Image: Courtesy of Hibiki Kawamata, Smith College
A drug developer's dream, rationally designed to quell inflammation, COX-2 inhibitors are also prime candidates for preventing cancer or its recurrence. Gary J. Kelloff, chief of the chemoprevention branch at the National Cancer Institute (NCI), lists the requirements for a molecular target such as the COX-2 enzyme: It must be highly expressed in precancer or cancer cells and not in others; blocking it isn't toxic and doesn't disrupt normal function; effects must be measurable; and there must be clinical benefit. "COX-2 is an ideal target," he says.
The COX-2 inhibitors shot to pharmaceutical fame in December 1998, when the Food and Drug Administration approved Celebrex (celecoxib) to treat osteoarthritis and rheumatoid arthritis. Five months later Vioxx (rofecoxib) followed, approved for osteoarthritis, acute pain, and dysmenorrhea.1 But the use for cancer--begun with the 1999 approval of Celebrex to treat a type of colon cancer, familial adenomatous polyposis (FAP)--fits right into NCI's goal to target the earlier stages of cancer, an approach called chemoprevention.2
Specifically, the plan is to target intraepithelial neoplasia, the prelude to invasive cancer, or even earlier stages. "IEN is a precursor lesion that serves as a surrogate endpoint, which is the prevention or decrease in size of this lesion," explains Kelloff. And with an aging population, better diagnostics, and the promise of proteomics, it makes sense to intervene sooner in addition to the traditional later in cancer treatment.
A TALE OF TWO COX ENZYMES COX-2 inhibitors are a refinement of non-steroidal anti-inflammatory drugs (NSAIDs). "The aspirin-like NSAIDs act pharmacologically as an analgesic, anti-inflammatory agent, and they decrease fever. But side effects are gastrointestinal ulceration and bleeding. In the United States each year, 7,000 die from aspirin poisoning," says Makoto Mark Taketo, a professor of pharmacology at Japan's Kyoto University Graduate School of Medicine. It turned out that NSAIDs dampen two forms of the same enzyme, only one of which--COX-1--causes the adverse effects.
NSAIDs inhibit cyclooxygenase (COX), which is synthesized from arachidonic acid in cell membranes. The constitutive or "housekeeping" variant, COX-1, is expressed in many cells all the time, providing basic functions of life. In contrast, the inducible COX-2 is not made in normal epithelium, but causes inflammation and promotes tumor formation in response to growth factors, cytokines, or oncogene signals. COX-2 does so by stimulating production of prostaglandin PGE2, which in turn activates a specific epithelium receptor that in turn increases cyclic AMP production. This stimulates synthesis of vascular endothelial growth factor (VEGF), which triggers the angiogenesis that helps a tumor spread. Taketo and his group worked out the steps to this pathway by knocking out the various players in mice, looking at cells of colon polyps that model FAP in humans.
Because NSAIDs inhibit both COX enzymes, yet COX-2 does not cause the adverse effects and is produced early in carcinogenesis, it made sense to develop a drug to block only it. "Drugs that inhibit COX-2 are small enough to hit a pocket that exists in COX-2 but not in COX-1. This is the basis of the specificity," says Taketo.
Evidence that COX-2 inhibitors intervene early in the development of cancer emerged epidemiologically. Clinicians noticed that people who regularly take NSAIDs--usually to combat the inflammation of arthritis or to prevent heart attacks--have very low incidence of colorectal cancer. An early case report of disappearing FAP polyps in a patient taking a nonspecific NSAID, sulindac,3 inspired placebo- controlled clinical trials to assess the ability of low or high doses of sulindac4 or Celebrex5 to slow progression of FAP. The evidence is overwhelming, and mounting. "A 15- to 20-year block of data shows that NSAIDs block cancer--42 of 43 colon cancer studies show this effect," says Kelloff.
Because COX-2 expression peaks at a particular stage of pathogenesis, timing of cancer treatment to block the enzyme may be crucial. The 1993 study from professor of medicine Francis M. Giardiello and colleagues at Johns Hopkins noted that COX-2 inhibition lost effectiveness after six months of treatment.4 Perhaps in this time, cancer cells that are resistant to COX-2 inhibition persist and accumulate as sensitive cells are wiped out, leading to drug resistance. The group's latest report follows 41 patients with FAP for four years, and reveals that nine of 21 (43%) individuals given sulindac had recurrent polyps, compared to 11 of 20 (55%) people given placebo.6 The researchers did not consider these distinctions to be significant, suggesting that efficacy of COX-2 inhibition drops off with time.
BEYOND THE COLON Oncologists hope that the COX-2 inhibitors that work so well on FAP will also help individuals who have more common forms of colon cancer. The drugs also work against FAP polyps growing in areas other than the colon. Kelloff's group assessed the effects of six months of Celebrex at low or high dose vs. placebo on the duodenum in FAP patients, monitoring the change (in percent) of the small intestine lining covered in polyps.7 The polyp area decreased much more (14.5%) in the patients given high doses compared to the placebo group (1.4%). In the most severely affected patients, Celebrex reduced the affected area 31%.
COX-2 inhibitors may also be effective on cancers that originate in the small intestine. Researchers from Hirosaki University School of Medicine in Japan found COX-2 production in all 26 patients they examined with Helicobacter pylori-associated intestinal-type gastric cancer, but not in four patients with diffuse gastric cancer. In addition, they found that COX-2 is predominant in the precancerous metaplasia stage, and suggest that the drugs be investigated further as an early treatment.8
Celebrex prevents ultraviolet-induced skin cancer in mice,9 and investigation of this use in humans is well under way.10 A multicenter trial headed by Craig Elmets, a professor of dermatology at the University of Alabama at Birmingham, is following 240 people for nine months who have red, scaly skin lesions called actinic keratoses, which progress to squamous cell carcinoma in 10% of cases. The study will assess whether the drug can prevent new lesions from forming or shrink existing ones. And at the University of California, San Francisco, professor of dermatology Ervin Epstein is leading a study of Celebrex's dampening effects on basal cell nevus syndrome, which can progress to basal cell carcinoma.
A preliminary study of Celebrex to treat non-small-cell lung cancer returns to the biochemical roots of the drug's action. David Johnson, deputy director of the Vanderbilt-Ingram Cancer Center in Nashville, is measuring levels of VEGF and PGE2 in the serum of patients, rather than COX-2 levels in tumor specimens. "In this group of patients, docetaxel [Taxotere] alone produces a median survival of about seven months. We're interested in looking at the combination [of docetaxel and Celebrex] in larger trials if we see a better survival. We're also interested in determining if changes in blood VEGF levels or urinary PGE-M, the metabolite of PGE2, correlate with what we see clinically. If either or both of these parameters correlate with the clinical findings, they could be used as possible surrogates of COX-2 inhibition activity," Johnson explains.
With the exception of the test case of FAP, so far the studies pitting COX-2 inhibitors against various cancers are preliminary, small, and short-term. But researchers anticipate an avalanche of supportive data that will reveal when, for how long, and with what other treatments the drugs should be taken. Taketo concludes: "COX-2 inhibition won't necessarily kill the cancer, but with chemotherapy, it may help to lower the dosage needed, with more effective results."
Ricki Lewis (firstname.lastname@example.org) is a contributing editor.
1. R. Lewis, "COX fighting," The Scientist, 14:1, May 29, 2000.
2. J.A. O'Shaughnessy et al., "Treatment and prevention of intraepithelial neoplasia: an important target for accelerated new agent development," Clinical Cancer Research, 8:314-46, 2002.
3. W.R. Waddell, R.W. Loughry, "Sulindac for polyposis of the colon," Journal of Surgical Oncology, 24:83-7, 1983.
4. F.M. Giardiello et al., "Treatment of colonic and rectal adenomas with sulindac in familial adenomatous polyposis," New England Journal of Medicine (NEJM), 328:1313-16, 1993.
5. G. Steinbach et al. "The effect of celecoxib, a cyclooxygenase 2 inhibitor, in familial adenomatous polyposis," NEJM, 342:946-52, 2000.
6. F.M. Giardiello et al., "Primary chemoprevention of familial adenomatous polyposis with sulindac," NEJM, 346:1054-9, April 4, 2002.
7. R.K. Phillips et al., "A randomized, double blind, placebo controlled study of celecoxib, a selective COX 2 inhibitor, on duodenal polyposis in familial adenomatous polyposis," Gut, 50:857-860, June 2002.
8. R. Yamagata et al., "Cyclooxygnease-2 expression is increased in early intestinal-type gastric cancer and gastric mucosa with intestinal metaplasia," European Journal of Gastroenterology and Hepatology, 14:359-63, April 2002.
9. I.F. Orengo et al., "Celecoxib, a cyclooxygenase inhibitor as a potential chemopreventive to UV-induced skin cancer," Archives of Dermatology, 138:751-5, June 2002.
10. A.P. Pentland, "Cyclooxygenase inhibitors for skin cancer prevention," Archives of Dermatology, 138:823-7, June 2002.