Novel Therapies: Chemoprevention

Chemoprevention is the use of natural or synthetic substances to reduce the risk of developing cancer, or to reduce the chance that cancer will recur (come back). According to the National Cancer Institute's (NCI), approximately 400 compounds are being studied as potential chemopreventive agents, mainly in laboratory research. Over 40 of these compounds are being studied in clinical trials (research studies with people). Some of these agents are being investigated as single agents; others are being tested in combinations of two drugs. Chemoprevention trials look at possible ways to prevent cancer with interventions that include drugs, vitamins, diet, hormone therapy, or other agents.

To identify possible chemopreventive agents, scientists analyze data obtained from studies of selected groups of people. Scientists might test chemopreventive substances in people at high risk for cancer because of a precancerous condition, a family history of cancer, lifestyle factors such as smoking, or other factors. Scientists might also study a group with a lower-than-average rate of cancer to determine what factors could be protecting them from the disease.

Five classes of chemopreventive agents have shown promise in clinical trials and are considered priority substances for study. These agents include selective estrogen receptor modulators (SERMS) such as tamoxifen, and other hormonal agents; nonsteroidal anti-inflammatory drugs (NSAIDS); calcium compounds; glucocorticoids (compounds that are a type of steroid); and retinoids (chemical cousins of vitamin A).

Chemoprevention should not be confused with chemotherapy. Chemotherapy's aim is to kill cells, particularly cancer cells to prevent cancer progression. Chemoprevention, on the other hand, involves administering nontoxic agents to otherwise healthy individuals who may be at increased risk for cancer. Chemopreventive agents can act in two ways: they can prevent or stop genetic mutations that lead to cancer, and they can prevent or stop processes that lead to excessive replication of damaged cells. The NCI has made chemoprevention research a top priority.

Additional Information

---

Physical and Emotional Stress Spur Cancer Growth

Patients diagnosed with terminal cancer undergo dramatic changes physically and psychologically. Sometimes these changes directly impact a patient's health by spurring cancer growth. Several factors influence cancer progression such as side effects from therapy, immunosuppression, and even stress, which has both emotional and physical components.

Physical Stress
Dr. Robert Cameron, Chief of Thoracic Surgery at UCLA Medical School in Los Angeles, California warns patients about the effects of stress: "Known physical stressors associated with cancer include: pain, surgery, chemotherapy, radiation, loss of appetite and weight loss, shortness of breath, anemia, exhaustion, medication, nausea, dehydration, nutritional status, loss of muscle tone, fatigue, and decreases in both functional status and capacity."

Patients should be aware of their physical stress and address those needs accordingly. Take appropriate pain medication if available or seek therapy to reduce pain. Even though loss of appetite and weight loss can be a common side effect following some cancer treatments, it is important to maintain a healthy diet. Eating nutritional foods and staying hydrated nourishes the mind and body. Each person is unique and maintaining one's health should fit every one differently and appropriately.

Emotional Stress
Dr. Cameron lists known emotional stressors for terminal cancer patients: "Fear, anger, anxiety, excitement, self-esteem, body image, intimacy, sexuality, depression, dependency, adjustment disorder, phobia, sadness, disbelief, despair, worthlessness, loss of pleasure, abandonment, adjustment and panic disorder, diminished concentration, suicidal ideation, and immanency of death."

Certainly not every patient will experience such a range of emotional stress. Nonetheless, it is important to be aware of situations that might induce emotional stress so they can be avoided or dealt with properly.

"Stressors create and escalate stress. Many types of stress activate the body's endocrine (hormone) system, which in turn can alter the way the immune system (the body's defense against infection and disease, including cancer) functions. As one example of the immune system's soldiers, natural killer cell (NK cells), often are important in the body's first defense against abnormal cells, including cancer cells that threaten one's health, serving to destroy these cells," says Dr. Cameron.

Biology of Stress
Dr. Cameron says, "Stress can influence the responses of the body's NK cells. Uncontrolled emotional stress may lead to fatigue and lower the cancer patient's already compromised immune system, inhibit NK cells, disrupt the body's metabolic pathways, and hasten tumor proliferation and tumor metastasis. Stress may also alter the risk of infection and other immune-related diseases, especially among patients receiving chemotherapy. When confronted by emotional or physical stress, the brain produces catecholamines, which are neurotransmitters that produce the "fight or flight" response. It directly suppresses the NK cell function and other aspects of cellular immunity that relate to innate immunity."

Additionally when the body releases the stress hormone norepinephrine, it also stimulates production of three compounds that contribute to aggressive tumor growth. Norepinephrine causes the tumor to produce two "metalloproteinase" compounds which break down part of the tumor structure to which the cancer cells adhere. Once these cells are no longer bound to the primary tumor, the cells spread throughout the body and metastasize elsewhere, causing rapid tumor growth. Norepinephrine also increases production of the compound vascular endothelial growth factor, or VEGF. VEGF stimulates the growth of new blood vessels that feed cancer cells. Increased blood supply to the cancer cells directly accelerates the spread and growth of the tumor.

Psychological Stress
Fatigue is a common a physical feeling that many cancer patients experience. However, Dr. Cameron suggests that "fatigue is a major psychological symptom that corresponds with low NK cell function, as well. Fatigue is the most common and distressing symptom associated with cancer and cancer therapies. Fatigue has been identified as significantly interfering with quality of life (QOL) in people of all ages who have cancer, regardless of diagnosis, treatment or prognosis. Although there are established medical interventions for most cancer-related symptoms, there are only limited medical treatments for fatigue. Physical and emotional stress both contribute to a cancer patient's fatigue."

Prolonged stress can be detrimental for cancer patients physically, emotionally, and mentally. Skills such as learning, memory recall, and performing small daily tasks may become affected. It is important to keep stress at a minimum to avoid some of these indirect problems.

*Dr. Robert Cameron's quotes are taken from his declaration in the Michael Mikul vs. BONDEX INTERNATIONAL, INC., et al. July 13, 2005. For the County of Los Angeles.

---

Stem Cells Fend Off Lung Cancer: Cancer Vaccine Harnesses Similarities between Embryos and Tumors (11/15/06)

A team of researchers led by John Eaton at the University of Louisville in Kentucky has discovered a new use for embryonic stem cells-cancer prevention.

How it works:

Eaton says that "embryos and tumors both grow as balls, they derive nutrients from the host, and they both express peculiar proteins-some of them in common." Because of these similarities, Eaton believed that a vaccine eliciting an immune response to embryonic stem cells would similarly spark an attack against tumors.

In the lab, Eaton injected a vaccine made from embryonic stem cells into mice. Ten days after the mice were injected with the stem cell vaccine, they were given a booster shot. Then, researchers transplanted lung cancer cells just under their skin to induce tumor growth.

What happened?

The researchers "were absolutely shocked." Twenty out of 25 mice who received the stem cell injection showed no tumor development whereas tumors formed in all unvaccinated mice. More impressively, some mice received a mixture of both stem cells and cells designed to make a molecule that stimulates the immune system. None of these mice developed tumors.

Additionally, the combination vaccine of stem cell and immune stimulant showed more promising results in further testing. Instead of implanting lung cancer cells under the skin, researchers exposed some mice to chemicals designed to mimic the effects of cigarette smoke. Eight of these nine mice were protected from these chemicals using the vaccine.

What does it mean for us?

John Eaton and other researchers like Jeffrey Weber, an immunotherapist at the University of Southern California in Los Angeles, are worried about the safety of stem cell injections in humans. Even though the animals showed no dangerous side effects, this may not be true for humans. When injected with stem cells, the body might in turn attack its own stem cells. Because of these concerns, researchers believe that regulatory agencies might prevent the vaccine from being tested in humans.

This is not discouraging to Eaton who is already testing the approach on other cancers. Additionally, he hopes to improve the current vaccine by locating the specific molecules on the embryonic stem cells that prevent and kill tumors. His team has already located one protein and hopes further research will be more promising and useful for humans.

Schubert, Charlotte. www.nature.com/news/2006/061106/full/061106-17.html. Published November 10, 2006.

---

Predictors of Lung Cancer among Asbestos-exposed Men in the ß-Carotene and Retinol Efficacy Trial (2005)

Dr. Mark Cullen, Department of Internal Medicine, Yale University School of Medicine. American Journal of Epidemiology 2005.

Click here for more information.

• Study followed men recruited from diverse jobs and occupations involving asbestos exposure as participants in the ß-Carotene and Retinol Efficacy Trial (CARET). CARET tried to test the efficacy of daily pharmacologic doses of vitamin A and ß-carotene to prevent lung cancer among heavy smokers and asbestos workers that was begun in the mid-1980s.
  
• The intervention was discontinued 21 months ahead of schedule in 1996 when accrued evidence proved that the vitamins did not prevent lung cancer and strongly suggested increased risk of lung cancer, an effect most pronounced among the asbestos workers.
  
• Vitamin A and ß-carotene has an adverse effect in preventing lung cancer among heavy smokers and asbestos workers. Below are additional articles that concur with this conclusion:
  
  The New England Journal of Medicine, Volume 334:1150-1155 May 2, 1996 Number 18,
  Gilbert S. Omenn, M.D., Ph.D., Gary E. Goodman, M.D., M.S., Mark D. Thornquist, Ph.D., John Balmes, M.D., Mark R. Cullen, M.D., Andrew Glass, M.D., James P. Keogh, M.D., Frank L. Meyskens, M.D., Barbara Valanis, Dr.P.H., James H. Williams, M.D., Scott Barnhart, M.D., M.P.H., and Samuel Hammar, M.D.
  
  Journal of the National Cancer Institute, Vol. 88, No. 21, 1550-1559, November 6, 1996
  Gilbert S. Omenn, Gary E. Goodman, Mark D. Thornquist, John Balmes, Mark R. Cullen, Andrew Glass, James P. Keogh, Frank L. Meyskens, Jr., Barbara Valanis, James H. Williams, Jr., Scott Barnhart, Martin G. Cherniack, Carl Andrew Brodkin, Samuel Hammar

---

Chemoprevention of cancer: lessons to be learned from beta-carotene trials (March, 2005)

Vainio, H. Division of Health Risk Assessment, National Institute of Environmental Medicine, Stockholm, Sweden. Toxicology Letters 2000.

Click here for more information.

• Increased intake of fruits and vegetables seems to be one of the simplest means of decreasing the risk for cancer. Many observational studies indicate a lower incidence of various cancers with higher intakes of carotenoid containing foods (fruits and vegetables. Beta-carotene is one of the naturally occurring carotenoids. However, the results of randomized intervention trials have shown that beta-carotene supplements are of limited value and may even be deleterious in the case of smokers and asbestos exposed workers.

• In order to resolve these paradoxes, we need to better understand the underlying biology, identify interactions, develop mechanistic hypotheses and test them in clinical trials in humans. Until that time, we should confine any premature enthusiasm for chemopreventive supplementation.

---

Fruits and Vegetables Are Associated with Lower Lung Cancer Risk Only in the Placebo Arm of the ß-Carotene and Retinol Efficacy Trial (CARET) (April, 2003)

Neuhouser ML, Patterson RE, Thornquist MD, Omenn GS, King IB, Goodman GE.
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington. American Association for Cancer Research 2003.

Click here for more information.

• This report provides evidence that plant foods have an important preventive influence in a population at high risk for lung cancer. However, persons who use ß-carotene supplements do not benefit from the protective compounds in plant foods.
  

• The principal causative agents of lung cancer are exposure to cigarette smoke, asbestos, radon, and several industrial chemicals. Avoidance of these substances could prevent almost all cases of lung cancer and should remain the primary focus of prevention efforts.
  

• Nonetheless, the findings from this report show that, among heavy smokers and asbestos-exposed workers, consumption of fruits and vegetables, especially from the rosaceae and cruciferae families, and vegetables, such as onions and corn, may lower risk by 32 to 44%, a magnitude of reduction that has substantial public health implications.
  

• However, this report shows that persons at risk for lung cancer who use ß-carotene supplements do not benefit from the compounds in plant foods, probably due to interference of the supplements with the effects of bioactive phytochemicals. These results may provide a partial explanation for the adverse and no effect lung cancer incidence findings reported from randomized clinical prevention trials of ß-carotene supplementation in CARET.

---

Chemoprevention of lung cancer: the rise and demise of beta-carotene (1998)

Omenn, G.S. School of Public Health & Community Medicine, University of Washington, Seattle. Annual Review of Public Health 1998.

Click here for more information.

Beta-carotene and retinoids were the most promising agents against common cancers when the National Cancer Institute mounted a substantial program of population-based trials in the early 1980s. Observational studies linked a lower incidence of various cancers with higher intakes of carotenoid containing foods (fruits and vegetables). However, major lung cancer chemoprevention trials not only showed no benefit, but had significant increases in lung cancer incidence and total mortality. A new generation of laboratory research has been stimulated. Rational public health recommendations at this time include:

• Five-A-Day servings of fruits and vegetables, a doubling of current mean intake.
  
• Systematic investigation of the covariates of extremes of fruit and vegetable intake.
  
• Discouragement of beta-carotene supplement use, due to adverse effects in smokers and no evidence of benefit in non-smokers.
  
• Multilevel research to develop and evaluate candidate chemoprevention agents to prevent lung and other common cancers.
  
• Continued priority for smoking prevention, smoking cessation, and avoidance of known carcinogens in the environment.

---

Recruitment for the beta-carotene and retinol efficacy trial (CARET) to prevent lung cancer in smokers and asbestos-exposed workers. (May, 1992)

G S Omenn, G Goodman, J Grizzle, M Thornquist, L Rosenstock, S Barnhart, G Anderson, J Balmes, J Cone, M Cherniack, et al. Fred Hutchinson Cancer Research Center, Seattle, WA 1993

Click here for more information.

• Recruitment notice from this landmark study explaining the nature of the study and asking for qualified subjects.
  

• Study's goal: "We expect CARET, combined with the results of the other two major trials, to determine by the end of the decade whether or not vitamin A and ß-carotene can be recommended to occupationally defined high-risk groups and to the public as chemopreventative agents against lung cancer."
  
• Despite the unexpected results later published from (CARET) showing that supplementation with ß-carotene increased, rather than decreased, lung cancer incidence, this is a model example of a randomized, double-blinded, placebo-controlled trial.

---