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Cancer Chemoprotection and a New Program at LPI


David E. Williams, Ph.D.
Professor of Environmental
and Molecular Toxicology
LPI Principal Investigator


Photo of David Williams

The association between diet and cancer has been recognized for many years. In a seminal paper published in 1981, Doll and Peto estimated that 35% of all cancers are related to diet, a contribution as great as or greater than that associated with tobacco use (see table).

Proportions of Cancer Deaths Attributed to Various Factors

Factor

Percent of all cancer deaths
 
Best estimate
Range of acceptable estimates
Tobacco
Alcohol
Diet
Food additives
Reproductive/sexual behavior
Occupation
Pollution
Industrial products
Medicines/medical procedures
Geophysical factors
(radon, elevation, etc.)
Infection
30
3
35
<1
7
4
2
<1
1

3
10
25 - 40
2 - 4
20 - 60
-5* - 2
1 - 13
2 - 8
<1 - 5
<1 - 2
0.5 - 3

2 - 4
>1
*Assumes a possible protective role for natural or synthetic antioxidants like BHA or BHT. Adapted from Doll and Peto (JNCI 66, 1981) and Doll (Cancer Research 52, 1992).

How does one arrive at these estimates? Many strategies are employed to study the relationship between diet and cancer. One of these methods utilizes epidemiological data. In these studies, dietary intakes of various foods are correlated with the incidence of certain kinds of cancers after taking into account other variables like age, gender and smoking. Epidemiological studies have provided important clues as to how lifestyle differences, including diet, affect cancer rates around the world. (For some comments on nutritional epidemiological studies, see Dr. Santana-Riosís article in this newsletter.) An excellent example of such a study examined cancer rates in different organs in native Japanese compared to Japanese immigrants in Hawaii and Caucasian Hawaiians. Native Japanese exhibit a higher incidence of esophageal and stomach cancer than Caucasians living in Hawaii. Conversely, native Japanese are somewhat protected from cancers of the colon, breast and prostate.

Japanese who move to Hawaii exhibit a pattern more similar to Caucasians living there--their relative risk for esophageal and stomach cancer goes way down and their susceptibility to cancer of the colon, breast, ovary, uterus and prostate goes way up. Results from studies like these suggest a predominant role for lifestyle, rather than genetics, in cancer risk. What are these lifestyle factors? The data strongly suggest that high esophageal and stomach cancer rates in Japanese relate to their high intake of salted and pickled foods. The Western diet is much richer in fat and red meat, factors that probably contribute to relatively high rates of colon and breast cancer, although the link between dietary fat and breast cancer is uncertain.

Diet plays a role in cancer risk when we either ingest too much of a substance that enhances cancer or when our diets are low in chemoprotective agents. In the ethnic and regional differences in cancer rates mentioned above, the ingestion of high levels of fat or salted or pickled foods are thought to be important. These are agents that are thought to promote cancer. Foods can also contain carcinogenic chemicals that initiate cancer, including mycotoxins (aflatoxins produced by a mold growing on peanuts or corn), nitrosamines (formed by the reaction between nitrites/nitrates found in preserved meats and amines), and polycyclic aromatic hydrocarbons and heterocyclic amines (present in charred meat and fish). The risk associated with a deficiency of chemoprotective agents in the diet seems to be primarily related to the inadequate intake of fruits and vegetables. More than 200 epidemiological studies have confirmed that individuals in the upper quartile (25% of the population studied) of fruit and vegetable intake have half the cancer risk of individuals in the lowest quartile (see table). Protection afforded by fruits and vegetables was not as impressive for breast and prostate cancer, which are strongly influenced by hormonal factors.

Epidemiological Studies Documenting Correlation of
Cancer Risk with Dietary Intake of Fruits and Vegetables

Cancer
site

Studies documenting
protection/total studies

Relative
risk

   
(lowest vs. highest quartile)
Lung
Oral
Larynx
Esophagus
Stomach
Pancreas
Cervix
Bladder
Colorectal
24/25
9/9
4/4
15/16
17/19
9/11
7/8
3/5
20/35
2.2
2.0
2.3
2.0
2.5
2.8
2.0
2.1
1.9

The strength of the epidemiological evidence has prompted the National Cancer Institute to recommend a daily intake of 5-9 servings of fruits and vegetables. Unfortunately, the typical American diet fails to meet this recommendation. Sixty-eight percent of U.S. adults and 80% of U.S. adolescents and children fail to consume even the minimum of 5 servings a day. Therefore, it is important to determine which phytochemicals present in fruits and vegetables are responsible for cancer chemoprotection and understand how they work. If specific compounds can be identified as especially potent, then these could be provided as dietary supplements. It may also be possible and practical to engineer foods to contain higher levels of chemoprotective compounds, such as the selenium-enriched ramps discussed by Dr. Phil Whanger of OSU in the Fall/Winter 1997 LPI Newsletter.

The other obvious rationale for investigating chemoprotective agents from fruits, vegetables and other sources is that "an ounce of prevention is worth a pound of cure". Despite significant advances in cancer therapy in recent years, many cancers are still characterized by a discouraging low five-year survival rate, including cancers of the lung, pancreas, stomach and esophagus. Studies have shown that ample fruits and vegetables provide significant protection against these particular cancers.

Which phytochemicals protect against cancer? Some of these are listed in the table to the right. How do these phytochemicals inhibit cancer? Three different types of cancer chemoprotective compounds have been identified: 1) inhibitors of carcinogen formation, 2) blocking agents, and 3) suppressing agents.

Vitamin C inhibits the formation of carcinogenic nitrosamines (formed in the mouth from the reaction of nitrite in preserved meats with dietary amines). Some blocking agents, such as isothiocyanates, diallylsulfide, resveratrol and indole-3-carbinol, protect DNA from damage by inhibiting the metabolic activation of a procarcinogen (carcinogen precursor) into a carcinogen. Another blocking agent, chlorophyllin, hinders the ability of a procarcinogen to become converted to a carcinogen by competing for molecular binding sites. Other blocking agents like ellagic acid from raspberries and vitamin E inhibit reactive carcinogenic substances like free radicals. Suppressing agents, including quercetin, monoterpenes and green tea polyphenols, restrict the growth and proliferation of precancerous and cancerous cells. Some chemoprotective compounds, such as vitamin C, quercetin and other polyphenols, can affect cancer by more than one process.

The Cancer Chemoprotection Program at LPI

Dr. George Bailey, Distinguished Professor of Environmental and Molecular Toxicology and LPI Affiliate Investigator, has pioneered numerous studies in trout on the efficacy and mechanism of the dietary inhibition of cancer by indole-3-carbinol and chlorophyllin (see the Fall/Winter 1997 LPI Newsletter). Dr. Rod Dashwood, LPI Principal Investigator and Associate Professor of Environmental and Molecular Toxicology, is examining the molecular mechanisms by which chlorophyllin and the polyphenols found in green tea prevent colon cancer in rodents. I am a Professor of Environmental and Molecular Toxicology and LPI Principal Investigator and have worked closely with Dr. Bailey for over 12 years studying diet and cancer. In the Spring/Summer 1997 LPI Newsletter, I reported on our work on the potential cancer risk from the use of dehydroepiandrosterone (DHEA). Recently, our group has initiated chemoprotection studies in rodents on lung, liver and breast cancer.

These scientists and their associates now comprise the Cancer Chemoprotection Program at LPI. Each of the three principal faculty will serve as the Program Chief for a three-year period. For the initial three years, I will act as the Program Chief. We believe that uniting these scientists with a common research theme will accelerate our progress toward the goals of the program, which are to:

  • Identify novel plant chemicals that protect against cancer
  • Develop and evaluate promising antimutagenic or antioxidant compounds as anticarcinogens
  • Design and conduct protocols for safe testing of chemoprotective agents in humans
  • Disseminate information derived from these studies and from other laboratories worldwide

How will we achieve these goals? We will continue and expand our current research and educational efforts, encourage collaboration with newly recruited OSU faculty, and seek funding from the National Cancer Institute. One grant proposal, "Cancer Chemoprotection by Phytochemicals", will be submitted to this agency in June. The strategy of the Program will be to identify potent and effective chemoprevention agents by rapid in vitro screening followed by studies in trout and rodents, which will explore biochemical mechanisms of action. Such knowledge is critical to select effective and safe chemicals to test in humans. Exploratory human studies can then be successfully conducted with volunteers from our local community.

Chemoprotective Agents in Food

Food

Chemoprotective chemicals

Site of protection

Alliums
(garlic, onion)

Citrus fruits


Crucifers
(broccoli, cabbage,
Brussels sprouts)

Grapes, berries



Teas


Green, leafy
vegetables

Vegetable oils, nuts
Alkyl di- and trisulfides,
selenium

Monoterpenes, vitamin C


Isothiocynates, indoles,
selenium


Polyphenols, ellagic acid,
resveratrol, anthocyanins,
quercetin

Polyphenols


Chlorophyll


Vitamin E
Esophagus, colon, lung,
prostate, breast

Breast, pancreas, lung,
stomach

Liver, lung, breast,
prostate


Skin, colon, breast



Colon, lung, skin,
esophagus

Liver, colon, skin


Colon, skin, prostate,
mouth, lung, breast

An example of this approach is the chlorophyllin study described by Dr. Bailey in the Fall/Winter 1997 LPI Newsletter. Chlorophyllin is a derivative of chlorophyll that had been safely used clinically in geriatric patients for several years before it was demonstrated to be an effective antimutagenic compound in vitro. Using trout, Drs. Bailey and Dashwood were the first to demonstrate that this phytochemical could inhibit cancer in animals. Subsequently, Dr. Dashwood documented significant protection by chlorophyllin against various cancers in rodents. Based on the strength of these studies and others, the National Cancer Institute funded a small clinical trial in China, where liver cancer is endemic in certain regions because of exposure to high levels of aflatoxin in the diet and to the prevalence of hepatitis virus infection. The study is directed by Dr. Bailey and researchers from Johns Hopkins University.

In 1998 there were an estimated 1.2 million cancer diagnoses in the U.S. and 560,000 cancer deaths, with a health care cost of billions of dollars. The cost in human suffering is immeasurable. A reduction in cancer incidence by dietary chemoprevention of only a few percentage points of the estimated 35% of diet-related cancers would represent an enormous savings in this financial and emotional toll. At LPI's Cancer Chemoprotection Program, we expect to make substantial contributions to this effort.

Last updated May, 1999


Honoring a Scientific Giant with Research Toward Longer, Better Lives

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