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Sunday June 16, 2002 10:25 PM GMT

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Active oxygen species have long been known to be mutagenic, hence playing a role in cancer formation.


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Free Radicals; Types & Dangers
Antioxidants, classification and chemistry



The development of cancer is composed of a series of complex processes of cellular and molecular changes. Active oxygen species and other free radicals have long been known to be mutagenic. There is also evidence that they act as mediators of the other pheno and genotypic changes that lead from mutation to neoplasia. Free radical production is universal in all respiring organisms and is enhanced by many disease processes, carcinogen exposure and under conditions of stress.

This can be demonstrated both clinically and epidemiologically in addition to experimental evidence. One form of indirect evidence of the contribution of free radicals to carcinogenesis is the studies performed using antioxidants as protecting agents against cancer.

The intake of transition metals may facilitate the production of active oxygen species. Chronic inflammatory conditions in which oxidative stress dramatically increases also contributes to carcinogenesis. Many chemical carcinogens are thought to act through the production of free radical metabolites or processes.

Multistage carcinogenesis:

The concept of multistage carcinogenesis was initially developed in rodent skin models in the 1940s (Rous and Kidd 1941; Mottram 1944). Moreover, epidemiological data suggests that cancer is a multistage process. Experimental carcinogenesis proceeds through at least 3 distinct stages:

1. Initiation:

Initiation is the process in which a single somatic cell undergoes non-lethal, but heritable mutation. This initiating mutation may give the initiated cell the growth advantage needed in the second stage of promotion. In contrast to its neighbours, the initiated cell can escape the cellular regulatory mechanisms.

2. Promotion:

Is the process in which the initiated cell is exposed to a tumour promoter which causes these cells to undergo phenotypical clonal expansion. Tumour promoters could either be external or internal stimuli. Only initiated cells are stimulated to grow (Cerutti et al. 1988). The signal to expand clonally could be a result of the direct effect of the tumour promoter or as an indirect effect of the promoter on the adjacent cells. However, tumour initiation and promotion together produce relatively benign growths. It is the third step in which these growths undergo malignant conversion. This process is generally slow, occurs over a long time, and is altered greatly by agents that affect growth rates (e.g., hormones, growth factors, vitamin A and the retinoids, vitamin D, folate, calcium).

3. Malignant conversion:

Like initiation requires genetic alteration. Here cellular growth is further deregulated thus proceeds uncontrolled. Progression is probably the most complex of the three stages, because both acquired genetic and phenotypic occur, and cellular expansion is rapid. Retinoids affect this stage, as do other inhibitors of growth (e.g., polyamine synthesis inhibitors) and antioxidants. As the tumour progresses, sensitivity to dietary compounds, inhibitors of growth, and enhancers of differentiation gradually disappears until the tumour becomes progressively more autonomous and controllable only by more drastic intervention (Guyton and Kensler, 1993).

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