DUARTE, CALIF-- New research has shown that polycyclic aromatic hydrocarbons (PAHs)--carcinogenic compounds in cigarette smoke--produce DNA damage patterns that are similar to the p53 mutation patterns found in lung cancer tissues in smokers.[1] "This study increases our understanding of the mechanisms by which cigarette smoke might contribute to the development of lung cancer at the molecular level. These findings could be employed in science-based tobacco use prevention efforts, as has been done by the Australian government," Gerd P. Pfeifer, PhD, told RESPIRATORY REVIEWS.

Earlier studies had shown that exposure to one specific PAH, benzo[alpha]pyrene diol epoxide (B[alpha]PDE), induces guanine adducts at mutational hotspots within the p53 tumor suppressor gene, which is mutated in 60% of human lung cancers. But whether other PAHs found in cigarette smoke were implicated in the development of lung cancer was unclear.

To answer this question, Dr. Pfeifer and colleagues at the Beckman Research Institute of the City of Hope in Duarte, California, and the University of Texas M. D. Anderson Cancer Center in Smithville, Texas, exposed cultures of normal human bronchial epithelial cells to various concentrations of five different PAHs--chrysene (CDE), 5-methylchrysene (5-MCDE), 6-methylchrysene (6-MCDE), benzo[c]phenanthrene (B[c]PDE), and benzo[g]chrysene (B[g]CDE). Then they examined DNA from the cells for mutational damage patterns, including the formation of covalent adducts at specific sites along the DNA in the p53 gene. Next, the investigators compared the genetic changes caused by the five PAHs with the genetic changes that have been reported in lung cancer tissues from both smokers and nonsmokers.

MUTATIONAL PATTERNS FOUND IN SMOKERS

With the exception of CDE, which produced low levels of adducts, all of the other PAHs studied were highly effective at producing damage at one particular spot within codon 273. Whereas these mutations occurred in particular locations along the p53 gene in smokers, the mutations in nonsmokers occurred in random locations. Furthermore, the distribution of adducts produced by the other four compounds occurred in a pattern similar to that of sites of highest mutation frequency in the p53 gene in lung cancers from smokers. This pattern was distinct from that seen in lung cancers from nonsmokers.

However, the degree of adduction that occurred at each reactive site varied among the five compounds. "Although the different reactivities are not well-understood, they may be a function of the differences in the chemical structures of these compounds. The PAH compounds also appear to have an enhanced affinity for 5-methylcytosine--guanine base sequences," suggested Dr. Pfeifer.

"These results provide support for the critical role of metabolically activated cigarette smoke carcinogens in lung cancer in smokers," stated Stephen S. Hecht, PhD, of the University of Minnesota Cancer Center in Minneapolis, in an editiorial.[2]

However, "more study of the mutations produced by PAHs and the specific genes they target is needed," Dr. Pfeifer concluded.

--Deborah L. O'Connor

References
1. Smith LE, Denissenko MF, Bennett WP, et al. Targeting of lung cancer mutational hotspots by polycyclic aromatic hydrocarbons. J Natl Cancer Inst. 2000;92:803-811.
2. Hecht SS. Metabolically activated carcinogens and mutations in the p53 tumor suppressor gene in lung cancer. J Natl Cancer Inst. 2000;92:782-783.