Tracking cancer's path
For Hecht, knowing that tobacco causes cancer is not good enough. He and his team want to know why cancer occurs in those who smoke — as well as why it doesn't. There are more than 60 cancer-causing substances, or carcinogens, in tobacco smoke. But despite smokers' uniformly intense exposure to these carcinogens, only about 20 to 25 percent of smokers actually get lung cancer. Why the majority remain cancer-free is a puzzle that Hecht and his colleagues are close to solving.
A major contribution to the team's progress has been their discovery of what scientists call "biomarkers," the particular byproducts that develop after the body metabolizes tobacco-specific carcinogens. For example, the strongest carcinogen linked to tobacco use is a chemical commonly known as NNK. Researchers at the Cancer Center have found that the most reliable biomarker for NNK is a metabolite called NNAL — an essential key to understanding how harmful tobacco toxins really are in humans.
Dorothy Hatsukami, Ph.D., is using the biomarkers identified through the research of colleague Stephen Hecht, Ph.D., to study the true cancer risk of cigarettes labeled "light" and "ultralight."
Once the metabolites of the carcinogens form in the body, they react chemically with the DNA in genes, which causes substances called DNA adducts to form. Hecht and his colleagues (as well as other researchers) have found that DNA adducts are "absolutely critical" in the development of cancer because they change the sequence of DNA and can lead to uncontrolled cell growth, the basic step to cancer. The good news is that once the DNA adduct forms, the body usually has a DNA repair process that can fix the DNA and remove the adduct.
"All of these steps — from exposure to metabolism to the development of DNA adducts to the repair process — can vary from individual to individual," says Hecht. "Gradually, our team is discovering the intricacies of the process: why some people metabolize cancer-causing substances better than others, and why some people are better able to remove them from the body more effectively."
Studying tobacco and cancer at such a molecular level is critical to preventing further disease, says Hecht. "By knowing which steps in the cancer development process are most important, one can come up with drugs or find naturally occurring substances that can influence those steps — and eventually, perhaps, prevent tobacco-related cancer in those exposed."
Reducing smokers' risk: Too good to be true?
As any smoker will admit, kicking the habit is easier said than done. Most smokers in the United States want to quit. But while 41 percent of smokers actually attempt to quit in a given year, only 4.7 percent successfully stop for 3 to 12 months. So when smokers are told that they may be able to reduce their tobacco-related cancer risk without quitting, it can sound pretty attractive.
For Dorothy Hatsukami, Ph.D., and her colleagues, however, healthy skepticism comes by way of sound science. "Years of research have found that nicotine is incredibly addictive when delivered as a tobacco product, and some smokers switch to tobacco products that they think are safer — for example, light or ultralight cigarettes — to allow themselves to continue smoking," says Hatsukami, who directs the University of Minnesota Transdisciplinary Tobacco Use Research Center and holds the Forster Family Professorship in Cancer Prevention. "Our goal is to protect the public from being misled about these products." Using the biomarkers Hecht and his colleagues have identified, the TTURC team is exploring the effectiveness of various methods for reducing harm associated with smoking.
For most smokers, reducing the number of cigarettes smoked per dayeven significantlymay not improve their cancer risk. The best way to reduce disease continues to be quitting altogether.— Dorothy Hatsukami, Ph.D., University of Minnesota Cancer Center
One way that tobacco use can be purportedly less harmful is through the use of so-called "reduced-exposure" tobacco products, which tobacco manufacturers have developed over the past several years. Some work by altering the tobacco curing process. Others work by adding chemicals or genetically modifying the tobacco. By enlisting study participants to use the products and then measuring the level of NNAL and other biomarkers, the team has determined that the reduced-exposure products currently on the market are ineffective in reducing disease. They hope that the results of these and future studies will have a positive impact on public health.
"The main point in doing this work is to make sure consumers are informed," says Hatsukami. "Of course, tobacco companies currently have the right to continue to sell their products with as many toxins in them as they wish. But what we can do is provide more strong evidence for the need for FDA regulation, which may then require the tobacco companies to reduce toxin levels in their products."
Using "light" cigarettes was once touted as a way to reduce disease risk. In response to the U.S. surgeon general's landmark 1964 report that declared a link between cigarette smoking and cancer, tobacco manufacturers introduced filters and lowered the machine-measured levels of tar and nicotine levels that their cigarettes produced. The implication to consumers is that lower-tar or light cigarettes are somehow associated with reduced risk. But when Hecht and his colleagues measured the levels of NNAL among smokers of regular, light, and ultralight cigarettes, they found no significant differences among the three groups.
"With no detectable difference, we have to conclude that there would be no decreased risk for lung cancer in smokers of ultralight and light cigarettes," explains Hecht. "So the findings reinforce the message to consumers that these products really aren't safer at all."
Finally, the TTURC team has explored whether reducing the amount of cigarettes smoked daily has any significant bearing on the risk for cancer. Researchers asked study participants to reduce their smoking by 50 to 75 percent, then they measured their NNAL levels. While the reducers did lower their levels of this carcinogenic biomarker, the decreases were modest compared with how much they reduced their cigarette intake. Reducing cigarettes by 55 percent to 90 percent, for instance, yielded an NNAL reduction of only 27 to 51 percent.
"The take-home message here is that for most smokers, reducing the number of cigarettes smoked per day — even significantly — may not improve their cancer risk," says Hatsukami. "Smokers who cut back may even be compensating by taking larger puffs of the cigarette or puffing more frequently, which may counteract whatever benefits could occur from the cigarette reduction itself. The best way to reduce disease continues to be quitting altogether."