Pharmacology Journal

The notion that the prevention of disease is better than having to cure it is probably as old as the concept of restoration of human health by medical intervention. Many human cancers are preventable because their causes have been identified in the human environment. The finding that regular consumption of certain constituents of fruits and vegetables might protect us from this deadly disease, which was first proposed by Wattenberg, has aroused much interest among the medical establishment and the general public. Chemoprevention or chemoprotection can be defined as the use of specific diets, or natural or synthetic chemicals, to reverse, suppress, or prevent carcinogenic progression to invasive cancer. Minimisation of exposure towards carcinogens in the environment (‘primary prevention’) is undoubtedly an effective strategy in cancer prevention. However, most environmental factors which initiate cancer remain to be identified and, once identified, the avoidance of such factors necessitates life-style changes, which may be difficult to implement. Epidemiological data suggesting that cancer is preventable by intervention with chemicals are based on time trends in cancer incidence and mortality, geographic variations and effect of migration, identificaton of specific causative factors and lack of simple patterns of genetic inheritance for the majority of human cancers. In order to understand how chemopreventive agents exert their activity, one has to recall that epithelial carcinogenesis proceeds via multiple discernible steps of molecular and cellular alterations. Invasive cancer is the ultimate product of this sequence of critical events, many of which can theoretically be prevented. These events can be separated into three distinct phases: initiation, promotion and progression. Initiation is rapid, it involves direct carcinogen binding and damage to DNA, and the resulting mutation is irreversible. Promotion follows initiation and involves clonal expansion of initiated cells induced by agents acting as mitogens for the initiated cell. This stage is generally reversible. The progression stage of carcinogenesis is an extension of promotion and results from it in the sense that cell proliferation caused by promotors allows the cellular damage inflicted by initiation to be further propagated. During tumour progression genotypically and phenotypically altered cells gradually emerge. Both promotion and progression phases are prolonged. Depending on which phase of carcinogenesis chemopreventive agents affect, they can be divided into tumour ‘blocking’ agents, which counteract cancer by interfering with initiation, and tumour ‘suppressors’, which intercept promotion or progression. Blocking agents probably play a significant role in reducing the accumulation of initiating mutations, but the fact that initiation can occur very early in life confounds clinical chemoprevention strategies based on anti-initiation only. Hence suppression of the development of the initiated cell to a full-blown tumour is undoubtedly the strategy of choice in human cancer chemoprevention, and tumour-suppressing agents are the focus of this review. Its aim is to outline mechanisms by which such substances suppress tumours and to highlight the importance of the understanding of these mechanisms for the discovery and clinical development of novel and safe chemopreventive substances.

Filed under: Clinical Pharmacology