Tobacco Smoke and Tobacco Smoke and Lung Cancer:Lung Cancer:

A Mechanistic OverviewA Mechanistic Overview

Ryan UbelhorRyan Ubelhor

Topics of the DayTopics of the DayLung Cancer MechanismsLung Cancer Mechanisms

Common Misconceptions and Clearing the AirCommon Misconceptions and Clearing the Air

General Path Towards Lung CancerGeneral Path Towards Lung CancerInteresting Compounds in Tobacco SmokeInteresting Compounds in Tobacco Smoke

DNA MathDNA MathAdditionAddition

Benzene DerivativesBenzene DerivativesSubtractionSubtraction

Free RadicalsFree Radicals

SummationSummation

Lung Cancer MechanismsLung Cancer Mechanisms

MisconceptionMisconception

The mechanisms by The mechanisms by which tobacco smoke which tobacco smoke leads to lung cancer are leads to lung cancer are not well known due to not well known due to the complex nature of the complex nature of tobacco smoke.tobacco smoke.

No Clear PathNo Clear Path

ProvenProven

Tobacco smoke is Tobacco smoke is complex but ongoing complex but ongoing studies from the past 50 studies from the past 50 years clearly show the years clearly show the multitude of paths multitude of paths towards lung cancer.towards lung cancer.

Multitude of PathwaysMultitude of Pathways

General Path Towards Lung General Path Towards Lung CancerCancer

While the path for each compound is slightly different, the While the path for each compound is slightly different, the overall train wreck follows a consistent pattern.overall train wreck follows a consistent pattern.

Intake Intake → Activation → DNA damage → Miscoding → Lung Cancer→ Activation → DNA damage → Miscoding → Lung Cancer

Some compounds of interest present in tobacco smoke, not including products of combustion such as NO, CO2 CO, etc.

The two most studied The two most studied pulmonary pulmonary carcinogens are BaP carcinogens are BaP and NNK.and NNK.

There is as much There is as much NNK in tobacco NNK in tobacco smoke as the smoke as the cumulative amount of cumulative amount of Polycyclic aromatic Polycyclic aromatic hydrocarbons (PAH’s)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.

Types of DNA Damage and Types of DNA Damage and RepairRepair

There are many possible There are many possible ways to damage DNA. ways to damage DNA.

Primarily fall into two Primarily fall into two categories: Mutation and categories: Mutation and Breakage/NickingBreakage/Nicking

Most repair enzymes Most repair enzymes operate by recopying operate by recopying one strand.one strand.

DNA Math: AdditionDNA Math: Addition

Once inside the cells of the lungs, the body’s Once inside the cells of the lungs, the body’s own enzymes are used to cause problems. own enzymes are used to cause problems.

Organic compounds are activated into forms that Organic compounds are activated into forms that can cause adducts on DNA.can cause adducts on DNA.

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

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

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

p53 Tumor Suppressor Damagep53 Tumor Suppressor Damage

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

DNA Math: SubtractionDNA Math: Subtraction

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

SummationSummation

Much is known about the pathways in which tobacco Much is known about the pathways in which tobacco smoke causes lung cancer. The confusion arises when smoke causes lung cancer. The confusion arises when trying to speak specifically about a general concept.trying to speak specifically about a general concept.

Tobacco smoke Tobacco smoke generallygenerally causes cancer via damage to causes cancer via damage to DNA that is not always caught and then goes on to cause DNA that is not always caught and then goes on to cause further problems. further problems.

Each Each specificspecific compound in the soup that is found in compound in the soup that is found in tobacco smoke can be activated by different enzymes and tobacco smoke can be activated by different enzymes and damage different genes.damage different genes.

ReferencesReferences

Primary:Primary:Hecht, Stephen S., Hecht, Stephen S., Journal of the National Cancer Journal of the National Cancer Institute, Vol. 91, No. 14, Institute, Vol. 91, No. 14, July 21, 1999. “Tobacco Smoke Carcinogens and Lung Cancer”July 21, 1999. “Tobacco Smoke Carcinogens and Lung Cancer”

Additional Images:Additional Images:P&S Journal: Winter 1995, Vol.15, No.1P&S Journal: Winter 1995, Vol.15, No.1“The Renaissance Reshaping Cancer at Columbia Presbyterian Medical “The Renaissance Reshaping Cancer at Columbia Presbyterian Medical Center”Center”

Environmental Health Perspectives 105, Supplement 4, June 1997Environmental Health Perspectives 105, Supplement 4, June 1997““Approaches to Chemoprevention of Lung Cancer Based on Carcinogens in Approaches to Chemoprevention of Lung Cancer Based on Carcinogens in Tobacco Smoke”Tobacco Smoke”Stephen S. Hecht Stephen S. Hecht University of Minnesota Cancer Center, Minneapolis, Minnesota University of Minnesota Cancer Center, Minneapolis, Minnesota