Researchers Prove Chemoprevention Can Work

February 16, 1999

A team of researchers has shown that a certain type of chemoprevention used to experimentally deter liver cancer from developing is effective. The researchers gave the drug oltipraz, originally developed to treat schistosomiasis, to a group of people at high risk for developing liver cancer. The oltipraz changed the way in which the study group metabolized aflatoxin, a liver carcinogen produced by a fungus that contaminates foods like corn and peanuts.

They were able to show that the oltipraz induced phase 2 enzymes which altered the disposition of aflatoxin in the study group. This was the first time that the mechanism by which this chemopreventive agent worked was identified and confirmed with human subjects. The study establishes proof of principle that chemo-preventive agents can work by changing the disposition of environmental carcinogens. It appears in the February 17, 1999, issue of the Journal of the National Cancer Institute.

Liver cancer is a major cause of cancer deaths worldwide and claims approximately 400,000 lives in China each year. It is one of the fastest growing cancers in the United States and is also a problem in Canada which has large numbers of Chinese immigrants. Two of the major risk factors for liver cancer in China are infection with hepatitis B and aflatoxin in the diet. Aflatoxins are produced by some strains of the Aspergillus fungi and are found in much of the food supply in certain parts of China. They are commonly found in corn, peanuts, soya sauce, and fermented soy beans.

Senior author Thomas Kensler, PhD, professor, Environmental Health Sciences, said, "We know a lot about how aflatoxin works. We were able to develop the analytic tools to measure aflatoxin elimination, and that enabled us to see if oltipraz made a difference in that process." Lead author Jia-Sheng Wang, MD, PhD, research associate, Environmental Health Sciences, said, "Because we had developed the tools, we were able to frame the question properly."

The team studied 233 men and women from Qidon, People's Republic of China, with detectable aflatoxin in their blood. All were generally in good health and had no history of major chronic illnesses. They were divided into three groups. One group received 125 mg of oltipraz every day for eight weeks. The second group received 500 mg of oltipraz once a week for eight weeks, and the third received a placebo.

They found that oltipraz affects the way in which people metabolize aflatoxin B1, a potent hepatocarcinogen. Oltipraz stimulates the production of phase 2 enzymes which enhance the detoxification of aflatoxin and makes it easier for the body to eliminate the harmful forms of aflatoxin. Dr. Kensler said, "The enzymes carry the aflatoxin out like a skateboard, and it does no harm." Aflatoxin, like most environmental carcinogens, is metabolized by multiple steps and each of these steps can be altered. Co-author John Groopman, PhD, professor and chair, Environmental Health Sciences said, "What we discovered was that with one of the doses we were able to affect multiple pathways and for the other dose we were able to affect only one of the pathways."

Drs. Kensler, Wang and Groopman have studied the relationship between aflatoxin and liver cancer in the People's Republic of China for more than twenty years. In studies in the 1990s they demonstrated that when oltipraz was given to rats who had been exposed to aflatoxin, the drug protected them from getting cancer by altering the way in which the aflatoxin was metabolized.

In 1995, the same process was tried with people. Dr. Groopman said, "We can't prove that we've prevented a single liver cancer in China, but our oltipraz study gives proof of principle. We have proved that we can alter the underlying mechanisms that protect cells from becoming cancerous."

Understanding the mechanism of the metabolic action is critical because it allows researchers to most effectively design an intervention. Screening has already begun for the second phase of the clinical trials, which will be used to refine and extend the initial observations. The researchers will also be looking at what the effects of taking oltipraz are on the body since the drug is traditionally used for short-term treatment not long-term for prevention.

Eventually, they hope to move toward the development of a non-drug-based strategy that provides the same protection. Dr. Groopman said, "The grand strategy here would be to develop a food source that provides the same protection at a lower cost."