Rationale and mechanisms of cancer chemoprevention.

Chronic degenerative diseases, including cancer, have a multifactorial origin. An intricate network connects each disease with multiple risk factors and also with multiple protective factors. From the point of view of preventive medicine, this implies that removal of a single risk factor will have a beneficial impact on the epidemiology of several diseases. However, in contrast to the situation in infectious diseases, it will never be possible to eradicate any chronic degenerative disease in this way, because each of them is associated with other risk factors at the same time. Similarly, a single protective factor can decrease the risk of contracting different diseases, and the risk of developing a single disease can be attenuated by different protective factors, often in a coordinated fashion. It is thus evident that cancer can be prevented not only by avoiding exposure to recognized risk factors, but also, as a complementary approach referred to as chemoprevention, by favouring the intake of protective factors and by fortifying the physiological defences of the host organism. Chemoprevention can be applied in a primary prevention setting when it is addressed to healthy individuals with the goal of inhibiting occurrence of the disease. Conversely, it is applied in a secondary prevention setting when it is addressed to individuals affected by premalignant tumours, with the goal of reversing the carcinogenesis process. A rational use of chemopreventive agents is based not only on the assessment of their efficacy and safety but also on understanding of their mechanisms of action. A detailed classification is proposed, which covers a variety of mechanisms interfering with different phases of mutagenesis and carcinogenesis. However, this sequence of events does not fit in with a rigid scheme, and several mechanisms, such as inhibition of genotoxic effects, antioxidant activity and scavenging of free radicals, inhibition of cell proliferation, and signal transduction modulation are reiterated several times throughout evolution of these processes. Some of these mechanisms are also involved in advanced stages of tumour progression towards malignancy, invasion and metastasis, and can therefore conveniently be applied for the tertiary prevention of cancer. Most inhibitors work through multiple mechanisms, examples of which are given for 18 chemopreventive agents.