Multiple points of intervention in the prevention of cancer and other mutation-related diseases.

Multiple points of intervention are the target for dietary and pharmacological interventions aimed at preventing cancer and other diseases in which mutations in somatic cells play a pathogenetic role. For instance, our studies showed that DNA adducts can be consistently detected in arterial smooth muscle cells from human atherosclerotic lesions. Their levels were significantly correlated with the occurrence of atherogenic risk factors known from traditional epidemiology and were strikingly enhanced in atherosclerotic patients lacking the GSTM1 genotype. Cancer chemoprevention has a dual goal, i.e. prevention of occurrence of the disease (primary prevention) and early detection and reversion of tumors at a premalignant stage (secondary prevention). At a later stage, attempts can be made to prevent local recurrences as well as invasion and metastasis of malignant cells (tertiary prevention). For a rational use of chemopreventive agents it is essential not only to evaluate their efficacy and safety but also to understand the mechanisms involved. Sometimes it is difficult to discriminate whether modulation of a given end-point is actually a specific mechanism or rather the epiphenomenon of other events. For instance, we recently found that apoptosis is considerably stimulated in the respiratory tract of smoke-exposed rats; whereas certain chemopreventive agents work by further enhancing smoke-related apoptosis, other agents appear to downregulate apoptosis simply because they inhibit the genotoxic events signaling this process. We propose here a detailed, updated classification of the points of intervention exploitable in the prevention of mutation and cancer. The general outline includes a variety of extracellular and cellular mechanisms modulating the genotoxic response and tumor initiation as well as tumor promotion, progression, angiogenesis, invasion, and metastasis. This classification is not intended to provide a rigid scheme, since several intervention points are reiterated several times over different phases of the process. Moreover, some mechanisms are strictly interconnected or partially overlapping. Interestingly, a number of chemopreventive agents work through multiple mechanisms, which warrants a higher efficacy and a broader spectrum of action. It is also convenient to combine chemopreventive agents working through complementary mechanisms. In recent preclinical studies, we observed that combination of N-acetylcysteine with either oltipraz or ascorbic acid produces additive or more than additive protective effects towards early biomarkers and/or experimentally-induced tumors.