Mechanistic Approaches To The Prevention Of Mutation And Cancer

Abstract

AbstractCancer and other mutation-related diseases can be prevented at three levels: primary prevention, which is addressed to healthy individuals in order to prevent occurrence of the disease; secondary prevention, which is addressed to early stage patients in order to prevent progression of the disease; and tertiary prevention, which is addressed to patients after therapy in order to prevent relapses of the disease. Although the most obvious approach to prevention is to minimize exposures to recognized risk factors, a complementary strategy is represented by chemoprevention, using dietary and pharmacological agents that reinforce the host defence machinery. Since 1988, I proposed detailed classifications of mechanisms of inhibitors of mutagenesis and carcinogenesis. They may apply not only to cancer but also to other degenerative diseases that have replaced infectious diseases as the leading causes of death in the population. In fact, certain mechanisms, such as damage to nuclear DNA and mtDNA, oxidative stress, chronic inflammation, signal transduction alterations and epigenetic changes may be involved in the pathogenesis of different diseases. Studies performed in our laboratory have shown that certain genomic alterations that are usually investigated in cancer research may also be detected in other chronic diseases, such as atherosclerosis, degenerative heart diseases, chronic obstructive pulmonary diseases, neurological disorders, eye diseases, skin ageing, and alopecia. Similar alterations were investigated in critical periods of life, such as birth and ageing. The nucleotide alterations occurring at birth in the lung render the newborn particularly vulnerable to the action of environmental agents. In fact, we demonstrated that cigarette smoke becomes a potent carcinogen in mice when exposure starts at birth and continues early in life. We investigated a number of chemopreventive agents by evaluating modulation of intermediate biomarkers and carcinogenicity. An optimal agent should not excessively alter the physiological patterns of gene expression, microRNA and proteome profiles, but at the same time it should be effective in inhibiting alterations induced by mutagens and carcinogens. It should be noted that most chemopreventive agents possess pleiotropic properties. The knowledge of mechanisms can be exploited to combine different agents working with complementary mechanisms. Like the therapy of important diseases, such as cancer, cardiovascular diseases, AIDS, etc., uses combinations of drugs, combined chemoprevention is a quite promising strategy. Although a large number of agents are potentially able to prevent cancer, we are in search of tools to predict, hopefully in the single individual, their efficacy and safety in humans.