LINUS PAULING INSTITUTE RESEARCH REPORT

Gayle Orner

Chemoprevention of Colon Cancer

Gayle Orner, Ph.D.
LPI Research Assistant Professor

Summary: Special mutant mouse strains that develop colon cancer were used to investigate the prophylactic effect of various teas and/or a non-steroidal anti-inflammatory drug called sulindac. The combination of white tea plus sulindac was most effective in decreasing the number of colon tumors in mice.

The non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin, the anti-arthritis drug sulindac, and the newer, more selective drugs like Celebrex®, show great promise for the prevention of colon cancer. NSAIDs are effective chemoprevention agents in genetically predisposed and chemically-induced animal models of intestinal cancer, and high aspirin intake is associated with a 40-50% decrease in colon cancer mortality in humans. Although potent chemopreventive agents, some conventional NSAIDs can cause severe side-effects, including gastrointestinal (GI) bleeding, GI perforation, renal toxicity, and even death. NSAIDs are responsible for at least 100,000 hospitalizations and 10,000 to 20,000 deaths annually and are responsible for more serious adverse drug reactions reported to the FDA than any other class of drugs. These adverse effects are generally dose-dependent, with higher doses more likely to cause toxicity.

One strategy to minimize toxicity and increase efficacy of NSAIDs is to use very low doses of these drugs in combination with other chemopreventive agents. Natural products like tea may be effective in combined chemo- prevention strategies. Support from a Linus Pauling Institute pilot project grant allowed us to test tea alone and in combination with the NSAID sulindac for effectiveness against intestinal cancer in mice.

Familial adenomatous polyposis (FAP), a hereditary condition that predisposes affected people to colon cancer, is caused by a mutated adenomatous polyposis coli (APC) gene. FAP patients develop hundreds to thousands of colonic polyps, beginning at about 16-years old. Without treatment, the disease progresses to colorectal cancer. The NSAID sulindac has been shown to cause regression of polyps in FAP patients. However, the drug is not effective as a sole treatment for FAP because drug resistance occurs, and cancer has developed in patients while being treated with sulindac. Instead, the primary treatment for FAP remains the surgical removal of the colon, typically when patients are in their late teens or early 20s. A special strain of mice, called Apcmin mice, have a mutation in the same gene that causes FAP and, like FAP patients, these mice develop large numbers of intestinal tumors at an early age. Apcmin mice have been useful for testing pharmaceuticals and natural products that may be useful for the treatment of FAP. In the first part of our pilot project, we tested tea alone and in combination with sulindac in Apcmin mice to find out if these substances protected against the development of colon cancer.

Apcmin mice were given either green or white tea in their drinking water for 12 weeks. White tea is minimally processed, whereas green tea has been withered and then fired or steamed, resulting in more oxidized constituents. Black tea, commonly consumed in the U.S., is the most processed and oxidized tea—it has been withered, fully fermented, and fired. Teas were prepared by adding 1.5 grams of tea to 100 milliliters of boiling water and allowing the teas to steep for 2 minutes, which produces a tea concentration similar to that typically consumed by people. Other Apcmin mice were given a low dose of sulindac or a combination of white tea plus sulindac. Apcmin mice treated with sulindac, green tea, or white tea had only half the number of tumors as did the control group of Apcmin mice. Mice treated with the combination of white tea plus sulindac had fewer tumors than the mice given either tea or sulindac alone. Indeed, the protection provided by a combination of white tea plus low-dose sulindac was equivalent to what has been reported for double this concentration of sulindac. Therefore, tea may be a useful complementary treatment for FAP.

Hereditary cancers like those occurring in individuals with FAP account for only a small percentage of human colon cancers. Most human colon cancers are considered sporadic in origin, arising from some combination of genetics, environment, and lifestyle. Another strain of mice that may be well suited to study for sporadic colorectal cancer was developed by Dr. Matthias Ernst of the Ludwig Institute for Cancer Research in Australia. These mice, known as A33DNb-cat mice, contain a mutation in a gene coding for b-catenin, which is a protein that controls a key signaling pathway frequently disrupted in human colon cancers. While A33DNb-cat mice do not develop large numbers of tumors spontaneously, they are highly susceptible to chemically-induced colon cancer. In the second part of our project, we tested white tea alone and in combination with sulindac in this mouse model of sporadic colon cancer. In contrast to our results in Apcmin mice, white tea and sulindac alone did not inhibit tumor formation in A33DNb-cat mice at the concentrations we used. However, the combination of white tea plus sulindac significantly inhibited tumor formation in A33DNb-cat mice. Therefore, the combination of white tea plus sulindac was effective in mouse models of both hereditary and sporadic intestinal cancer.

We now have funding from the National Cancer Institute and the National Center for Complementary and Alternative Medicine to conduct additional studies that may help to move this promising combination of white tea and sulindac into human clinical trials.

Last updated November 2004

 

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