Suppression of tumour development by substances derived from the diet--mechanisms and clinical implications

Abstract

The concept that cancer can be prevented, or its onset postponed, by certain diet-derived substances is currently eliciting considerable interest. Agents which interfere with tumour development at the stage of promotion and progression in particular are of potential clinical value. As chemopreventive agents have to be administered over a long period of time in order to establish whether they possess efficacy in humans, it is of paramount importance to establish their lack of toxicity. The desire to select the best chemopreventive drug candidates for clinical trial, and the necessity to monitor efficacy in the short and intermediate term, render the identification of specific mechanism-based in vivo markers of biological activity a high priority. Antioxidation, inhibition of arachidonic acid metabolism, modulation of cellular signal transduction pathways, inhibition of hormone and growth factor activity and inhibition of oncogene activity are discussed as mechanisms by which the soya constituent genistein, the curry ingredient curcumin and the vitamin A analogue 13-cis retinoic acid exert tumour suppression. A better understanding of these mechanisms will help the establishment of screens for the discovery of new and better chemopreventive agents and the identification of surrogate markers to assess the outcome of clinical chemoprevention trials.

Figure 1

Hypothetical phases of multistep carcinogenesis.

Figure 2

Structures of tumour-suppressive agents.

Figure 3

Signalling pathways which are known to be subject to pharmacological manipulation [modified from 99]. In this hypothetical scheme the initial signal is considered to be a growth factor or other ligand interacting with a cell surface receptor. The receptor acts as the originating detector for the signal, which is subsequently transduced to produce second messengers to bring about biological responses. Specific examples of components of signalling pathways which can be influenced by cancer chemopreventive agents and which are mentioned in the text are shown below the boxes.