Study Shows How Chemical in Smoke May Lead to Cancer

Though a mountain of research has established that cigarettes can cause lung cancer, a study released Thursday shows for the first time exactly how a chemical in smoke sets the stage for the disease by damaging a key human gene.

Scientists said the study--done at the City of Hope Medical Center in Duarte and the M.D. Anderson Cancer Center in Smithville, Texas--offers a new kind of evidence that smoking triggers molecular events leading to lung cancer, the nation’s No. 1 malignancy. Lung cancer is expected to kill about 158,700 Americans this year.

“This is a very important finding,” said Dr. Curtis Harris, chief of the National Cancer Institute laboratory of human carcinogenesis, which studies cancer-causing processes. “It adds weight and specificity to the evidence that carcinogens found in cigarette smoke are the major causes of lung cancer.”

City of Hope molecular biologist Gerd Pfeifer speculated that the technique used to reach the new findings might someday be applied to a blood test that screens for exposure to cigarette smoke, either firsthand or secondhand. Or, he suggested, it might serve as the basis of a new test-tube method for determining a chemical’s cancer-causing potential.

“That’s for the long term, though,” he said.

The Tobacco Institute, an industry trade group, declined to comment on the new study.

Medical scientists have long believed that a complex chain of biological events leads from cigarette exposure to the sprouting of a tumor.

Over the decades, researchers have shown that smokers were up to 20 times more likely to develop lung cancer than were nonsmokers; that lab animals doused with smoke chemicals develop cancers; and, last year, that cancer victims who smoked have tumor cells that harbor a damaged form of a certain gene, known as P53.

The new study refines that reasoning even further, focusing on the first link in the causal chain: What happens when cells are exposed to a chemical in smoke?

The researchers zeroed in on one of the more than 40 known cancer-causing substances in cigarette smoke, benzo[a]pyrene, which the body converts into another compound, BPDE. After adding BPDE to lung tissue cells growing in a dish, they also analyzed the P53 gene in those cells. That gene, a so-called tumor suppressor, is involved in preventing tumors from starting.

The main finding was that BPDE formed a tough chemical bond at several places along the P53 gene’s DNA strand. Those chemical bonds, like a wrench in the gears, would interfere with the gene’s function, presumably by causing errors, or mutations, as the DNA gets copied during cell division. And eventually, the researchers say, those mutations would block the P53 gene from preventing the runaway cell growth that is a tumor.

“What we have here is a different type of evidence,” said Pfeifer. “It’s not based on populations or epidemiology but molecular biology, and it shows a direct relationship between a specific compound and cancer.”

“It binds the whole field [of smoke research] together and takes it to a new level of understanding,” said Dr. David Sidransky, a cancer specialist and geneticist at the Johns Hopkins University School of Medicine. “It confirms a whole body of epidemiological evidence that cancers are caused by cigarette smoking.”

Dr. Stanton Glantz, a UC San Francisco researcher who has archived decades of secret tobacco company documents dealing with the potential health dangers of cigarettes, said: “I think it’s a nice piece of science that helps get at a mechanism, but I don’t see it as having a major public health or legal or political impact.

He said internal tobacco company papers acknowledged that benzo[a]pyrene “was a carcinogen and involved in adverse effects of smoking.” The new research, he added, is not “suddenly going to make the tobacco industry admit that water rolls down hill.”

Possible future applications of the method used in the research include a test-tube screening of a chemical’s cancer-causing potential. Its ability to form bonds with the DNA of an important gene--as revealed, say, in a test tube--could flag it as a hazard, researchers said.

That approach, said Michael Thun, an epidemiologist with the American Cancer Society, “may at some point speed up our ability to recognize carcinogens that are a particular hazard.” But, he added, “that’s the future.”

One of Pfeifer’s Texas collaborators, Moon-Shon Tang, suggested another potential application. He said that such a DNA scan might be used to check whether someone was on the way to developing cancer as a result of exposure to a carcinogen like smoke.

Tang said he has received funding in the past from the Council on Tobacco Research, an industry group that has been criticized for fostering pro-industry studies. But the new research was funded by grants from the National Institutes of Health.