Nutritional Intervention Trials to Prevent Cancer Move Forward

NEW ORLEANS—There have been mountains of evidence from laboratory and epidemiologic studies about cancer prevention through nutrition, but only a “molehill” of intervention trials that will move the cancer prevention field forward, Dr. Daniel W. Nixon, president of the Society for Nutritional Oncology Adjuvant Therapy (NOAT), said at the 4th International Symposium on Nutrition and Cancer, jointly sponsored with the Cancer Treatment Research Foundation.

Nonetheless, such trials are moving forward, some with the participation of industry and of volunteers, and often with the use of precancerous markers as study endpoints. The major nutritional interventions include manipulation of fat and fat calories, increase in fiber intake, and addition of single or multiple phytochemicals to the diet.

At least 1,000 compounds in fruits, vegetables, and grains are thought to have anticancer properties, offering a number of opportunities to target specific cancers earlier in the course of disease, for instance, by exploiting tumor growth through mechanisms such as apoptosis, angiogenesis, and hormonal manipulation, said Dr. Nixon, of the Medical University of South Carolina and Hollings Cancer Center, Charleston.

Substance in Red Raspberries

Dr. Nixon’s laboratory is quite interested in the area of apoptosis. His studies have focused on a substance called ellagic acid, which appears to invoke apoptosis in tumor cells in vitro. Ellagic acid is found in some foods, particularly in red raspberries, strawberries, and grapes. (The Washington State Red Raspberry Commission has funded this research, he noted.)

The studies will evaluate absorption and metabolism of the substance in various dosages given to human volunteers, to determine the maximum chemopre-ventive effect in vitro and in vivo. The ultimate goal is to determine the impact of dietary ellagic acid in reducing the risk of colorectal and other cancers.

Company Partnership

Partnerships with private industry and philanthropy can help move chemopre-vention efforts forward. In partnership with the Kellogg and Westway companies, for example, NOAT is evaluating a component of fiber called lignin, a waste product of paper manufacturing that may be the protective agent in fiber.

Kellogg is supplying three kinds of breakfast cereal containing various amounts of wheat fiber in a human colon polyp prevention trial also supported by the American Cancer Society and the Samuel Freeman Charitable Trust.

The study is expected to cost a fraction of the typical NCI grant because of a heavy reliance on volunteer colonos-copists and American Cancer Society staff, Dr. Nixon said.

Such preventive trials, he said, “can be fiendishly difficult,” largely because of the time it takes for normal cells to become malignant. It is estimated to take 30 years for colon cancer cells and 15 years for breast cancer cells to progress from normal epithelium to dysplasia, cancer in situ, and invasive cancer. Therefore, intermediate markers, such as adenomatous polyps for colon cancer, are needed.

Importance of Surrogate Markers

Gary Kelloff, MD, chief of the NCI’s Chemoprevention Branch, said that it is important to look at precancer histology as a primary endpoint in chemopre-vention trials. Almost all cancer pro-gresses through a precancerous stage that can be detected if the tools are sophisticated enough, he said.

Computer-assisted image analysis is being refined so as to be able to demonstrate histologic changes, such as increasing nuclear size, increasing or abnormal mitosis, disordered shape, and other pathologic hallmarks of carcinogenesis.

Halting the multiyear process of mutagenesis by slowing the maturation, differentiation, and proliferation of cells is the goal of chemoprevention through synthetic drugs or chemicals present in the food chain.

Biomarkers of this process must be able to get into the tissue itself, not just the blood, and must support the hypothesis under study, Dr. Kelloff said. Biomarkers must be differentially expressed in high-risk versus normal tissue, have short latency, be linked to the causal pathway for cancer, have an acceptable sensitivity and specificity for accuracy, and be modulated by the chemo-preventive agent.

He said that there are currently 39 agents in clinical phase II and III trials, and 24 agents being studied in clinical phase I trials. These include some of the better known agents such as DFMO (eflornithine, Ornidyl), sulindac, and DHEA, and some that are newer to the scene, such as tumeric and curcumin (herbs of the ginger family), isoflavones, lycopene (found in tomatoes), perillyl alcohol (found in citrus), ibuprofen, and green tea.

These and other agents are often administered in preclinical models of cancer precursors—such as colon polyps, oral leukoplakia, and Barrett’s esophagus—to determine the lowest effective doses and ultimately their effect on lesion regression or progression.