What is cancer chemoprevention?
Principles of chemoprevention
Many human cancers are preventable, because their causes have been identified in the human environment. Minimization of exposure towards carcinogens in the environment (1° prevention) is an effective strategy in cancer prevention, e.g. smoking avoidance or cessation. However, most environmental factors that initiate or promote cancer remain to be identified, and, once identified, the avoidance of such factors may necessitate difficult lifestyle changes.
Epidemiological data suggesting that cancer is preventable by intervention with chemicals are based on:
- time trends in cancer incidence and mortality
- geographic variations and effect of migration
- the identification of specific causative factors
- a lack of simple patterns of genetic inheritance for the majority of human cancers.
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 which is 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 interfere with cancer initiation, and tumour-‘suppressing’ agents, which inhibit promotion or progression. Blocking agents, such as oltipraz, that prevent the metabolic activation of carcinogens or their subsequent binding to DNA probably reduce the accumulation of initiating mutations.
Altered states of cell and tissue differentiation are characteristic of pre-malignant lesions, long before they become invasive. It may be 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 these cells.
Although, in the past, cancer chemopreventive agents have been discovered serendipitously or developed empirically, recent advances in the understanding of the molecular biology of carcinogenesis offer hope for a more rational drug design.