Drugs 101
Cancer
Cancer is uncontrolled growth
Hyper-proliferative lesion - benign
Benign lesions can be fatal in developing countries
Hyper-proliferative lesion - malignant
Causes of death – Canada (2011)
Cause
Deaths
Percent of Total
Cancer
72, 476
29.9
Heart Disease
47, 627
19.7
Cerebrovascular diseases
13, 283
5.5
Chronic lower respiratory diseases
11, 184
4.6
Accidents
10, 716
4.4
Diabetes
7, 194
3.0
Alzheimer’s disease
6, 356
2.6
Influenza and Pneumonia
5,767
2.4
Suicide
3, 728
1.5
Cancer is a disease of the Aged
Over 75% of all cases occur after age 55
Causes 570,000 deaths per year in North America (1500 per day)
Cancer death rate by age
Cancer in children is extremely rare
Cancer treatments are unpleasant
Change in the US death rates* by cause,
1950 & 2001
Rate Per 100,000
1950
2001
155.9
(2016)
Heart
Diseases
Cerebrovascular
Diseases
Pneumonia/
Influenza
* Age-adjusted to 2000 US standard population.
Sources: 1950 Mortality Data - CDC/NCHS, NVSS, Mortality Revised.
2001 Mortality Data–NVSR-Death Final Data 2001–Volume 52, No. 3.
2006 Mortality Data: US Mortality Data 2006, NCHS, Centers for Disease Control and Prevention, 2009.
Cancer
Cancer death rates*, US
*Age-adjusted to the 2000 US standard population.
Source: Surveillance, Epidemiology, and End Results Program, 1975-2016, Division of Cancer
Control and Population Sciences, National Cancer Institute, 2016.
US Cancer death rates*, men
*Age-adjusted to the 2000 US standard population.
Source: US Mortality Data 1960-2016, US Mortality Volumes 1930-1959,
National Center for Health Statistics, Centers for Disease Control and Prevention, 2016.
US Cancer death rates*, women
*Age-adjusted to the 2000 US standard population.
Source: US Mortality Data 1960-2016, US Mortality Volumes 1930-1959,
National Center for Health Statistics, Centers for Disease Control and Prevention, 2016.
Normal cells become cancerous
“Make-your-own” parasite
Cell division is closely regulated
• Cells divide only “on command”
• Maximum of 50 cell divisions
• Cells must be touching similar cells (tissue)
Cancer cell division is uncontrolled
• Cells divide continuously
• More that 50 cell divisions (immortal)
• Cells are mobile (metastisis)
Many cancer cells are immortal
HeLa cells from Henrietta Lacks 1951
Cancer requires 20 years to develop
• Requires 8 to 10 mutations in same cell
Every cancer tumor is different
• Every tissue can spawn
– More than 100 forms
– Each tumor is unique
• Basic processes are similar
– Loss of control over cell division
Cancer mutations involve loss of function
• Proteins STOP working properly
– Random mutations destroy function
• Cannot repair the damage with today’s
technology
– Genetic repair expensive, difficult and
unreliable
• Only way to treat it is to kill the cancer
Biological regulation is complex
Control using systems working
in “opposite” way at the same
time
- One system switches on
- One system switches off
- Body balances both to control
Cell division is regulated in 2 ways
• Stimulation (accelerator)
• Repression (brakes)
“Off” switch for cell division is broken
• Cell division gets
switched on
• Cannot switch off
• “gas pedal” stuck
to the floor
Ras is a common ON/OFF switch
• Non-functional in 30 % of tumors
• Gets “stuck” in the ON position and cannot
switch OFF
“Brakes” for cell division are broken
• “Brake pedal” does not work
p53 is an important braking protein
Non functional in more than 50 % of tumors
Apoptosis – programmed cell death
Programmed cell death in embryo development
Programmed cell death in wound healing
Programmed cell death protects the body
from viruses and cancer
p53 is an important suicide protein
Non functional in more than 50 % of tumors
Normal cells count cell divisions
Average cell can divide approximately 50 times
Dies once it reaches the max # divisions
Chromosomes tips are like shoe laces
Chromosomes become “frayed” with age
Cancer cells are immortal
Activate an enzyme that rebuilds chromosome tips
The system breaks that prevents the enzyme from being used
Tumor formation requires 8 to 10 mutations
• In the same cell
• Mutations happen continuously
• Damaged cells are eliminated from the body
• Several mutations within the same cell are rare
• Accumulation of enough mutations for cancer
requires more than 20 years on average
Gene is a set of instructions to make
protein
DNA
A
T
G
C
C
G
T
A
T
G
G
C
C
T
A
A
A
T
C
G
Gene uses 3 letter words called codons
DNA
C odon
A
T
G
C
C
G
T
A
T
G
G
C
C
T
A
A
A
T
C
G
Each codon specifies an amino acid in
a protein
DNA
A
T
G
C
C
G
T
A
T
G
G
C
C
T
A
A
A
T
C
G
Protein
Met
Pro
Tyr
Gly
Leu
Asn
Sequence of amino acids determines
protein structure
P r o te in
M e t
P ro
T y r
G ly
L e u
A s n
Sequence of amino acids determines
protein structure
DNA
A
T
G
C
C
G
T
A
T
G
G
C
C
T
A
A
A
T
C
G
Protein
Met
Pro
Tyr
Gly
Leu
Asn
Mutation is a “typo” in the gene
DNA
A
T
G
C
C
G
T
A
T
G
G
C
C
T
A
A
A
A
C
G
Protein
Met
Pro
Tyr
Gly
Leu
Lys
Get a non-functional version of
the protein (wrong shape)
Genetic basis for cancer
• Proto-oncogenes
–Genes involved in control of cell division
• Mutations change proto-oncogenes into
oncogenes
–Form found in cancer
Genetic susceptibility - mutations
• Some individuals are more susceptible to
cancer
–Have pre-existing genetic changes in protooncogenes
–Proto-oncogenes are easier to damage (spelling
mistakes have bigger consequences)
Genetic susceptibility – form and
function
• Some individuals are more susceptible to
some cancer types
than others
•Behavior
•Body type
Genetic susceptibility – biochemical
differences
e th y l a lc o h o l
a lc o h o l d e h y d r o g e n a s e
a c e t a ld e h y d e
a c e ta ld e h y d e d e h y d r o g e n a s e
a c e t ic a c id
Most cancer death is caused by controllable
factors
Tobacco
Diet and Obesity
Viruses
Everything else (in order of prevalence)
alcohol
lack of exercise
UV radiation
environmental exposure (2 - 4 %)
genetics
medical procedures
(X-rays and chemotherapy)
Tobacco smoke contains over 4800 chemicals
• 400 toxic (harmful at low doses)
– 40 carcinogenic
Nicotine is the addictive substance
N
N
Carcinogens in tobacco - Polonium 210
a emitters are normally safe
Polonium anti static brushes
Radioactive spark plugs
Polonium spinthariscope in KIX cerial
Cereal is just not cool anymore
Heat from burning vaporizes polonium
Tobacco smoke combustion products
B
e
n
z
o
p
y
r
e
n
e
s
NO
N
O
N
it
r
o
s
a
m
in
e
s
E
t
h
y
le
n
e
O
x
id
e
Benzopyrene carcinogenicity
OH
DNA
DNA Damage
and mutation
DNA
Cy P450
O
Hydrolase
OH
HO
Removal by Kidney
5000
100
4500
90
4000
80
Per capita cigarette consumption
3500
70
3000
60
2500
50
Male lung cancer death rate
2000
40
1500
30
1000
20
500
Female lung cancer death rate
10
2000
2005
1995
1985
1990
1975
1980
1970
1960
1965
1950
1955
1940
1945
1935
1925
1930
1915
1920
1905
1910
0
1900
0
Age-Adjusted Lung Cancer Death
Rates*
Per Capita Cigarette Consumption
Tobacco use in the US
Year
*Age-adjusted to 2000 US standard population.
Source: Death rates: US Mortality Data, 1960-2005, US Mortality Volumes, 1930-1959, National Center for Health
Statistics, Centers for Disease Control and Prevention, 2006. Cigarette consumption: US Department of
Agriculture, 1900-2007.
Tobacco companies recruit women
Mommy it’s good for you
US Cigarette smoking prevalence*
Men
Women
*Redesign of survey in 1997 may affect trends.
Source: National Health Interview Survey, 1965-2007, National Center for Health Statistics, Centers for Disease
Control and Prevention, 2008.
Strong correlation of cancer with diet and
obesity
Cooking for safety and flavor
Meat spoils quickly and must be cooked
Cooking generates flavor and some nasty
materials
Food preparation creates carcinogens
OH
DNA
DNA Damage
and mutation
DNA
Cy P450
O
Hydrolase
OH
HO
Removal by Kidney
Beneficial foods protect us
• Fruits and vegetables
Fruits and vegetables protect us
OH
DNA
DNA Damage
and mutation
DNA
Cy P450
O
Hydrolase
OH
HO
Removal by Kidney
Fiber promotes the passage of waste
Consumption of five or more vegetable and
fruit servings for cancer prevention
35
Prevalence (%)
30
25
24.2
24.4
24.1
24.4
23.6
24.3
24.7
1994
1996
1998
2000
2003
2005
2007
20
15
10
5
0
Year
Note: Data from participating states and the District of Columbia were aggregated to represent the United
States.
Source: Behavioral Risk Factor Surveillance System CD-ROM (1984-1995, 1996, 1998) and Public Use Data Tape
(2000, 2003, 2005, 2007), National Center for Chronic Disease Prevention and Health Promotion, Centers for
Disease Control and Prevention, 1997, 1999, 2000, 2001, 2004, 2006, 2008.
Obesity* (%), by gender, adults aged 20 to
74
45
40
35
33
Prevalence (%)
35
34 35
34
36
32
31
28
30
26
23
25
21
20
15
13
16 17
15 15
11
17
12 13
10
5
0
Both sexes
Men
NHES I (1960-62)
NHANES I (1971-74)
NHANES II (1976-80)
NHANES 1999-2002
NHANES 2003-2004
NHANES 2005-2006
Women
NHANES III (1988-94)
*Body mass index (BMI) at or above the sex-and age-specific 95th percentile BMI cutoff points from the 2000
sex-specific BMI-for-age CDC Growth Charts.
National Health and Nutrition Examination Survey, 1971-1974, 1976-1980, 1988-1994, 1999-2002, National Center
for Health Statistics, Centers for Disease Control and Prevention, 2002, 2004. 2003-2006: Ogden CL, et al. High
Body Mass Index for Age among US Children and Adolescents, 2003-2006. JAMA 2008; 299 (20): 2401-05.
Obesity increases your risk for EVERYTHING
Changes in eating habits
Changes in portion size
Viruses responsible for about 15 % of cancer
death
• Contain oncogenes
High risk viruses target p53
Guardasil for HPV induced cervical cancer
Excess alcohol increases your risk
Alcohol as a carcinogen
e th y l a lc o h o l
a lc o h o l d e h y d r o g e n a s e
a c e t a ld e h y d e
a c e ta ld e h y d e d e h y d r o g e n a s e
a c e t ic a c id
Leisure-time physical activity
Adults with less than a high school education
All adults
Note: Data from participating states and the District of Columbia were aggregated to represent the United
States. Educational attainment is for adults 25 and older.
Source: Behavioral Risk Factor Surveillance System CD-ROM (1984-1995, 1996, 1998) and Public Use Data Tape
(2000, 2002, 2004, 2005, 2006, 2007), National Center for Chronic Disease Prevention and Health Promotion,
Centers for Disease Control and Prevention, 1997, 1999, 2000, 2001, 2003, 2005, 2006, 2007, 2008.
Exposure to UV light induces skin cancer
Environmental exposure – man made
Environmental exposure – natural sources
Strongest carcinogens occur naturally
O
O
O
H
O
H
O
O
M
e
A
f
l
a
t
o
x
i
n
Phorbol is used to induce cancer
O
H
O
H
H
H
O
H
O
H
O
O
H
Medical procedures X-rays and chemo
5 Year Survival Rates
1974-1976
50 %
1992-1999
60 %
2009-2015
67 %
*5-year relative survival rates based on follow up of patients through 2000.
Source: Surveillance, Epidemiology, and End Results Program, 1975-2000, Division of Cancer Control and
Population Sciences, National Cancer Institute, 2003.
Cancer very difficult to target selectively
• Abnormal human proteins (junk protein)
– Non-functional enzymes
– Non-functional protein
• Poor drug targets
– Drugs can block protein function
– Cannot restore protein function
Cancer cells are human cells
• Normal cells have 23,000 genes
• Only 8 or 10 are changed in a cancer cell
– Changes very small (typo)
– Drug has to “know” which cell to target
• Major difference is cell division
– Cancer drugs are strong poisons
– Cancer drugs target cell division
– Fast growing cells killed first
Strategy for cancer chemotherapy
• Kill the cancer faster than you kill the
patient
• Side effects are guaranteed – 100 %
• Side effects are severe
– Death
– Cancer
– Extreme nausea, vomiting
– Hair loss, immune suppression, sterility
Nitrogen mustards in World War I
Nitrogen mustards destroy tissue
Nitrogen mustards in World War II
Air raid on Bari, Italy
Survivors had fewer white blood cells
C
l
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l
D
N
A
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a
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S
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l
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D
N
A
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N
AD
a
m
a
g
e
Mustine was the first cancer drug
C l
C l
D N A
C e ll D e a th
S
S
C l
D N A
D N A D a m a g e
M u s ta rd g a s
C l
C l
D N A
T u m o r C e ll D e a th
N
C l
M u s tin e
N
D N A
D N A D a m a g e
N
o
rm
a
lC
e
ll
D
N
A
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p
a
ir
Fast growing cells are more susceptible
Cancer drugs cause death and cancer
C
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th
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N
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N
A
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N
A
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a
m
a
g
e
C
a
n
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r
Rapid cell growth provides selectivity
Normal cells have time to repair damage from drugs
Cancer cells reproduce before damage repaired
Serendipitous discovery with E. coli
• Effects of electric fields on bacteria
• Generated chemicals that stopped bacterial
growth
Current and oxygen corroded the electrode
O
,
C
l
C
l
N
H
2
3
P
t
P
l
a
t
i
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C
l
N
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3
Peyrone's salt
(Discovered 1845)
• Damage DNA in fast growing cells
(bacteria)
• Tests with tumors in rats proved
successful
Long road for Cisplatin
•
•
•
•
First synthesized 1845
Inhibition of cell division discovered 1965
Anticancer activity discovered 1969
Approved for human use 1978
– Cure rate for testicular cancer approx 90 %
• Today used in 40 – 80 % of all cancer
patients
C
l N
H
P
t3
C
l N
H
3
Cisplatin moves in and out of normal
cells
Cisplatin activated and trapped in
cancer cells
C a n c e r C e ll
C l-
C lC l-
C l-
C l-
C lC l-
C lC l
N H
P t
C l
N H
3
C l
N H
P t
C l
N H
in a c t iv e
3
in a c tiv e
C l-
C lC l-
C l-
C l-
3
3
H
H
2
2
O
O
P t
t o x ic
N H
N H
3
3
USDA searches for new poisons – 1950’s
• Poisons can be medications
Yew bark extract found to be cytotoxic - 1964
Taxol identified as toxic substance - 1971
Taxol effective against breast cancer 1989
• 30 %
Taxol is a complex molecule
Impossible to make a synthetic version
O
AcO
O
OH
PhNH
O
Ph
O
OH
HO
O
AcO
BzO
Taxol manufacture from yew trees
• 13,000 Kg of bark gave 1 Kg of Taxol
• 38,000 trees gave 25 Kg of Taxol
• Total demand in North America
– More than 360,000 trees per year
Clear-cutting the ENTIRE Pacific North West
• A 5 year supply
People or trees?
Taxus baccata is the European yew
Semi synthesis of Taxol
HO
O
OH
TESCl,
HO
HO AcO
BzO
O
10-Deacetylbaccatin III
(10-DAB)
AcO
O
Ph
Ph
O
OH
AcO
O
1)OH
LiHMD
O
NH O
PhNH
O
O
2) HF
O
HO
O
AcO
OH
BzO HO
O
AcO
Ph
OH
Taxol
BzO
Robert Holton – Florida State University
– Between 1993 and 2007 FSU made
$350,000,000
• 40 % to Holton
• 30 % to Chemistry Department
• 30 % to University
Taxol now manufactured using cell culture
- Plant cells suspended in growth medium
- Genetically modified to maximize production
Cancer drugs are unpleasant
• Kill the cancer faster than you kill the
patient
• Side effects are common – 100 %
• Side effects are severe
– Death
– Cancer
– Extreme nausea
– Hair loss, immune suppression
Much cancer death is avoidable
Tobacco
Diet and Obesity
Viruses
Everything else (in order of prevalence)
alcohol
lack of exercise
UV radiation
environmental exposure (2 - 4 %)
genetics
medical procedures
(X-rays and chemotherapy)