Chemopreventive agents and their molecular targets

Epithelial carcinogenesis proceeds via multiple, discernible steps of molecular and cellular alterations, culminating in invasive neoplasms. These events can be separated into three distinct phases:

♦ Initiation (rapid; involves direct carcinogenic damage to DNA; and the resulting mutation is irreversible).

♦ Promotion (follows initiation and is generally reversible; involves the clonal expansion of initiated cells induced by agents acting as mitogens for the initiated cell).

♦ Progression (results from promotion in the sense that cell proliferation caused by promoters allows 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 they affect, chemopreventive agents can be divided into tumour 'blocking' agents, which counteract cancer by interfering with initiation, and tumour 'suppressing' agents, which intercept promotion or progression. The synthetic dithiolethione compound, oltipraz, and the organic selenium compound, selenomethionine, are examples of blocking agents. 13-cis retinoic acid, a member of the retinoid family (which are natural and synthetic compounds related to vitamin A), is a tumour-suppressing agent.

Blocking agents such as oltipraz, which prevent metabolic activation of carcinogens or their subsequent binding to DNA, probably play a significant role in reducing the accumulation of initiating mutations. The fact that initiation can occur very early in life confounds clinical chemoprevention strategies based only on anti-initiation. Suppression of the development of the initiated cell to a malignant tumour is probably the strategy of choice in human cancer chemoprevention.

Altered states of cell and tissue differentiation are characteristic of pre-malignant lesions long before they become invasive and metastatic. This pathology of differentiation (dysplasia) offers a defined target for pharmacological intervention because, in some circumstances, it is possible to reverse abnormal differentiation with a hormone-like non-toxic agent. Two other approaches to the control of pre-neoplastic lesions are to block their expansion with non-toxic agents that suppress cell replication, or to induce an apoptotic state in cells which ordinarily would be programmed to die but may have undergone carcinogenic mutations providing an extended life span.

Although in the past, cancer chemopreventive agents have been discovered serendipitously or developed empirically, recent advances in the molecular biology of carcinogenesis suggest that it will be possible to develop new and better agents by a more mechanistic approach. A good example is colon cancer—the recent discovery that over-expression of the gene coding for inducible cyclo-oxygenase (COX-2), a key enzyme in the formation of prostaglandins from arachidonic acid, is an early and central event in colon carcinogenesis now provides an important target for new drug development. Recently, the novel specific COX-2 inhibitors, celeoxib, was approved by the FDA for the reduction of polyps in familial adenomatous polyposis (FAP) patients.

Tumour-suppressing compounds such as the retinoids, genistein, an isoflavonoid constituent of soya, and curcumin (the pigment which gives curry its characteristic colour) affect, in a complex fashion, several biochemical and physiological cell parameters potentially associated with carcinogenesis. Some of these agents not only suppress tumour formation but also possess a tumour-blocking component.

Information about the pharmacokinetic behaviour of chemo-preventive agents is scarce. It is therefore not yet possible to assess whether the concentrations at which these agents are known to elicit biochemical responses are achieved in vivo after eating foods that contain them.

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