COLUMBUS, Ohio—Recent experiments with rats showed that a restricted-calorie diet led to reductions in prostate tumor size and progression, Steven K. Clinton, MD, PhD, said at the Society for Nutritional Oncology Adjuvant Therapy (NOAT) meeting. Dr. Clinton is director of Cancer Prevention, James Cancer Hospital and Solove Research Institute, Ohio State University.

His group’s preclinical studies were designed to test the hypothesis that changes in host nutritional status can influence tumor angiogenesis, which, in turn, regulates tumor apoptosis and tumor cell proliferation.

In the experiment, rats with prostatic adenocarcinoma (Dunning tumor R3327 H prostate cancer) were randomly assigned to four dietary treatment groups. In the first group, the rats were allowed to eat all they wanted. These were the “ad lib” animals. In the second group, the animals were fed a diet that restricted their calories by 20%. In the third group, the animals were fed a diet that restricted calories by 40%. “Neither of the groups on restricted calories lost a significant amount of lean body weight but were clearly less ‘obese’,” Dr. Clinton said. In the fourth group, the rats were castrated and allowed to eat all they wanted.

The scientists found that restricting calories significantly reduced prostate tumor weight. The castrated animals also showed reductions in tumor weight. This result was anticipated and is observed in men suffering from prostate cancer and treated with antiandrogen therapy.

The tumors of restricted-calorie rats also exhibited changes in tumor architecture, characterized by increased stroma and more homogeneous and smaller glands. These changes correspond to a low Gleason score in humans and are associated with an improved prognosis.

Proliferating cell nuclear antigen (PCNA) levels changed little in the restricted-calorie animals. However, the apoptotic index—a measure of cell death—increased more than twofold in the restricted-calorie groups. “Most interesting,” he said, “was that prevalence of blood vessels also corresponded with status, with the restricted-calorie animals having the fewest blood vessels.” Microvessel density (vessels per square centimeter) decreased more than 50%.

Dr. Clinton’s team is investigating how the calorie-restricted diet decreases angiogenesis and increases apoptosis in the tumor. He explained that his work builds upon recent advances in the understanding of tumorigenesis. Discoveries by Judah Folkman, MD, and others have led to an appreciation of how blood vessel growth, necessary to tumor development, is dependent upon interactions between positive and negative regulators.

In mice experiments, Dr. Folkman has shown that the proteins angiostatin and endostatin serve as negative regulators of angiogenesis. It is believed that cancer cells control the balance of angiogenic growth factors and antiangiogenic proteins in response to the tumor’s own metabolic needs.

“We’re now realizing that a tumor is a very complex microenvironment,” Dr. Clinton said. “It is an environment in which metastasis, tumor growth, and invasion are determined by interactions between immune cells, vascular cells, matrix cells, and the tumor cells.”

Dr. Clinton is looking at a number of endogenous angiogenic factors, including vascular endothelial growth factor (VEGF). In the rat experiment, 25% of all cells in the ad lib animals produced VEGF. By contrast, VEGF was reduced more than 90% in the restricted-calorie animals. “Such results,” Dr. Clinton said, “suggest that changes in diet may be used to enhance the efficacy of antiangiogenic tumor therapy.”