Each day, some 11 million Americans pop a small pill known as a ‘statin’ to help them keep their blood cholesterol levels low and stave off a heart attack. Millions more take a daily aspirin—not for chronic pain, but under their doctor’s guidance to prevent heart disease.
These are examples of a promising area of medicine known as chemoprevention, the use of a drug or other agent to slow, stop or reverse the development of disease.
Chemoprevention is entirely different from chemotherapy, the use of drugs to treat cancer. First, chemoprevention is used by people who do not have active cancer. Second, while chemotherapy kills cancer cells, chemoprevention agents prevent cells that might become cancerous from doing so.
Also, chemoprevention agents should have minimal side effects because people may take them for years. For this reason, they are usually used only by people with an elevated risk for cancer, a group that encompasses about one-third of the American public.
“Over 100 million people in the United States have a higher-than-normal risk for cancer and could potentially benefit from chemoprevention agents,” says Gary D. Stoner, PhD, professor of internal medicine and head of a major chemoprevention research program at The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSU CCC-James).
For example, chemoprevention might help people with an inherited predisposition to cancer. These individuals are identified by their family history or by genetic testing. Chemoprevention agents might lower their hereditary risk.
Mutations in the gene known as BRCA1, for example, raise the risk of breast cancer. “Some women with these mutations have bilateral mastectomies to prevent the disease,” says Steven K. Clinton, MD, PhD, a medical oncologist and co-director along with Stoner of the OSU CCCJames Molecular Carcinogenesis and Chemoprevention Program. “Chemopreventive agents may one day give these women the same measure of protection without the disfiguring surgical procedure.”
Chemoprevention might help smokers and others exposed to cancer-causing agents, including people who routinely eat smoked foods or mold-contaminated grains. Chemoprevention also might halt or correct conditions that can lead to cancer, such as Barrett’s esophagus and leukoplakia in the mouth. Other precancerous conditions can arise in the lungs, breast, cervix, bladder, colon and skin.
Last, chemoprevention might prevent recurrent cancer or cancers caused by certain therapies in people treated earlier for a malignancy.
“Oncologists will be recommending more chemoprevention in the next five to 10 years,” says Peter Greenwald, MD, DrPH, director of cancer prevention at the National Cancer Institute (NCI). “I think it will also advance into other medical disciplines. Gastroenterologists, gynecologists, urologists and family doctors will be seeing more people with cancer risk factors. These physicians will want to help their patients lower that risk.”
But in spite of its promise and some tantalizing successes, advances in chemoprevention come slowly. The obstacles include a lack of federal funding, the research necessary to identify the groups of people who will be aided by particular agents and the high cost of proving that an agent is safe and effective.
For example, a five-year study testing whether a substance will prevent lung cancer in smokers requires a certain number of smokers to be statistically sound. “Because only about one in 10 smokers gets lung cancer,” Stoner says, “the study may require 20,000 volunteers and might cost $75-80 million.” Costs like that and the time involved also discourage pharmaceutical companies from undertaking chemoprevention research, and that is also slowing the field’s advance.
And then the study might show that the agent has no effect or even a contrary effect. A large chemoprevention study in the 1990s tested whether beta carotene, a precursor of vitamin A, would prevent lung cancer in smokers. The trial involved 29,311 men 50 to 69 years old.
Surprisingly, the study found that beta carotene actually upped the incidence of lung cancer by 18 percent. This study taught investigators that the anticancer benefits of food are more likely due to many components in foods and not to just one of them.
Also slowing chemoprevention research is the lack of valid indicators, or biomarkers, that can predict the probable effectiveness of potential agents. Reliable biomarkers would enable researchers to end studies early if they don’t see promising effects along the way. For more about biomarkers and biomarker research at the CCC-James, see “Cancer’s Subtle Signposts” in the Summer 2004 Frontiers.
These obstacles are being tackled by chemoprevention research under way at the OSU CCC-James and other NCI-funded cancer centers. At the OSU CCC-James, chemoprevention is a priority research area, along with cancer genetics and experimental therapeutics. Investigators are developing classic cancer chemoprevention agents, along with so-called nutriceuticals and functional foods, and potential chemoprevention biomarkers.
Cancer prevention today, Greenwald explains, follows two broad strategies: a lifestyle approach—avoid tobacco, eat healthy, exercise, get regular screenings—and a medical approach. “The medical approach,” he says, “uses bioactive food constituents or drugs, often in people at high risk but at times it includes the general population, to lower the occurrence rate of cancer.”
Medical approaches to cancer prevention range from classic chemoprevention to diet and nutritional measures, with nutriceuticals and functional foods falling in between. Nutriceuticals are food products or supplements that combine aspects of chemoprevention and diet and nutrition; functional foods are foods that have been enhanced to provide added health benefits.
No matter its form, the goal of chemoprevention is to stop socalled precancerous cells from becoming cancerous. Just as driving a car involves starting the engine, then moving on down the street, cancer develops in two main phases: initiation and progression. Initiation refers to the initial gene mutations that start the cancer process. Progression refers to the additional genetic damage that causes initiated cells to form tumors, invade neighboring tissue and metastasize, or spread to other p a rts of the body. Most cancer chemoprevention agents slow progression.
FINDING CHEMOPREVENTION AGENTS
The development of chemopreventive agents begins with pharmaceutical chemists who isolate natural substances from foods, plants and other sources, or who build new substances from drugs known to have preventive properties.
A. Douglas Kinghorn, PhD, the Jack L. Beal Professor and Chair of Natural Products Chemistry and Pharmacognosy at OSU, is nationally known for his identification of potential chemopreventive agents from plants. Currently, for example, Kinghorn is obtaining a substance found in licorice known as isoliquiritigenin to test for its possible chemoprevention properties.
Researchers like Kinghorn try to determine if such substances have anticancer properties. These include antioxidant activity or the ability to slow cancer-cell growth, trigger the self-destruction of cancer cells or slow the growth of new blood vessels.
Promising substances are then tested in animals with human cancers. This “preclinical testing” phase can take three to five years and examines whether the potential agent is safe and may reduce tumor development. Animal testing also can reveal the potential agent’s effects on a variety of biomarkers including those related to bloodvessel growth, the flow of messages within and between cancer cells, and the activation of genes involved in cancer development. These biomarkers can then be employed when the agent is tested in humans.
Substances that show sufficient efficacy and acceptable side effects may then enter human testing. First, though, they must also meet practical criteria. For example, they must be affordable and something people are likely to use. “If an agent tastes bitter or smells like garlic, people may not want to take it for 10 years,” Stoner says.
Like clinical trials for other drugs, chemoprevention trials have three phases. Phase I studies, which can take two years, test the safety of the substance and determine optimal dosages.
Substances that pass phase I trials enter phase II testing. This may involve 100 to 200 volunteers and take two to five years. These studies test the substance’s safety, but also its effectiveness against some precancerous condition. The study might examine, for example, whether the condition recedes. It will also examine whether its effect on biomarkers monitored during animal testing shows the expected responses.
Substances that have sufficient safety and effectiveness then enter Phase III testing. These are expensive studies that can involve thousands of volunteers and can last a decade or more. They are usually also randomized and double-blinded.
Highly successful trials have shown that the hormone-like drug tamoxifen can prevent breast cancer in high-risk women. Others have shown that the drug finasteride can reduce the risk of prostate cancer, and that the nonsteroidal anti-inflammatory drug Celebrex can reduce the number of colon polyps in people with an inherited condition known as familial adenomatous polyposis. That, in turn, should lower the high risk of colon cancer in these individuals.
Epidemiological studies strongly suggest that eating lots of fruits and vegetables reduces cancer risk. Consequently, cancer prevention researchers at the OSU CCCJames are studying a variety of foods and food components that might prevent cancer.
Stoner and his colleagues, for example, are examining whether freeze-dried black raspberries and strawberries can prevent cancer. The dehydrated berries become a powder that is mixed with water to make a drink or a paste that is eaten. “Berries contain at least 30 known agents that prevent cancer in animals,” Stoner says.
“Removing water from the berries concentrates those agents 10-fold. Because these agents act on different targets involved in tumor development, we feel this is a promising strategy.” (See the spring 2004 issue of Frontiers for more on berry research by Stoner and his colleagues.)
Michael A. Pereira, PhD, professor of internal medicine and Alan R. Dahl, PhD, a specialist in environmental health, are conducting a preclinical study of bexarotene, a retinoid X receptor agonist, to prevent lung cancer. The drug is delivered by inhalation, which maximizes the amount of agent reaching the lung tissue while minimizing the amount delivered to the rest of the body.
Pereira and Dahl also work with Gregory A. Otterson, MD, a medical oncologist with the Molecular Biology and Cancer Genetics Program, to identify other lung-cancer preventing agents that can be inhaled. Otterson will oversee clinical trials of promising agents.
Susan R. Mallery, DDS, PhD, an oral pathologist and Peter E. Larsen, DDS, professor of maxillofacial surgery, both in the College of Dentistry, are studying whether a black-raspberry gel applied to precancerous conditions in the mouth known as oral leukoplakia and oral erythroplakia will lower the proportion that progress to cancer. Christopher M. Weghorst, PhD, associate professor in the Division of Environmental Health, School of Public Health, is studying whether freeze-dried berries will reduce the risk of second primary tumors in animal models and, in collaboration with head and neck surgeons, Amit Agrawal, MD, and David E. Schuller, MD, reduce the activity of certain genes associated with oral cancer development in humans.
As part of a phase I trial testing freeze-dried berries to prevent Barrett’s esophagus, researcher Laura Kresty, PhD, is collaborating with gastroenterologist John Fromkes, MD, and clinical coordinator Cindy Hammond to investigate changes in biomarkers measured before berries are given and at intervals after berry treatment. Each day, participants eat one-anda- half to two ounces of freeze- dried berries, an amount that equals nearly a pound of fresh berries.
Physician-scientist Steven Clinton studies the use of drugs, nutriceuticals, nutrient supplements and foods for the prevention of prostate and bladder cancers. Clinton oversees the Prostate Cancer Prevention Trial (PCPT) and the Selenium Vitamin E Cancer Prevention Trial (SELECT) at OSU. Both are large multi-institutional NCI studies. The PCPT of over 15,000 men, now completed, has determined that the drug finasteride lowered the risk of prostate cancer by 25 percent in men age 50 and over. The SELECT trial involves 32,000 men and tests whether selenium or vitamin E alone or in combination reduces prostate-cancer risk.
In conjunction with investigators in OSU’s College of Agriculture, Clinton has several studies of nutriceuticals and functional foods. One study involves a nutriceutical based on tomato juice containing high doses of soy germ, which is rich in substances that inhibit prostate or bladder cancer in laboratory tests.
Clinton’s recent studies include one showing that the supplement lycopene, which is isolated from tomatoes and sold in many health food stores, probably does not lower the risk of prostate cancer when taken alone, as is often believed, but that eating whole tomatoes or tomato products probably does. Clinton is now working with other OSU investigators to identify novel agents that will inhibit prostate and bladder cancers.
Clinton’s laboratory also tests new substances produced by Ching-Shih Chen, PhD, a researcher in the College of Pharmacy and a member of the OSU CCC-James Molecular Carcinogenesis and Chemoprevention Program. Chen’s lab alters the structure of known drugs to produce new compounds with greater anticancer activity.
Chemoprevention of breast cancer is also under study at the OSU CCC-James. For example, breast surgeon William B. Farrar, MD, oversees the Study of Tamoxifen and Raloxifene (STAR) at OSU. This multi-institutional, NCI-sponsored trial compares the safety and effectiveness of tamoxifen and raloxifene for prevention of breast cancer in high-risk women who have not had the disease. In addition, medical oncologist Charles L. Shapiro, MD, and Robert W. Brueggemeier, PhD, dean of the College of Pharmacy, have three clinical trials examining new approaches using aromatase inhibitors, which treat estrogen- sensitive breast cancer by lowering the amount of estrogen in the body.
FUTURE OF CHEMOPREVENTION
Because of research like that at the OSU CCC-James, Greenwald is optimistic about the future of chemoprevention. “One of the major approaches to reducing cancer occurrence, morbidity and mortality will be chemoprevention,” he says. “We have many, many exciting leads.”
Clinton sees chemoprevention working hand-in-hand with cancer screening to identify high-risk individuals at a young age. This, he says, “will be most useful when improvements in diagnostic testing allow us to catch tumors early and at a more curable stage, or when improvements in prevention enable us to stop tumors from developing. We want to integrate these efforts.
“Likewise, a genetic test may put you in a high-risk category for cancer, as does having a premalignant condition like oral leukoplakia or Barrett’s esophagus. People at high risk for cancer need safe and effective prevention strategies, coupled with screening. In a growing number of cases, that strategy is likely to include chemoprevention.” ■
Written by Darrell E. Ward
Illustrations by Walter Vasconcelos