As the population ages, fewer and fewer people will die from cardiovascular disease. More and more will die from cancer, making it the major contender for the title of major cause of death in the United States. As most people know, treatments for cancer have not made an appreciable dent in mortality rates for the more common cancers. Scientists are now looking closely at the other end of the disease chain--prevention.

Recently, three researchers at the School of Public Health completed their study of a chemopreventive agent for liver cancer and concluded that it works on humans. Their study marks the first time that anyone has altered the metabolism of carcinogens in people in the context of a clinical trial and analyzed the results. The study appears in the Feb. 17 issue of the Journal of the National Cancer Institute.

The researchers' story begins some 20 years ago in eastern China in the agricultural village of Qidong, where liver cancer accounts for one out of every 10 adult deaths. It was there that the team of Jia-Sheng Wang, Thomas Kensler and John Groopman, all from the Department of Environmental Health Sciences, first identified the two major factors that caused liver cancer.

Jia-Sheng Wang

They were hepatitis B, or HBV, and aflatoxin, a fungus that thrived on the corn and peanut crops in the humid, delta area that holds the village of Qidong. The researchers' work showed that HBV teamed with aflatoxin made a potent carcinogen. People exposed to both risk factors were 60 percent more likely to get liver cancer than those with no exposure. In Qidong 10 percent of the population are chronic carriers of HBV, and 95 percent of those tested showed evidence of exposure to aflatoxin.

The researchers decided to see if they could reduce the odds of getting liver cancer by finding a way to block aflatoxin from acting as a carcinogen. The tool they used was oltipraz.

Thomas Kensler

Originally developed as an antiparasitic drug for schistosomiasis, oltipraz had been shown to inhibit liver cancer development in cell culture and animal studies.

"We know a lot about how aflatoxin works," Kensler said. "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."

They were looking to see if oltipraz could change the way a person's body metabolized aflatoxin so that the aflatoxin would become harmless and pass out of the body. The team screened more than 1,000 people and admitted 233 men and women into the study. All had detectable aflatoxin in their blood, were in good general 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.

The oltipraz changed the way people metabolized aflatoxin. Like most environmental carcinogens, aflatoxin is metabolized by multiple enzymes in a process with many steps. Each step can be altered. Oltipraz stimulates phase 2 enzymes, which enhance the detoxification of aflatoxin and make it easier for the body to get rid of it. "It acts like a skateboard, whisking away the aflatoxin before it reaches cellular DNA and alters it," Kensler said.

In other words, the oltipraz keeps the aflatoxin from acting as a carcinogen.

John Groopman

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."

The second phase of their clinical trials has already started. In this phase, the researchers will try to determine in greater detail exactly how the oltipraz works in the metabolic process. They will also look at the effects of oltipraz on the body, since it is traditionally used for short-term treatment, not for long-term prevention.

The successful development of chemopreventive agents is still an uncharted process. Although the oltipraz study does not define a generic paradigm for the development of chemopreventive agents, it does document the major structural elements that must be considered. Eventually, the researchers hope to move toward a non-drug-based strategy that provides the same protection. Groopman said, "The grand strategy here would be to develop a food source that provides the same protection at a lower cost."

Understanding how the metabolic process works is critical because it allows researchers most effectively to design an intervention.