1. Tobacco Smoke and Lung Cancer: A Mechanistic Overview Ryan Ubelhor

2. Topics of the Day Lung Cancer Mechanisms Common Misconceptions and Clearing the Air General Path Towards Lung Cancer Interesting Compounds in Tobacco Smoke DNA Math Addition Benzene Derivatives Subtraction Free Radicals Summation

3. Lung Cancer Mechanisms Misconception Misconception The mechanisms by which tobacco smoke leads to lung cancer are not well known due to the complex nature of tobacco smoke. No Clear Path Proven Tobacco smoke is complex but ongoing studies from the past 50 years clearly show the multitude of paths towards lung cancer. Multitude of Pathways

4. General Path Towards Lung Cancer While the path for each compound is slightly different, the overall train wreck follows a consistent pattern. Intake → Activation → DNA damage → Miscoding → Lung Cancer

5. Some compounds of interest present in tobacco smoke, not including products of combustion such as NO, CO 2 CO, etc.

6. The two most studied pulmonary carcinogens are BaP and NNK. There is as much NNK in tobacco smoke as the cumulative amount of Polycyclic aromatic hydrocarbons (PAH’s) BaP is well studied and a highly documented as a dependable carcinogen, however, it is not the strongest tumerogin of the PAH’s. Dibenzo[a,h]anthracene, 5-methylchrysene and dibenzo[a,i]pyrene are substantially stronger. NNK is lung specific and will arrive there to cause damage regardless of exposure method.

7. Types of DNA Damage and Repair There are many possible ways to damage DNA. Primarily fall into two categories: Mutation and Breakage/Nicking Most repair enzymes operate by recopying one strand.

8. DNA Math: Addition Once inside the cells of the lungs, the body’s own enzymes are used to cause problems. Organic compounds are activated into forms that can cause adducts on DNA.

9. BaP and NNK form adducts that cause mutation two different ways after being activated.

10. BaP normally distorts the DNA framework but it can also cause base pair substitutions.

11. NNK is only known to cause substitutions of base pairs, specifically GGT -> GAT in codon 12 of the Kirsten-ras (KRAS) oncogene. An oncogene is basically a regular gene that has undergone mutation and now promotes cancerous growth. 25%-50% of human adenocarcinomas are found with this substitution.

12. p53 Tumor Suppressor Damage Normally very important in regulating cell death, but is found mutated in over 50% of all lung cancer cases. Typically, G T or G A transversions were the most common mutations. While not positively linked to NNK yet, these are NNK’s normal methods of attack on DNA.

13. DNA Math: Subtraction The final steps of DNA nicking is the same as adduction. The modified DNA is not always caught and can then be replicated causing more errors and eventually cancer. The first steps are not from unwelcome additions but rather reactive species such as the NO radical that nick off chunks of DNA.

14. Summation Much is known about the pathways in which tobacco smoke causes lung cancer. The confusion arises when trying to speak specifically about a general concept. Tobacco smoke generally causes cancer via damage to DNA that is not always caught and then goes on to cause further problems. Each specific compound in the soup that is found in tobacco smoke can be activated by different enzymes and damage different genes.

15. References Primary: Hecht, Stephen S., Journal of the National Cancer Institute, Vol. 91, No. 14, July 21, 1999. “Tobacco Smoke Carcinogens and Lung Cancer” Additional Images: P&S Journal: Winter 1995, Vol.15, No.1 “The Renaissance Reshaping Cancer at Columbia Presbyterian Medical Center” Environmental Health Perspectives 105, Supplement 4, June 1997 “Approaches to Chemoprevention of Lung Cancer Based on Carcinogens in Tobacco Smoke” Stephen S. Hecht University of Minnesota Cancer Center, Minneapolis, Minnesota