Clinical prevention of recurrence of colorectal adenomas by the combination of difluoromethylornithine and sulindac: an important milestone.

Michael B. Sporn and Waun Ki Hong The spectacular clinical results reported by Meyskens, Gerner and colleagues in a lead article (1) of this very first issue of this new AACR journal on cancer prevention represent a landmark advance in efforts to stop the current worldwide epidemic of cancer deaths. This study also sets a new, exceptionally high standard for future clinical research on the chemoprevention of cancer. This article is of great importance for many reasons. The authors show conclusively that the combination of low doses of two drugs, each relatively ineffective as preventive agents when given singly at low doses, caused a striking inhibition of colorectal adenomas in a large study involving almost 300 patients, all of whom had a previous resection for such adenomas and were thus at high risk for recurrence. The drugs used were difluoromethylornithine (DFMO), an inhibitor of polyamine synthesis, and sulindac, an anti-inflammatory drug, and they were given safely in combination over a 3-year study period with almost no adverse effects. These new results represent the first demonstration of the clinical validity of the basic concept of “combination chemoprevention,” first proposed in 1980 (2, 3). The magnitude of the combined chemopreventive effect of the two drugs is stunning. Overall, the incidence of adenoma recurrence was reduced 70%, from 41% in the control population to 12% in the patients treated with the drug combination. Even more striking are the effects on the number and severity of new adenomas. Thus, only 1 patient in the treated group was found to have multiple adenomas at the final colonoscopy, compared with 17 patients in the placebo control group, a 95% reduction compared with control. Furthermore, at the end of the study, 11 patients in the placebo group had advanced adenomas (at least 1 cm in size in 9 of these patients), whereas only a single patient in the treated group had an advanced adenoma, a >90% reduction compared with control. All of these preventive effects are highly statistically significant (P < 0.001). Such a marked level of preventive activity has never been seen before in any clinical chemoprevention trial involving any organ site. The practical clinical chemopreventive activity of the DFMO-sulindac combination reported here is clearly superior to that which has previously been shown for any of the nonsteroidal anti-inflammatory drugs, including aspirin, celecoxib, and rofecoxib, for suppression of adenomas (4–8). The lack of any significant toxic side effects of the DFMOsulindac combination in this study is extremely important. Meyskens, Gerner and colleagues have deliberately chosen to use the lowest possible effective doses of both drugs as an approach to avoid toxicity. Elegant previous “dose de-escalation” studies with DFMO have been particularly important in this regard. Thus, in two large clinical studies started more than 10 years ago, the present investigators determined the lowest dose of DFMO that would deplete levels of polyamines in the target tissue, colorectal mucosa (9, 10). The dose of sulindac used in the present study was only one half that used in a previous study that showed efficacy in treatment of colonic and rectal adenomatous polyps (11). This dose de-escalation approach is in marked contrast to conventional treatment studies in clinical oncology, in which doses of drug are escalated to determine the maximum tolerated dose before a full-scale treatment protocol is actually begun. Concerns about safety are a recurring theme in the objections of both oncologists and prospective patients to the general concept of chemoprevention. In response to these concerns, the present study has definitively shown that chemoprevention with combinations of low doses of drugs is an ideal way to diminish toxicity, while at the same time obtaining desired therapeutic synergy and efficacy. There are several aspects of the pharmacology of both DFMO and sulindac that are worthy of comment. First of all, neither drug is new; both were synthesized for the first time more than 30 years ago, and they have been in clinical or experimental use for almost as long. Furthermore, neither drug fits currently fashionable paradigms for development of new cancer drugs. Neither DFMO nor sulindac is targeted to control a specific geneticmutation relevant to carcinogenesis. BothDFMOand sulindac are classic multifunctional drugs, the exact opposite of the targeted “magic bullets” that are so currently fashionable. If one looks for any functional selectivity of DFMObeyond inhibition of polyamine synthesis (by virtue of its potent irreversible inhibition of ornithine decarboxylase), there is no compelling evidence to suggest that DFMO has a unique genetic target. DFMO inhibits polyamine synthesis, and increased polyamine synthesis has been known to be associated with cell growth and cancer for almost 50 years (12). The reported association of myc,APC, orKraswith the expression of ornithine decarboxylase (12) does little to explain the overall chemopreventive activity of DFMO; these are associations related to upstream control of ornithine decarboxylase expression, and do not address more significant and still unanswered questions of downstream targets of polyamines. There is no known unique signal transduction pathway regulated byDFMO, althoughmany investigations have attempted to fit this drug into one. DFMO, although a specific Authors' Affiliations: Department of Pharmacology, Dartmouth Medical School, Hanover, New Hamsphire, and Division of Cancer Medicine, M. D. Anderson Cancer Center, Houston, Texas Received 03/03/2008; accepted 03/07/2008. Requests for reprints: Michael B. Sporn, Department of Pharmacology, Dartmouth Medical School, 7650 Remsen, Hanover, NH 03755. Phone: 603650-6557; Fax: 603-650-1129; E-mail: [email protected]. ©2008 American Association for Cancer Research. doi:10.1158/1940-6207.CAPR-08-0049