Strategies for Identification and Clinical Evaluation of Promising Chemopreventive Agents

Chemoprevention: Pharmacology or Biology?

elloff and colleagues have been key players in the recent development of chemoprevention strategies--as initiators of their own studies and minders of others. The succinct summary of their approach is of particular value to oncologists, both because it provides a great deal of data on the current state of chemoprevention research itself and because it draws some useful distinctions between chemoprevention and chemotherapy.

One role for a commentary on such a useful contribution is to set it in a wider context and to ask some questions that Kelloff and coauthors, by their very commitment to the enterprise, are unable to pose. Such a commentary can ask several related questions:

1. Do we know enough about cancer to undertake chemoprevention in the determined pharmacologic way described?
2. What can we learn from the results of completed chemoprevention trials?
3. Can we draw any other comparisons between chemotherapy and chemoprevention that may help keep us on track?

Do We Know Enough About Cancer?

Asking whether we know enough about cancer to do chemoprevention is not to subvert the current enterprise, nor even to question the enthusiastic pursuit of new and better agents. It is, however, intended to remind us that our models of cancer have been evolving rapidly, and that there have been many surprises over the last 10 years. Among these, we can count the semiorganized and cancer-specific nature of the sequence of somatic genetic changes;[1-3] the role of DNA repair and microsatellite instability;[4-8] the tumor-suppressor role of inherited genes like BRCA1 with little evidence of

somatic mutation in sporadic tumors;[9,10] the mimicking of a second "hit" by hypermethylation;[11] clear evidence that agents thought to cause mutation actually act by selection;[12] the place of apoptosis in carcinogenesis;[13-15] the possibility of roles for transposons[16-18] and imprint-ing;[19-21] and the heterogeneity of consequences when a gene mutates at different loci or in the germ line as opposed to somatically.[22-24]

At the very least, this incomplete catalog suggests that we should consider agents beyond those that suppress proliferation or prevent mutagenesis. More importantly, it reminds us that we will discover whole new processes relevant to carcinogenesis that may undermine our confidence in existing models. Such undiscovered processes may even explain the failure of agents that, until recently, we felt secure enough to test in large-scale trials.

In the face of growing evidence of heterogeneity in the cancer process, we should adopt an attitude of appropriate humility while looking for opportunities both to interrupt the sequence and to revise our models of it. While cultivating such an attitude, it probably makes sense to eschew the concepts of "toxicity" and "side effects," as these are derived solely from the pharmacologic notion that we know what an agent ought to do, and not from a biologic understanding of what it actually does. There are no "main effects" and "side effects," only effects.

What Have We Learned From Recent Chemoprevention Trials?

The results of recent chemoprevention studies are so at variance with expectation that it is already clear that some of our models are wrong. Human experiments show that modest doses of b-carotene do not prevent cancer in average-risk[25] or high-risk individuals.[26, 27] But what are we to make of an increase in lung cancer[26,27] and large polyps[28] following b-carotene supplementation in high-risk individuals? A null answer to the chemoprevention question can mean: good hypothesis, good science, but wrong agent. An increase in risk, however, strongly suggests that the model, not the agent, is wrong.

Can We Draw Parallels Between Chemotherapy and Chemoprevention?

One of the parallels between chemotherapy and chemoprevention that the article does not draw is the outcome of using a single agent. Extensive clinical trials, in both adults and children, have proven the efficacy of multiple agents, in combination and sequentially. The rationale is so deeply embedded in the way that we think about chemotherapy that it is almost subliminal.

Single agents select for clones of cancer cells capable of surviving. Polypharmacy reduces the likelihood of such clones emerging. Selection occurs because specific cells are capable, by a variety of means, of resisting the cytotoxic, apoptosis-inducing, and other actions of the therapeutic agents. Chemopreventive agents, by inducing differentiation or reducing proliferation or mutation, are equally capable of acting as agents of selection, however. Furthermore, the cells that survive chemopreventive agents may be as capable of clonal expansion as any survivor of a cytotoxic agent.

Indeed, it is this kind of selection that may explain why agents as apparently benign and beneficial as b-carotene can actually increase the risk of lung cancer in individuals known to have large numbers of initiated cells. One plausible mechanism for this outcome is that bcl-2, an inhibitor of apoptosis, may operate via an antioxidant pathway.[29] Although, on the face of it, b-carotene may not be a sufficiently powerful antioxidant to induce comparable inhibition of apoptosis, nonetheless, the presence of high concentrations of even a weak antioxidant may be sufficient to prevent the normal apoptotic death of abnormal cells. The agent then is not working to prevent mutation-inducing oxidative damage in the DNA of normal cells, but rather, to inhibit the very mechanism by which the organism sheds abnormal cells.

This is a testable hypothesis. If it is true, what it argues for most strongly is the use of chemopreventive polypharmacy (or diet, of course [30]). If we begin with a single agent and a high-risk group, we may indict an agent or class of agents as being useless or even cancer-promoting when what we have actually discovered is that our models of cancer are not very good. Some principles that derive from both evolutionary biology and chemotherapy apply also to chemoprevention.