Cancer Chemoprevention a ‘Hot Topic’ at AACR Meeting

NEW ORLEANS—A number of investigators reported studies of chemopreventive substances at the 92^nd Annual Meeting of the American Association for Cancer Research (AACR).

In a study of heavy smokers, M. D. Anderson Cancer Center researchers found that a synthetic vitamin A compound significantly reduced the activity of telomerase, which is evident in up to 90% of lung cancers.

The double-blinded study included 57 participants without evidence of cancer who were randomized to receive either the synthetic retinoid N-(4-hydroxyphenyl) retinamide (4-HPR) or placebo. Lung biopsies were taken before and after the 6-month treatment period.

The study used hTERT, the catalytic subunit of telomerase, as a biomarker to measure the effectiveness of 4-HPR. At baseline, expression of hTERT was similar in both groups, about 62% to 65%. Treatment with 4-HPR, however, significantly reduced the expression of hTERT over placebo, 46% vs 68%. This indicated that telomerase activity had been reduced; therefore, the risk of lung cancer had probably been reduced as well.

"To my knowledge, this is the first set of data to provide promising evidence that a molecular biomarker may sensitively measure the efficacy of a chemopreventive agent in the lung," said Li Mao, MD, director of the Molecular Biology Laboratory in M.D. Anderson’s Department of Thoracic/Head and Neck Medical Oncology.

The hTERT biomarker was also found in morphologically normal bronchial epithelium, confirming that telomerase activation occurs very early in the process of malignant transformation, he added.

Quercetin, an Antiandrogen

Nianzeng Xing, MD, PhD, reported that quercetin, a natural substance found in certain fruits and vegetables, significantly reduced the expression of androgen receptors in prostate cancer cell lines.

This is the first research to demonstrate that quercetin has significant activity against the androgen receptor, said Dr. Xing, a research fellow in Dr. Charles Young’s Laboratory of Urology Research, Mayo Clinic, Rochester, Minnesota. The substance is most common in apples, onions, green leafy vegetables, beans, citrus fruits, tea, and red wine,

For doses over 10 µM, quercetin showed significant inhibition of androgen-receptor-mediated function. A dose of 50 µM induced a dramatic reduction in prostate-specific antigen (PSA) (6.5-fold) and hK2, another androgen-regulated tumor marker (11-fold). This dose also impeded expression of androgen receptor protein by up to 60%, Dr. Xing reported. The investigators plan to replicate this in vitro study in a mouse model.

Synthetic Vitamin D

Sergio Huerta, MD, a postdoctoral fellow at the UCLA Center for Human Nutrition, reported significant antitumor activity in mice that received a synthetic version of vitamin D, called Ro 26-9114, for colon cancer. The substance displayed the antitumor effects of vitamin D without the usual toxic effects, including loss of appetite and weight, he said.

This appears to be the first study of Ro 26-9114 in Apc^min mice, which have a genetic mutation similar to that of familial adenomatous polyposis. In the study, mice received Ro 26-9114, vitamin D, or placebo for 10 weeks. Both forms of vitamin D reduced the total tumor surface area (36% and 45%, respectively), but the synthetic analog produced milder and more delayed side effects.

Cysteine and Riboflavin

A large study of residents in Linxian, China, found that those with the lowest levels of serum cysteine and riboflavin were most likely to develop squamous esophageal and adenomatous gastric cardia cancers. "Both of these diseases occur at epidemic rates in this region," said Steven D. Mark, MD, ScD, of the Division of Cancer Epidemiology and Genetics, Biostatistics Branch, National Cancer Institute. "We have long suspected that vitamin deficiencies contribute to the high incidence of these cancers."

In this study, 30,000 residents of Linxian were monitored for the development of cancer from 1985 to 1991. Dr. Mark’s team measured B vitamins, homocysteine, and cysteine in serum obtained in 1985. Approximately half of the residents were found to be deficient in riboflavin and vitamin B12, and 30% were deficient in folate and vitamin B6.

To determine the effect of low vitamin levels in 1985 on the subsequent development of cancer, the team compared 1985 vitamin levels in 498 persons who developed esophageal cancer and 255 who developed gastric cardia cancer by 1991, with the levels of 913 persons who remained cancer free.

The risk of both esophageal and gastric cardia cancer decreased significantly with increasing serum cysteine levels, Dr. Mark said. Individuals in the highest quartile of cysteine had 27% fewer cancers than those in the lowest quartile. The study also found that those in the highest quartile of riboflavin developed 50% fewer esophageal cancers than those in the lowest.

Effect of NSAIDs on Colon Cancer

Several reports substantiated previous findings of a protective effect of non-steroidal anti-inflammatory drugs (NSAIDs) on colon cancer. With 4 years of follow-up, the prospective Polyp Prevention Trial Study Group reported a significant reduction in overall adenoma recurrence among baseline users of NSAIDs, with a univariate analysis odds ratio (OR) of 0.77. The greatest effect was seen in advanced polyps (OR, 0.51) in multivariate analysis, said Joseph Anthony Tangrea, MPH, PhD, of the National Cancer Institute.

Aspirin was the most commonly used NSAID. The effect of baseline aspirin alone paralleled that of NSAIDs on overall recurrence (OR, 0.82), and on recurrence of advanced polyps (OR, 0.64). With aspirin, there was a significant dose response, with more than 325 mg/d yielding an OR of 0.54 for any adenomatous polyp recurrence, Dr. Tangrea said.