SUPERCOMPUTER ANALYSIS OF DNA-CARCINOGEN INTERACTIONS             
   
   It is widely believed that the process that leads to cancer can be
   initiated when certain biochemically active chemicals bind to DNA to
   form a combination molecule called an adduct. This reaction can disrupt
   the normal double-helical shape of the DNA, causing mutations when the
   DNA replicates, when the cell's DNA repair mechanisms fail to work
   properly, or when other unusual genetic events start the cellular
   process that leads to the development of cancer. As a result, an
   understanding at the atomic level of the effect of chemicals on DNA
   structure is critical to understanding chemical carcinogenesis.            
         
   
   Researcher Brian Hingerty of the Health and Safety Research Division
   describes the challenge of determining the relationship between various
   chemicals and cancer: "If one could establish structural hallmarks that
   distinguish DNA bound by a malignant chemical from DNA bound by a benign
   one, it might be possible to employ computational tools instead of
   bacterial or animal testing to screen chemical substances for mutagenic
   and tumorigenic potential."            
   
   One chemical substance of particular interest is benzo[a]pyrene, a
   material present in automobile exhaust and, therefore, common in the
   environment. Once ingested, this chemical becomes activated, forming a
   number of derivatives, including a pair of mirror-image molecules called
   (+) and (-) anti-benzo[a]pyrene-diol-epoxide (BPDE). Interestingly,
   these mirror-image molecules have very different biological effects; in
   studies with mice, the (+) version has proven to be tumorigenic, whereas
   the (-) variant is apparently benign.               
   
   Both of these molecules can bind to DNA at the amino group of the base,
   guanine. In fact, this particular type of BPDE-bound DNA is the most
   common adduct formed by the tumorigenic (+) BPDE and is believed to be
   responsible for benzo[a]pyrene's carcinogenic effect. Determining at the
   atomic level how this (+) adduct differs in structure from its benign
   (-) mirror image is a first step in understanding why these two
   chemicals have such divergent biological properties.                    
   
   Using computer-modeling methods at DOE's National Energy Research
   Supercomputer Center at Lawrence Livermore National Laboratory, Hingerty
   and his collaborator, Professor Suse Broyde of New York University,
   explored the differences between the two adducts by determining the
   molecular structure of both chemicals in a short piece of DNA. They
   found that both the (+) and (-) versions of BPDE are positioned in the
   "minor groove" of double-helical, right-handed DNA; however, they point
   in opposite directions.          
   
   This structural difference between the two bound adducts could produce
   different treatments by the enzymes involved in DNA replication and
   damage repair, resulting in only one of the adducts being tumorigenic.
   "Our future plans," says Hingerty, "include examining other substances
   related to the benzo[a]pyrenes, some of which are tumorigenic and others
   not, to learn whether the distinction we have uncovered is more general.
   

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   Date Posted:  1/10/94  (ktb)