced tumour induction times. The interpretation of these models
is, however, not straight forward, and the long-term animal models still act as
reference assays for the observed effects.
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