Plants provide prevention. (Cancer).

Worldwide, approximately 473,000 new cases of liver cancer are diagnosed annually, with 80% occurring in the developing world. Two risk factors work synergistically to greatly increase the risk of liver cancer: chronic infection with hepatitis B virus (HBV), which affects approximately 350 million individuals, and chronic exposure to aflatoxins, especially aflatoxin B1, highly potent liver toxicants produced by molds that contaminate dietary staples. Both risk factors are especially prevalent in the developing world, but one step toward reducing this threat may be chemoprevention, the use of drugs or dietary supplements to derail aflatoxin exposure effects. In a study published in the 4 December 2001 issue of Proceedings of the National Academy of Sciences, scientists found that chlorophyllin, an artificially produced water-soluble salt of the plant pigment chlorophyll, shows promise as such a chemopreventive agent.

Thomas Kensler, a professor of environmental health sciences at the Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland, directed the chlorophyllin trial. He says a two-pronged approach is needed to combat the problem: HBV vaccination --the most important part--for the viral component, and chemoprevention for the aflatoxin component. "Since there is this multiplicative interaction between the chemical and the virus, if either one can be knocked down, there can be a pretty dramatic impact, at least in theory, on cancer burden," he says.

As a step toward proving that theory and to test the efficacy of chlorphyllin as a chemopreventive agent, researchers looked to the Chinese city of Qidong, where liver cancer is the leading cause of cancer death and accounts for up to 10% of all adult deaths in some rural townships. The researchers recruited 180 individuals from villages near Qidong, all of whom had demonstrable aflatoxin exposure but were healthy. They were randomly assigned to take either a placebo or a 100 mg dose of chlorophyllin three times daily, 20 minutes before each meal, for 16 weeks.

The key finding came from urine samples collected in week 12. These samples revealed a significant decrease in urinary aflatoxin-N7-guanine, a biomarker of aflatoxin-induced DNA damage, in the treated group compared to the placebo group. The level of this biomarker allows researchers to assess chemoprevention efficacy. In the Qidong trial, participants who received chlorophyllin had approximately half as much urinary aflatoxin-N7-guanine as those in the placebo group. A study published by University of Washington researcher Lawrence A. Loeb in the 15 April 2001 issue of Cancer Research suggests that reducing aflatoxin-induced DNA damage by this margin might delay liver cancer development for decades.

Chlorophyllin's mechanism of action is still unclear, but there is some indication that it attaches to the aflatoxin, thereby impeding absorption and shuttling the toxin through the digestive tract. Kensler says other mechanisms may be involved as well. What makes chlorophyllin especially attractive is that it's inexpensive and safe. There were no side effects reported by the study group other than darker-than-normal stool. The sole drawback appears to be the number of times the treatment must be taken each day.

According to Kensler, the next question is whether chlorophyllin can reduce the incidence of liver cancer itself. "We're taking tentative steps to moving in that direction, but that's a major undertaking so we want to make sure we know exactly how to [design and conduct the study] to [get] the best likely outcome," he says.

"Chlorophyllin is certainly a promising chemopreventive compound for aflatoxin exposure reduction, given the dramatic effects seen on DNA damage levels observed in the Chinese study," say Paul Turner and Christopher Wild, molecular epidemiologists at the University of Leeds School of Medicine in Great Britain, whose own research has focused on the HBV-aflatoxin relationship and alternative aflatoxin intervention approaches in West Africa.

Although HBV vaccination will have the greatest influence on reducing liver cancer incidence, Turner and Wild emphasize that addressing the problem of aflatoxin exposure is also important. Aflatoxin exposure itself probably contributes to the incidence of liver cancer independently of HBV infection, they say, and vaccination will provide no protection for the millions who already carry the virus. In addition, say the researchers, "despite World Health Organization recommendations, economic and logistic problems result in only one percent of children in Africa currently having access to HBV vaccination. For these groups of people, aflatoxin exposure intervention could significantly reduce their liver cancer risk."