Transcript Document

Tobacco Smoke and
Lung Cancer:
A Mechanistic Overview
Ryan Ubelhor
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
Lung Cancer Mechanisms
Misconception
Proven
The mechanisms by
which tobacco smoke
leads to lung cancer are
not well known due to
the complex nature of
tobacco smoke.
Tobacco smoke is
complex but ongoing
studies from the past 50
years clearly show the
multitude of paths
towards lung cancer.
No Clear Path
Multitude of Pathways
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
Some compounds of interest present in tobacco smoke, not including
products of combustion such as NO, CO2 CO, etc.
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.
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.
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.
BaP and NNK form adducts that cause mutation two
different ways after being activated.
BaP normally
distorts the DNA
framework but it
can also cause
base pair
substitutions.
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.
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.
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.
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.
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