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Colorectal Cancer:
Early Detection and Prevention


Roderick H. Dashwood, Ph.D.
Associate Professor of
Environmental and Molecular Toxicology
LPI Principal Investigator


Roderick Dashwood in the lab

Colorectal cancer is the second leading cause of cancer related deaths in the U.S. According to the American Cancer Society, more than 95,000 new cases of colon cancer and 36,000 cases of rectal cancer will be diagnosed in 1998, and 47,700 people (24,600 women and 23,100 men) will die of colon cancer alone this year. Whereas the major risk factor for developing the leading cause of cancer is known (cigarette smoking implicated in lung cancer), less is known about the cause of colorectal cancer. Certainly, a family history increases the likelihood of developing colorectal cancer, and individuals who know that polyps or colorectal cancers run in their family are advised to consult their doctor. For these individuals, as well as for those with no family history of colorectal cancer, the most important considerations for long-term health may be early detection and prevention.

Early detection

The chance of long-term survival for colon, rectal, or other cancers improves significantly with early detection. For example, the 5-year survival rate for people whose colorectal cancer is found and treated at an early stage is greater than 90%, but once the cancer has spread to nearby organs the 5-year survival rate drops to 64%, and it is less than 10% when the spread includes distant organs, such as the liver and lungs.

Because the survival rates improve with early detection, considerable effort has gone into devising screening tests that might provide an "early warning system" for individuals with no symptoms as well as for those who exhibit one or more symptoms. The major symptoms for colorectal cancer include a change in bowel habits that persists for more than a few days, rectal bleeding or blood in the stool, and cramping or steady stomach pain. Since these conditions are not unique to colorectal cancer but can be caused by infections, inflammatory bowel disease, and hemorrhoids, the doctor should be consulted early so that screening tests can be performed. Screening methods currently available include the digital rectal examination, fecal occult blood, sigmoidoscopy, and colonoscopy. Additional tests may become available in the future, as the early signs of colorectal cancer are better defined. Some of these could be based on the identification of very early pre-cancerous changes, called "intermediate biomarkers".

Intermediate biomarkers

If intermediate biomarkers are identified, one might be able to recognize very early stages of cancer development, long before the formation of a frank tumor. With appropriate intervention, progression of the lesion could be reversed or slowed significantly. One promising candidate for an intermediate biomarker for colon cancer, called an aberrant crypt focus, or "ACF", was first described in 1987 by Dr. Ranjana Bird at the University of Toronto. She observed that in experimental animals given a synthetic colon carcinogen, certain changes occur in the topography of the colon in a few weeks, long before any tumor develops. When the colon was removed, cut open lengthwise, stained with a blue dye, and viewed under the microscope, small clusters or "foci: of darkly stained crypts with thickened walls could be seen. Importantly, the ACF has also been observed in resected human colons, and some contain mutations that are found commonly in human colon tumors.

microscopic photo of colon tumor induced by a heterocyclic amine
colon tumor induced by a heterocyclic amine
We are interested in the ACF because it affords a relatively quick and simple way to screen for compounds in the diet that might either cause or inhibit colon cancer. Our initial work used mutagenic compounds called heterocyclic amines isolated from cooked meat and fish. Heterocyclic amines were first discovered 20 years ago by Drs. Minako Nagao and Takashi Sugimura at the National Cancer Center Research Institute in Tokyo. They found that the cooking of meat and fish, particularly at high temperatures and for prolonged periods, can lead to the generation of potent mutagenic compounds. More than a dozen heterocyclic amines have now been identified in cooked foods, including the compound 2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine (PhIP), discovered by Dr. James Felton and colleagues at the Lawrence Livermore Laboratory in California. PhIP, the most abundant heterocyclic amine mutagen in fried ground beef, has been demonstrated to produce colon tumors when fed to male rats for one year (see photo below). On a much shorter time scale, PhIP and related heterocyclic amines generate ACF in rats after only a few weeks of treatment. For example, we exposed rats to these mutagens for two weeks, and the ACF were first detected within about six weeks. The ACF assay also provides a quick method to screen compounds that might be effective at inhibiting the development of colon cancer, and several promising candidates for chemoprevention have been identified in our laboratory, including conjugated linoleic acids, chlorophylls, and tea polyphenols.

Most animal experiments use doses of heterocyclic amines that exceed the exposure that we might get from a "typical" diet that includes cooked meat or fish. Indeed, cancer scientists have debated the real significance of heterocyclic amines as human carcinogens. It has been argued that heterocyclic amines are present at such low levels in the diet that they pose negligible risk, since the endogenous detoxification and repair processes in our bodies would prevent lasting damage to DNA. An assessment of the risk that heterocyclic amines might pose for developing colon cancer (and possibly cancer at other sites) is complicated by the diverse eating habits of each individual. The type and quantity of food consumed, the cooking method, the doneness of the food, and other factors give rise to a 5,000-fold variability in heterocyclic amine intake.

According to a study by Dr. Rashimi Sinha and colleagues at the National Cancer Institute in Bethesda, chicken that is well done by flame-broiling has up to 500 parts per billion of PhIP. Dr. Ken Turteltaub and colleagues at the Lawrence Livermore Laboratories have used a sensitive new technique called Accelerator Mass Spectrometry to show that the amount of heterocyclic amines found in a single hamburger can produce measurable changes in the DNA of exposed animals and humans. These changes, known as "adducts", involve the covalent binding of the metabolically activated forms of the mutagen to specific bases in the DNA (e.g. guanine, one of the four bases in DNA, is a favorite target). The adducts, if left unrepaired, can give rise to mutations that may lead to cancer.

While the issues remain to be resolved, it seems prudent to follow some sensible guidelines to reduce risk. For example, it has been shown that marinating or briefly cooking by microwave before frying or grilling greatly reduces the levels of PhIP in meat and chicken. In a well-done steak or hamburger, most of the hetercyclic amines are formed near the surface, where the meat has been in direct contact with the cooking heat. This is especially the case in the blackened regions produced by barbeque cooking, and one should avoid the charred portion since it contains not only heterocyclic amines but also other classes of carcinogens, such as polycyclic aromatic hydrocarbons. It is advisable to remove the skin of chicken or fish and the blackened portion of meat after high-temperature cooking to reduce exposure to the mutagens. Of course, this helps reduce excess fat and calorie intake, too. Finally, and perhaps most importantly, since diet contributes to approximately 30% of all cancers in the U.S., one should eat a balanced diet that includes cereals, grains, fruits, and vegetables. Accumulated scientific evidence indicates that these foods are a rich source of compounds, some identified and many unknown, that play an active role in cancer prevention.

Other risk factors

Although early detection is a key consideration in the fight against cancer, ideally, we would like to be able to prevent cancer from developing. For this, a clear understanding of the cause of the disease is required. In the case of colorectal cancer, the main causes are:

  • Aging - Colon cancer is most commonly diagnosed in people over the age of 50.
  • Insufficient physical activity - People who are active are less likely to develop colorectal cancer, particularly those with a daily or weekly regimen of exercise who maintain a healthy body weight.
  • Family history - Less than 15% of colorectal cancers are due to inherited changes in DNA, but the study of individuals with such diseases as familial adenomatous polyposis and hereditary nonpolyposis colon cancer has provided insight into the genes that play a role in the development of colon cancer. These include oncogenes, such as Ki-ras and b-catenin, tumor suppressor genes, and repair genes that, in a mutated form, fail to correct the mistakes and damage in DNA.
  • Poor diet - A diet high in fat and low in fiber appears to increase the risk of developing colorectal cancer, whereas consumption of a wide variety of cereals, fruits, and vegetables lowers the risk. The American Cancer Society recommends at least five servings of fruits and vegetables each day, plus six servings of foods like breads, rice, pasta, grains, and beans. It is suggested that these foods be eaten at the expense of high-fat foods, particularly those from animal sources. In addition to general nutritional benefits, these recommendations should lower the exposure to mutagenic heterocyclic amines and also increase the levels of dietary constituents that are believed to play a role in cancer chemoprevention.

Chemoprevention

In recent years, we have come to realize that our diet contains many compounds that can inhibit cancer, at least in experimental animals. This is also supported by epidemiological studies in humans. The inhibitors, or "anticarcinogens", have been broadly categorized as "blocking" agents (preventing DNA damage) or "suppressing" agents (preventing cells with damaged DNA from progressing to tumors). Some blocking and suppressing agents from plants (phytochemicals) have been identified, but synthetic agents, such as aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), can also be highly effective at inhibiting colorectal cancer. Some of the most promising chemopreventive agents against colorectal cancer are summarized in the table below. Two of these effective inhibitors, selenium and vitamin E, have been discussed in previous issues of the LPI Newsletter (see "Selenium and Cancer: New Views" by P. D. Whanger, LPI Newsletter Fall/Winter 1997).

Some Promising Chemopreventive
Agents Against Colorectal Cancer

NATURAL

Calcium
Vitamin D
Vitamin E
Selenium
Flavonoids
Tea polyphenols
Ursodeoxycholic acid
Conjugated linoleic acids
Folate

SYNTHETIC

Nonsteroidal anti-
inflammatory drugs

a-Difluoromethylornithine

Synthetic antioxidants

Chlorophyllins

Results from our laboratory suggest that drinking tea might protect against colorectal carcinogenesis. For example, rats exposed to mutagens from cooked meat had significantly fewer ACF in the colon when they were also given either green tea (popular in Japan and China) or black tea (popular worldwide, but with highest per capita consumption in Ireland, U.K., New Zealand, and Australia). Using the Salmonella mutagenicity assay, we showed that the compounds that are effective against the heterocyclic amines are rapidly released from tea leaves (within 2-3 minutes of brewing). To identify the inhibitory components, tea constituents were separated by high-performance liquid chromatography and then tested for antimutagenic activity. The most active component appeared to be the polyphenol epigallocatechin-3-gallate (EGCG), a compound that has been widely reported as an effective "free-radical" scavenger. Since free radicals can damage cellular components and have been implicated in cancer, aging, heart disease, immune dysfunction, and other pathologies, there is much excitement surrounding the study of these tea polyphenols. However, our studies and those of Dr. C. Ioannides and colleagues at the University of Surrey in the U.K., revealed additional inhibitory mechanisms of tea against the heterocyclic amines. These included induction of detoxification enzymes like glucuronyl transferase, inhibition of certain enzymes that can activate carcinogens (e.g. acetyltransferases), and direct scavenging of the activated metabolites before they damage DNA. Which of these mechanisms is most important in protecting against ACF formation in the colon awaits more detailed study. A major goal of the Cancer Chemoprevention Program within LPI will be to resolve some of these issues, not only for tea but for other inhibitors of carcinogenesis, and eventually to take the results from the laboratory bench into human clinical trials. This approach has been applied successfully in the study of the cancer chemopreventive effects of chlorophylls, in which results from collaborative studies using trout and rodents set the stage for human intervention trials in Daxin, China (see "Chlorophylls: Can These Green Food Pigments Prevent Some Cancers?" by G.S. Bailey, LPI Newsletter Fall/Winter 1997).

It is important to note that the agents listed in the above are at various stages of study, including human clinical trials in some cases. Many other potential anticarcinogens have been identified, but it is premature to offer specific dietary recommendations for any particular compound. This applies even in the case of aspirin and related nonsteroidal anti-inflammatory agents; a group of experts convened by the International Agency for Research on Cancer recently concluded: "Although these drugs consistently prevent colorectal cancers in experimental animal models, the evidence that they prevent colorectal cancer in humans was considered to be inadequate." Certainly, improved knowledge of the inhibitory mechanisms will be required before the risks and benefits can be assessed. As new information emerges, it may allow explicit recommendations for long-term use of chemoprevention compounds. In the interim, we know that a diet high in fruits, vegetables, grains, and cereals will offer some real measure of protection against this dreaded disease.

Last updated November, 1998


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