Oxford American handbook of oncology. Second Edition. Oxford University Press (2015)
Principles of chemoprevention
Many human cancers are preventable because their causes have been identified in the human environment.
- Minimization of exposure of carcinogens in the environment (primary 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 the following:
- Time trends in cancer incidence and mortality
- Geographic variations and effect of migration
- Identification of specific causative factors
- 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; it 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 tumor 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 tumor “blocking” agents, which interfere with cancer initiation, and tumor “suppressing” agents, which inhibit promotion or progression (see Table 3.2).
Blocking agents such as oltipraz that prevent 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 premalignant lesions long before they become invasive. It may be possible to reverse abnormal differentiation with a hormone-like nontoxic agent.
Two other approaches to controlling preneoplastic lesions are (1) to block their expansion with nontoxic agents that suppress cell replication or (2) 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 understanding of the molecular biology of carcinogenesis offers hope for more rational drug design.
Table 3.2. Mechanisms of tumor suppression and examples of cancer chemopreventive agents
|Scavenging oxygen radicals||Polyphenols (curcumin, genistein), selenium, tocopherol (vitamin E)|
|Inhibition of arachidonic acid metabolism||N-acetylcysteine, NSAIDs (sulindac, aspirin), polyphenols, tamoxifen|
|Modulation of signal transduction||NSAIDs, retinoids, tamoxifen, genistein, curcumin|
|Modulation of hormonal/growth factor activity||NSAIDs, retinoids, curcumin, tamoxifen, finasteride|
|Inhibition of oncogene activity||Genistein, NSAIDs, monoterpenes (D-limonene, perillyl alcohol)|
|Inhibition of polyamine metabolism||2-Difluoromethylornithine, retinoids, tamoxifen|
|Induction of terminal differentiation||Calcium, retinoids, vitamin D3|
|Induction of apoptosis||Genistein, curcumin, retinoids, tamoxifen|
NSAIDs = nonsteroidal anti-inflammatory drugs.