COLON CANCER
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Presenters: Daniel Nixon, M.D. and Michael Wargovich, Ph.D.
Moderator: William Fair, M.D.
Commentator: Thomas Brown, M.D.
Session: Sa16; June 12, 1999I. & II. Abstract and The Cancer-Related Issue Addressed
This panel focused on complementary therapies to prevent and treat colon cancer. The panel reviewed the evidence on dietary influences and the use of supplements and herbal therapies. Programs for making complementary and alternative therapies an integral part of comprehensive care for colon cancer were outlined. Dr. Nixon spoke about supplements. Dr. Nixon works in a cancer prevention research laboratory with outreach, clinical, and epidemiological components which relate to colon cancer. He stressed colon cancer prevention and treatment. Dr. Wargovich talked about research aspects of colon cancer prevention, the use of cylooxygenase (COX) inhibitors, herbs and diet. Patients with colon polyps or colon cancer are encouraged to increase fiber intake, decrease fat intake, exercise more and possibly supplement it with pharmacological agents such as cyclooxygenase inhibitors.
III. The Program Presented by Dr. Nixon
A. Philosophical Background
The American Cancer Society reports that cancer ‘strikes’ 1.2 million per year. This statement is somewhat inaccurate, since cancer does not ‘strike’. It progresses slowly through many stages, requiring many gene abnormalities, starting from a normal cell through what is called ‘dysplasia’, the ‘polyp’ stage in colon cancer, then through carcinoma in situ, when the polyp begins to develop cancer. It takes colon cancer between 30 and 40 years to develop from normal to invasive cancer. Therefore, there is a large window of opportunity for prevention of colon cancer, i.e. treatment of colon cancer before it becomes an invasive cancer. We will be discussing a number of ongoing clinical trials which deal with polyps and invasive cancers. About 20 million Americans are presently in the carcinoma in situ stage. This is the population that the preventive research community is targeting. The normal population, we want to keep normal, and our dietary guidelines pertain to that goal.
B. Mechanisms of Action
In epidemiological studies, the risk of colon cancer was found to be especially linked to diet. Total saturated and animal fat increase the risk. High consumption of vegetables, fiber and cereals decrease the risk of colon cancer. The daily recommended daily allowance of fiber is 20-30 grams. In Scotland, where the average fiber intake is 2-3 grams per day, there is a very high incidence of colon cancer. In Japan, where the diet is high-fiber and low-fat, there is a much lower incidence of colon cancer. Obesity, lack of exercise, a low-fiber and high-fat diet, all increase the risk of colon cancer.
What is the link between diet and colon cancer? It has to do with the carcinogens that are present in fecal matter (fecal bile acid). The incidence of cancer correlates increased fecal bile acid, which is increased in high-fat, low-fiber diets.
Fats. There are ‘good’ fats and ‘bad’ fats. The omega-3 and omega-9 fatty acids are relatively good, while the omega-6 fatty acids are relatively worse.
At the molecular level, there is evidence for a link between colon cancer and saturated fat consumption, cholesterol and oncogene activation. What we are doing is examining these connections in the laboratory, studying the results in clinical trials, and then taking the results out to the community; this is called ‘translational research.’ Most of the cholesterol in our bodies is made by the liver. Geranyl and farnesyl are two intermediates in the cholesterol biosynthetic pathway. These intermediates seem to aid in the action of the ras oncogene. Activated ras has been shown to be abnormally high in many cases of colon cancers (also in 90% of pancreatic cancers). The theory is that the more fat that is consumed, the more ras is active, and the greater propensity for colon cancer. In that sense, fat is perhaps acting as an initiator and/or promoter of colon cancer.
Fiber is a substance that is theoretically very useful to study in colon cancer prevention. There are clinical trials that have not been as conclusive as was hoped. Therefore, a new generation of clinical trials is now required and underway. Fiber is an indigestible carbohydrate component of plants. Lignin, a part of plant fiber (and a byproduct of paper production), has very interesting chemopreventive properties. It is found in very high concentration in corn and wheat flakes and may be one of the active moieties in fiber. Some data showed lignin to be 8 times more powerful as an absorber of those carcinogenic fecal bile acids. Through a grant from paper and cereal producers, the presenter’s group is researching lignin’s cancer prevention ability. The national recommendations for fiber consumption are 30 grams per day, but average US consumption is only 14 grams per day. This clearly correlates with a high rate of colon cancer.
C. Research
Most cancer patients die not of catastrophic events but of a wasting-away process called cachexia. At Emory University cancer patients were relatively overfed in an attempt to overcome cachexia, to let patients withstand chemotherapy better and to live longer and better. When compared with control patients (not given extra nutrition), the overfed patients became fatter but their lean body mass did not increase. Fattening patients was, of course, not desirable. The reason the intervention failed was that the patients were losing magnesium and phosphate, which are involved in energy metabolism. Thus, this intervention was apparently not repleting lean body mass, but tumor mass
In the next series of studies, the survival of hyperalimented patients was assessed. It was found that overfed patients died sooner. This results taught oncologists a very important lesson about food. If food can make things worse, then it is important to examine what is in food that can make things better. This has been the subject of a series of studies.
These studies are examining the ability of omega-3 fatty acids to prevent cancer cachexia. The rationale behind these studies is to use what was learned from the unsuccessful hyperalimentation studies and to hypoaliment them, giving them some fiber, omega-3 fatty acids in oral supplements. Preliminary data showed an encouraging increase in lean body mass in patients with advanced pancreatic cancer.
Other studies funded by Kellogg company and the American Cancer Society (ACS) using low-fat, high-fiber diet for cancer prevention were presented. The goal was to decrease polyp formation, progression of small polyps into bigger polyps, and large polyps into malignant cancer. In a pilot study, patients consuming low-fat cereals (4 mg per gram of cereal) were compared with patients consuming high-fat (20 mg per gram) cereals, then subjected to colonoscopies every three years. Initial data were promising but then information from related cases in studies using vegetable fiber forced researchers to rethink the cereal fiber trial. In one case, a patient presenting with familial adenomatous polyposis (FAP), a hereditary condition characterized by the presence of hundreds of small colon polyps which almost always lead to malignant colon cancer. For other medical reasons, this patient could not receive the usual total colonectomy treatment and instead received fiber supplements and an aspirin-like drug called sulindac. Colonoscopies following treatment showed a dramatic decrease in the number of polyps, which eventually disappeared completely. The Kellogg- and ACS-funded cereal fiber study is being redesigned to include groups of patients treated with sulindac alone, sulindac plus fiber and perhaps a group receiving raspberries (see below), as raspberries are thought to contain anti-cancer properties.
Other studies in Dr. Nixon’s lab are aimed at discovering what exactly in vegetables and fruits prevent cancer, where thousands of compounds are thought to be cancer preventive. Specifically, they are examining the ability of one such compound to prevent cancer -- ellagic acid, a tannin-like compound found in nature. It is contained in figs, grapes, walnuts, pomegranates, strawberries and raspberries. Ellagic acid is readily absorbed by the human body. The Washington State Red Raspberry commission has given Dr. Nixon funding for over a thousand compounds in fruits and vegetables that have cancer preventive properties. Ellagic acid, when added to cultured cancer cells in vitro, stops cell division and cancer cells eventually die by apoptosis, while sparing normal cells. In the clinic, the results of a study with patients who are administered raspberries are very encouraging, but not yet definitive.
III. The Program Presented by Dr. Wargovich
A. Background
Dr. Wargovich emphasized that components which have anti-inflammatory properties also tend to have anti-cancer properties.
There are two genetic abnormalities that lead to polyp development: the tumor suppressor pathway and the mutator pathway. When a tumor suppressor is lost, one of the ‘brakes’ of cell cycle progression is missing, and cells proliferate without control, thus favoring cancer progression. In the mutator pathway, there is deficiency in the ability of the cell to repair its DNA. A classic example of mutator pathway deficiencies is the hereditary non-polyposis cancer syndrome (HNPCC).
Colon cancer has been a very prevalent disease in the US for many years, but is now also becoming very prevalent in Asian countries, as they are adopting a US-like diet. As Dr. Nixon mentioned above, in light of recent studies our approach to designing dietary intervention studies must be modified. Although the two largest studies in the country failed to show an effect of diet on polyp recurrence, they do not rule out that cancer may be prevented by dietary intervention. The goal is to prevent the premalignant lesions from forming initially.
B. Mechanisms of Action
The Aspirin story
It has been recognized for more than 10 years that people who take an aspirin a day have a 40% lower risk of dying of colon cancer. Although it is not known whether other members of the aspirin family (non-steroidal anti-inflammatory drugs, NSAIDs) will have this beneficial effect on colon cancer, the NSAID ibuprofen has recently been shown to have similar effects. However, the downside of using NSAIDs to prevent colon cancer is that they are highly ulcer-causing. This is why they are not recommended for the general population.
Two enzymes are involved: COX-1 and COX-2. By causing the release of chemical messengers (thromboxanes and prostaglandins), they are involved in kidney function, platelet adhesion, inflammation and protection of the gastric mucosa. Inhibiting these enzymes with NSAIDs reduces inflammation and makes patients feel better, but it also leads to gastric erosion and changes in kidney function. We think these enzymes are related to colon cancer because the same process involved in the relief of fever and pain also maintains polyps and supports their progression to colon cancer.
Use of sulindac, as Dr. Nixon mentioned, has been recognized as a powerful cancer preventive factor, but once patients were taken off of sulindac, polyps began to develop again, so patients would need to remain on sulindac for long-term benefits.
Using an animal model, Dr. Wargovich can recapitulate polyp formation, and thus test the ability of various compounds in reducing polyp formation. All NSAIDs prevented the development of polyps in such tests.
The development of the NSAID celebrex, a specific inhibitor of COX-2, permits the inhibition of cyclooxygenase activity without the ulcer-causing effects. However, Dr. Wargovich questions whether or not drugs would need to inhibit both COX-1 and COX-2 in order to exert cancer-preventive effects.
The possibility of using botanical, particularly herbal, compounds to exert anti-inflammatory and anti-cancer effects is being actively investigated. There are many molecular targets for such actions, including the COX enzymes and the process of apoptosis. Dr. Wargovich’s list includes: polyphenols, anthrocyanins (the red pigments in plums and cherries), flavonoids, onions, phytoalexins, garlic volatiles, red wine, mistletoe extracts, ginseng and green tea.
Green Tea. All tea is green tea until oxidized (whereupon it becomes brown or black). Green tea extracts are very efficacious also. Among the few studies carried out, there is one from Japan and another one Sweden, both showing that tea consumption prevented colon cancer.
Onions. The chemical under study is called quercetin. It survives all cooking, but it is mostly found in the outer rings of the onion. Its cancer-preventing effects are well recognized, and they were also seen in Dr. Wargovich’s studies.
Garlic. Sulfur compounds in garlic volatiles are very readily absorbed (as anyone who eats garlic knows) and are thought to aid in the liver’s detoxification process.
Curcumin. Potent antioxidant which inhibits cancer. It scavenges singlet oxygen. It inhibits COX and may mimic the effects of aspirin.
Red Wine. Phytoalexins are the pigments that give the red color to grape juice and wine. Red wine also has a chemical with potent anti-inflammatory properties, and that may account for the ‘French paradox.’
Ginseng. Saponins are the active components in ginseng that may prevent cancer.
Mistletoe. Mistletoe extracts have traditionally been used in Europe for the treatment of colon cancer. MD Anderson is pioneering studies using mistletoe for the treatment of colon cancer. But they will also be tested against leukemias, etc.
V. Commentator’s Comments
Three main points to consider
1) Cancer initiation is a long-term process, so very large window to help.
2) We should view cancer as a chronic disease – slow the progression, and improve the quality of life. There is no quick fix; it’s the whole picture that’s important.
3) Natural products do have a role in cancer prevention and treatment.From the time the cells undergo the first cancer-causing change until it progresses to a full-blown cancer many years may elapse. In the case of prostate cancer, it can take as long as 30 years or more. Thus, discovering ‘what causes cancer’ is not as important as it is to understand what makes cells progress through these stages to eventually become a full-blown cancer. If we understand these factors, we can learn how to slow down their progression or even revert their growth.
This is a very exciting time to be developing therapies for cancer treatment. Both Drs. Nixon and Wargovich touched on several main themes in the colon cancer story. First, there is an ‘explosion’ in our knowledge of basic aspects of cancer formation and development. We also know the many stages of development of a given cancer. More recently, we have been identifying the genetic abnormalities associated with each of those stages of cancer development. What is especially exciting, and what both talks discussed, is the convergence of that explosion of knowledge and the investigation of many forms of complementary and alternative medicine and how this convergence may lead to cancer prevention. However, we know much less about the impact of these approaches on cancers at later stages of development. This remains an area of active investigation, for example through studies at MD Anderson, such as that described by Dr. Wargovich. Finally, Dr. Brown commented that it is worthwhile to continue to look at whole, and not just isolated products for cancer prevention or treatment.
VI. Audience Questions
What about eating seeds? Did eating seeds cause diverticulitis?
The puree was prepared using a special very fine grinder to ground seeds completely.
Are these approaches aimed at reducing polyp formation or at eliminating polyps?
They are aimed primarily at slowing down the growth of polyps.
Are there hyperalimentation studies that give excess vitamins and minerals, as opposed to calories and fat?
None known of by the person answering the question..
What about RNA vaccines?
Some RNA vaccines are studied, but the problem is that these RNAs may not be specific to the tumor so a vaccine of that RNA may prevent any number of normal functions in the body.
What about red meat or calcium?
Protein is linked to cancers, but, because fat accompanies protein often, it is difficult to tease them apart. Calcium may be beneficial, according to some studies.