Strategies for Identification and Clinical Evaluation of Promising Chemopreventive Agents
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:
- Do we know enough about cancer to undertake chemoprevention in the determined pharmacologic way described?
- What can we learn from the results of completed chemoprevention trials?
- 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; clear evidence that agents thought to cause mutation actually act by selection; 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 or high-risk individuals.[26, 27] But what are we to make of an increase in lung cancer[26,27] and large polyps 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. 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 ). 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.
1. Rowley J: Chromosome abnormalities in cancer. Cancer Genet Cytogenet 2:175-198, 1980.
2. Solomon E, Borrow J, Goddard A: Chromosome aberrations and cancer. Science 254:1153-1160, 1991.
3. Vogelstein B, Fearon E, Kern S, et al: Allelotype of colorectal carcinomas. Science 244:207-211, 1989.
4. Fishel R, Lescoe M, Rao MRS, et al: The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. Cell 75:1027-1038, 1993.
5. Leach F, Nicolaides N, Papadopoulos N, et al: Mutations of mutS homolog in hereditary nonpolyposis colorectal cancer. Cell 75:1215-1225, 1993.
6. Ionov Y, Peinado M, Malkhosyan, et al: Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature 363:558-561, 1993.
7. Parsons R, Li GM, Longley M, et al: Hypermutability and mismatch repair deficiency in RER+ tumor cells. Cell 75:1227-1236, 1993.
8. Thibodeau S, Bren G, Schaid D: Microsatellite instability in cancer of the proximal colon. Science 260:816-819, 1993.
9. Futreal PA, Liu Q, Shattuck-Eidens D, et al: BRCA1 mutations in primary breast and ovarian carcinomas. Science 266:120-122, 1994.
10. Takahashi H, Behkakht K, McGovern P, et al: Mutation analysis of the BRCA1 gene in ovarian cancers. Cancer Res 55:2998-3002, 1995.
11. Baylin S, Herman J, Wales MM, et al: Hypermethylation of CpG islands and inactivation of tumor suppressor genes. Proc Am Assn Cancer Res 36:691-692, 1995.
12. Jin Z, Zarbl H: Carcinogen induced mechanisms in mammary tumorigenesis. Proc Am Assn Cancer Res 36:658-659, 1995.
13. Hockenbery D: Bcl-2 in cancer, development and apoptosis. J Cell Sci 18:51-55, 1995.
14. Sinicrope F, Raun S, Cleary K, et al: Bcl-2 and p53 oncoprotein expression during colorectal tumorigenesis. Cancer Res 55:237-241, 1995.
15. Bronner M, Culin C, Reed J, et al: Bcl-2 protooncogene and the gastrointestinal mucosal epithelial tumor progression model. Am J Pathol 146:20-26, 1995.
16. Sager R: Transposable elements and chromosomal rearrangements in cancer--a possible link. Nature 282:447-448, 1979.
17. Morse B, Rothberg P, South V, et al: Insertional mutagenesis of the myc locus by a LINE-1 sequence in a human breast carcinoma. Nature 333:87-90, 1988.
18. Miki Y, Nishisho I, Horii A, et al: Disruption of the APC gene by a retrotransposal insertion of L1 sequence in a colon cancer. Cancer Res 52:643-645, 1992.
19. Reik W: Imprinting in leukemia. Nature 359:362-363, 1992.
20. Mannens M, Hoovers JMN, Redeker E, et al: Parental imprinting of human chromosome region 11p15.3-pter involved in the Beckwith-Wiedemann syndrome and various human neoplasia. Eur J Hum Genet 2:3-23, 1994.
21. Rachmilewitz J, Goshen R, Ariel I, et al: Parental imprinting of the human H19 gene. FEBS Lett 309:25-28, 1992.
22. van Heyningen V: One gene--four syndromes. Nature 367:319-320, 1994.
23. Eng C, Mulligan L, Healey C, et al: Heterogeneous mutation of the RET proto-oncogene in subpopulations of medullary thyroid carcinoma. Cancer Res 56:2167-2170, 1996.
24. Goodfellow P, Wells S: RET gene and its implications for cancer. J Natl Cancer Inst 87:1515-1523, 1995.
25. Hennekens C, Buring J, Manson J, et al: Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease. N Engl J Med 334:1145-1149, 1996.
26. Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group: The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med 330:1029-1035, 1994.
27. Omenn G, Goodman G, Thornquist M, et al: Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med 334:1150-1155, 1996.
28. MacLennan R, Macrae F, Bain C, et al: Randomized trial of intake of fat, fiber, and beta carotene to prevent colorectal adenomas. J Natl Cancer Inst 87:1760-1766, 1995.
29. Hockenbery D, Oltvai Z, Yin M, et al: Bcl-2 functions in an antioxidant pathway to prevent apoptosis. Cell 75:241-251, 1993.
30. Potter J, Steinmetz K: Vegetables, fruit and phytoestrogens as preventive agents. IARC Monographs, 1996 (in press).