Drugs for Cancer Flashcards
This lecture
The broad epidemiology of cancer
Why it’s hard to find evidence of cancer in the pre-science world
Ideas about cancer origins and treatment before scientific
medicine
How early scientific medicine grappled with cancer and its
transmission
How chemotherapy was developed
The pros and cons of chemotherapy in cancer treatment
The cultural impact of cancer and its treatment
Future directions
Learning Outcomes
To describe the broad global epidemiology of cancer.
To describe pre-science beliefs about cancer and its origins, spread, and
treatments.
To describe how the first chemotherapy treatment was developed.
To describe the social, cultural, and medical impacts of the discovery of
chemotherapy
What is
cancer?
The abnormal growth of cells within the body to the point
where they become malignant and invasive
Ranks among the most feared human diseases. Usually originates inside the human body where it is unseen. Is often only detected after it is too late for successful treatment. Cancer is a leading cause of death in developed countries: An ‘old person’s’ disease? You have to survive long enough to
develop some cancers.
In Western history, and in developing countries today, other diseases
will usually end a person’s life earlier, eg. infectious diseases, infant
mortality, death in childbirth
Humerus –
possibly female,
Central
America,
1300CE?
Possible
sarcoma
Cancer the Crab
In traditional astrology, Cancer was a star sign
indicated by a giant crab.
The Babylonians thought it was a turtle, and the
Egyptians thought it was a scarab beetle.
The constellation Cancer is one of the faintest in
the sky.
Cancer’s alleged astrological characteristics are
darkness, sinister behaviour, sideways creeping,
gnawing, and secrets.
Archaeology
and prehistory
It’s hard to find signs of cancer in ancient human remains.
This is also why some academics argue that cancer was rarer in the
past than it is today.
Some possible signs of cancer have been found in ancient
Egyptian mummies and in fossilised human bones.
But we can’t always tell whether these are truly cancerous
(i.e malignant), or benign tumours.
They could even simply represent skeletal erosion from the
elements.
Cancer can also affect muscles and organs, and these are generally
not preserved for archaeologists to discover.
No bog bodies or ice-men yet!
Why ‘cancer’?
Original Greek word καρκινος
(karkinos), used in the Hippocratic
Corpus, which originally meant
‘crayfish’ or ‘crab’.
Tumors can make a round shape
under the skin and stretch the veins
- like a crab with its legs radiating
outwards from its body.
The condition also caused gnawing
pain like a crab.
Hippocratic text The Aphorisms:
‘Itis better not to apply any
treatment in cases
of occult [hidden] cancer; for, if
treated, the patients die quickly;
but if not treated, they hold out for
a long time’ (Section IV, no 38)
Celsus and cancer
The Roman physician Celsus
translated καρκινος as carcinos
We use this word today: a carcinogen is a
chemical with proven cancer-causing potential.
Celsus identified a range of different cancers in
the body and also their symptomatology.
Recommended aggressive cutting, but only in
the early stage.
Recommended topical treatment for small
superficial cancers: cabbage, a salted mixture of
honey and egg white, or ripe figs.
Both Hippocratic and Roman medicine believed
that cancer was caused by excess of black bile –
purgatives were the best preventive medicine.
Ancient Egypt
The Edwin Smith Papyrus (c1500BCE, and one of the
most famous ancient Egyptian medical codices along with
the Ebers Papyrus) contains a description of what may be
thoracic cancer.
Case 45 describes ‘ball-like tumours’ on a man’s chest
which have spread, feel cold to the touch, and are solid
under the skin.
‘There is no treatment’: the Egyptians knew that cancer
which had spread this far was untreatable.
Cancer in the
classical world
Galen: oncos from theGreek όγκος
which means ‘swelling’ or ‘tumour’
Used today in words like oncology -
the medical specialisation dealing
with cancer
Ibn Sina (Avicenna), Canon of
Medicine : a growth which
‘progressively increases in size, is
destructive, and spreads roots
which insinuate themselves
amongst the tissue-elements.
It does not necessarily destroy
sensation unless it has existed for a
long time, and then it kills the
tissues and destroys the sensation
in the part.’ (Canon of Medicine,
s.213)
Trouble with
the written
records!
Because cancer was mysterious and
elusive, there was no one standard
name for the wide variety of tumours
and growths that can be cancerous.
The English language
took carcinos and turned it into canker,
which meant any type of swollen or
ulcerated sore.
Mouth ulcers are still sometimes
called cankers.
The French word chancre has now
come to mean genital ulcers
associated with syphilis - but it used to
mean any form of spreading ulcer.
What caused cancer?
Many different cultures had their own traditional ideas of what caused cancer.
Humoral theory – black bile.
Islamic cultures emphasised the role of proper diet in preventing cancers.
Medieval European societies believed it could also be contagious and could
spread through the air, or through contact.
This idea persisted well into the early twentieth century in the West.
1926 Nobel Prize
goes wrong!
Danish oncologist Johannes Fibiger (1867-1928)
was awarded the 1926 Nobel Prize for ‘discovering’
that stomach cancer was caused by roundworms.
Gongylonema neoplasticum – but Fibiger named
them Spiroptera carcinoma.
After his death in 1928, other researchers proved
that Fibiger had arrived at the wrong conclusions
about his experiments – roundworms were not
responsible, and the tumours were not cancerous.
Other forms of cancer treatment
Small benign tumours and other neoplasms (new and abnormal
tissue growths) could be removed even with very primitive surgery.
This included full amputation of limbs.
Ancient writers knew it was almost impossible to treat cancer once
it was well-established in the organs.
This included breast cancer.
Medieval physician Jean de Tournemire (1329-1396) said that ‘he had
practiced for forty years and had not seen any woman suffering
this kind of disease being cured
The nineteenth century
Improvements in microscopic technology and antiseptic
surgery improved knowledge of the body’s cells.
However, only slow progress occurred in the understanding
and treatment of cancer.
In 1829, French gynaecologist Joseph Recamier (1774-1852)
described how cancer could spread through the body via the
bloodstream.
He coined the word metastasis (from the Greek term
meaning ‘removal from one place to another’) to describe
this process.
Mustard gas
1914-1918 war: Imperial German Army developed sulphur
mustard, or mustard gas.
Actually a fine droplet mixture that was sprayed into the air –
not strictly a gas.
Had a distinctive peppery odour that evoked comparisons to
garlic, mustard or horseradish.
Mustard gas caused blisters to form on the skin and in the
lungs.
This caused terrible injuries, disability and death to both
humans and animals following battlefield exposure.
Gas masks were issued to soldiers but were not always effective
at saving lives or preventing injury
Lymph? Juice?Cells?
By the mid 19th century, most European researchers believed
that cancer was caused by deteriorating lymph from the lymph
glands.
German scientist and pathologist Rudolf Virchow (1821-
1902) believed that cancer spread via a ‘juice’ released by
primary tumours that somehow converted normal cells at other
sites into tumours.
1840:German surgeon Karl Thiersch (pictured) showed that it
was malignant cells moving throughout the body that caused
metastasis.
This growing knowledge also helped surgeons to be more
efficient in removing all of a cancerous growth from the body
when they operated.
X-rays and cancer
1895: physicist William Roentgen (1845-1923) produced a nowfamous image of his wife Anna Bertha’s hand using a strange new
type of electromagnetic energy which he called theX-ray.
This won him the 1901 Nobel Prize - the first ever awarded for
physics.
X-rays allowed researchers to see inside the human body for the
first time without cutting it open.
They also cured some types of skin cancers and conditions,
including lupus.
However, X-rays also caused cancer in many early experimenters
and their patients.
Ban on gas
warfare – but
was it?
Geneva Gas Protocol 1925 – signed by most
countries, banning the use of chemical and biological
weapons in warfare.
At the time of its signing, several major powers
(including the United Kingdom, France, and
the Soviet Union) explicitly reserved the right to use
the forbidden weapons for retaliatory purposes.
In other words, if a state decide to use chemical or
bacteriological weapons against another
country, the country under attack would legally be
allowed to respond in kind.
So mustard gas was ‘banned but not banned’ …
Mustard gas disaster at
Bari, Italy, 1943
Bari was a British-occupied port in Italy in WWII.
One of 29 US ships waiting to unload their cargo at
Bari carried a secret cargo of mustard gas.
German air attack September 2, 1943.
The merchant vessel John Harvey caught fire - killed
over 1,000 people and exposed many to mustard
gas.
Officially, some 617 mustard gas-related
casualties were recorded at Bari, with at least 84
deaths attributed to the toxic exposures.
The link is made
Lt Col Stewart Alexander, US military doctor, went to Bari
and correctly identified the cause of injuries as mustard gas.
Meticulously studied the survivors and conducted detailed
autopsies on deceased victims.
Observed that mustard gas was toxic towards bone
marrow and destroyed its victim’s white blood cells.
Floated the idea that mustard gas might slow the growth of
tumour cells, especially cancers such as leukaemia that
involve uncontrolled production of abnormal white blood
cells.
JD – the first human trial, Yale
University, 1943
Yale University – Drs Louis Goodman and Alfred Gilman (pictured)
carried out successful animal trials with nitrogen mustard.
JD – anonymous patient with advanced lymphoma - tumours in his jaw,
armpits and chest (considered terminal).
27 August 1942, JD was given ‘synthetic lymphocidal chemical’ or
‘substance X’.
This was nitrogen mustard.
Within a month his cancer was gone – he could sleep, eat, and was in
less pain.
However, his white blood cells had been decimated.
By December 1942, JD was dead.
Early forms of chemotherapy
Early examples included:
antifolates which could induce remission in some types of
lymphoma (cancer of the lymphatic system, part of the body’s
defence mechanism);
alkaloid drugs (including medicines extracted from the vinca
plant);
corticosteroids which were also effective against other forms of
cancer.
In 1965, the first forms of combination chemotherapy were developed which
involved giving two or more anticancer drugs to a patient.
Multidrug combination strategies were soon used widely
The downside of chemotherapy
No one treatment can work for all forms of cancer.
Traditional chemotherapy is fundamentally harmful to patients.
Designed to cause nonspecific DNA damage or inhibit normal cell
processes like cell division and growth.
Chemotherapy has many different side effects such as weight
gain, hair loss, nausea, aches and pains, and feeling unwell.
Some people choose to forgo it and use simply radiation and/or
surgery for a higher quality of life during the last stages of their
illness.
The social and
cultural impact of cancer
Lung cancer was the first major cancer to be
associated with a public health campaign (tobacco
use through cigarette smoking).
The early detection and treatment of breast cancer
has been a major public health cause for several
decades in most Western countries.
Skin cancer is a major concern for Australians, who
have one of the highest incidences of this condition
in the world.
The Pap smear was developed as a way of detecting
cervical cancer early in women.
What we’ve learned
from chemotherapy
Chemotherapy has taught us about how cells grow, proliferate
and die.
Some cancers are easy to treat with drugs while others are
very aggressive and treatment-resistant.
Tumours often become resistant to repeated doses of the
anticancer drug.
This tumour can also become insensitive to other anticancer
drugs – ‘multidrug resistance’.
However, chemotherapy combined with the newer pathwaytargeted therapies seem to be the only cancer treatments
which can reliably prolong a person’s life and sometimes save
it.
Where we’re going …
Progress has been made in modern pharmacological treatment of cancer - new ways of thinking
about and delivering cancer treatments.
Improved knowledge of the molecular events that convert normal cells into dangerous tumour cells.
Many cellular pathways are disrupted in tumour cells, accounting for their destructive behaviour.
This makes it possible to develop pathway-targeted therapies that selectively interfere
with genetic or metabolic defects in tumour cells.
Ideally this won’t cause collateral damage to normal cells.
Many tumours can now be treated with safer, less toxic anticancer drugs.
Early diagnosis is still the key predictor of survival from cancer
What you need to know
Name some preventable causes of cancer
Explain how cancer progresses by a stepwise acquisition of critical
mutations leading to uncontrolled cell proliferation and invasion
Describe how traditional chemotherapy drugs target highly
proliferative cancer cells
List their adverse effects on highly proliferative normal tissues
Explain how the newer targeted therapies target specific mutant
proteins in cancer cells while sparing normal proteins and cells
Outline how the recently introduced cancer immunotherapies reactivate anti-tumoral immune cells to kill cancer cells
What is Cancer?
There are hundreds of different types of cancer!
But all are characterised by:
cells containing mutations in critical ‘driver’ genes
many mutations cause uncontrolled proliferation,
i.e. cells divide all the time
A ’tumour’ is a tissue swelling that is considered
malignant if it has begun to invade local tissues
A cancer is metastatic when invading cells spread
via blood or lymph to colonise distant organs
How does a cancer begin?
Cancer is the 2nd leading cause of death globally
Exposure to risk factors causes ~45% of cases
Risk (carcinogenic) factors cause gene mutations:
Smoking → lung and many other cancers
Alcohol → liver and other cancers
Obesity → colorectal, breast and others
UV irradiation → melanoma
Asbestos → mesothelioma
“Driving a Car” Analogy
To move a (manual) car forward, several steps must occur:
correct gear selected!
hand brake off!
clutch engaged!
foot brake off!
foot on accelerator!
tumour cells accumulate a number of mutations (capabilities) to evade
normal cellular controls on survival, proliferation and other factors
mutations occur in a limited number of key genes (oncogenes)
these are ’driver mutations’ (others are ‘passenger mutations’)
Cancer mutations target one or more intrinsic control
mechanisms in cells to overcome their defences
Altogether at least eight mechanisms must be
overcome to produce a lethal, invasive cancer
Evolution of Cancer Treatments
Originally surgical - excision or debulking
Radiotherapy - ~100 years old
Chemotherapy - since the 1940s
Biological therapies - e.g. B/M transplants
Targeted therapies - since 1990s
Immunotherapies - since 2010
The first chemotherapy drugs
Sidney Farber - low folic acid in a type of anaemia
(megaloblastic)
Gave children with ALL folic acid but proliferation ↑!
So made folate analogues that acted as anti-folates and
produced ALL remission → anti-metabolites
Mechanisms of action of classical
chemotherapy drugs
Cancer cells proliferate uncontrollably → replication of their DNA for
cell division or function is essential for cancer cell proliferation
Therefore, most traditional anticancer drugs target cancer cells by
interfering with DNA synthesis and/or function through:
chemical damage to DNA → cross linking of strands and
damage to single strands
impaired synthesis of DNA bases → pyrimidines & purines
inhibition of transcription → DNA can’t uncoil
…but anti-mitotics inhibit mitosis
The first chemotherapy drugs
Mustard gas used in WWI
WWII bombing of Allied ships carrying mustard gas →
survivors had depleted bone marrow & lymph nodes
Nitrogen mustards → more stable derivatives developed
(Goodman and Gilman) to treat lymph cancers
(lymphomas) → alkylating agents
Further chemotherapy drug development
1950s - natural plant extracts (periwinkle) with cell
killing activity (cytotoxicity) noted
Found to target microtubules (green) in the cell
division spindle → drugs either stop spindle forming
or stop it breaking up → anti mitotic chemotherapy
Further chemotherapy drug development
1950-60s - antibiotic screening following success of
penicillin → anti-tumour effects were noted in some
Triggered hunts for more anti-tumoural antibiotics
→ cytotoxic antibiotics
- Alkylating Agents
Oldest class of chemotherapy agents (developed from mustard gas)
For example - cyclophosphamide
‘Platinum’ drugs - newer group developed in 1960s, e.g. cisplatin
Alkylate - add a methyl (CH3) or ethyl (CH2-CH3) group to guanine (G)
bases to damage or cross link DNA
Damaged and cross linked DNA leads to:
breaks in DNA strands
cross-linked DNA - can’t be replicated or transcribed
causes cancer cells to die
- Anti-Metabolites
Deprive proliferating cells of the building blocks they need for DNA synthesis
Two main groups:
Folic acid antagonists (Sidney Farber) -
deplete folate in cells, which is needed to
make purines (G & A), e.g. methotrexate
2. DNA base analogues - conceptually easier
as the drugs look like pyrimidines (C & T),
purines (G & A) or their nucleoside
analogues, e.g. 5FU, 6-mercaptopurine
- Mitotic Inhibitors of Natural Origin
Interfere with mitotic spindle formation or breakdown
The spindle is formed of microtubules of polymerised tubulin
- Mitotic Inhibitors of Natural Origin
Two main groups:
1. Vinca alkaloids - from the periwinkle → block polymerisation, e.g. vincristine
2. Taxanes - from bark of the pacific yew → block depolymerisation, e.g. docetaxel
- Cytotoxic antibiotics
Antibiotics or their derivatives with powerful cytoxic (cell killing) activity
- Cytotoxic antibiotics
Two main groups:
1. Anthracyclines - block uncoiling of supercoiled DNA by inhibiting the
enzyme topoisomerase II, e.g. doxorubicin
2. Bleomycin - damages DNA
Major Side Effects of Cytotoxic
Chemotherapy Drugs
Systemic agents - systemic effects → also
affect rapidly proliferating normal tissues:
Targeted Therapies in Cancer
Drugs targeting oncogene-driven signalling pathways
Not just highly proliferative cells
Oncogene = a mutated form of a proto-oncogene
Proto-oncogene = a gene that regulates normal cell
growth and division, i.e. proliferation
BUT survival has ↑↑ with
classical chemotherapy
survival rates have ↑↑ in many cancers, especially
paediatric cancers, leukaemia and lymphoma
for example:
BUT survival has ↑↑ with
classical chemotherapy
ALL
but new approaches are needed, especially
for solid tumours targeted therapies
- paediatric ALL
- Hodgkin’s lymphoma
Gastrointestinal tract → mouth ulcers, nausea &
vomiting, diarrhoea
Hair follicles → hair loss, esp. alkylating agents
Blood forming cells → infections (↓white cells),
anaemia (↓red cells) and bruising (↓platelets)
Drug class specific effects - neurotoxicity,
nephrotoxicity, cardiotoxicity, pulmonary fibrosis
Targeted Therapies
Inhibit oncogene-driven signalling pathways in
cancer cells → targeted enzymes are kinases
Inhibitors → only target mutant proteins via
two types of drugs:
Antibodies - humanised proteins, target
extracellular regions of receptors activating
growth pathways (or their ligands)
Small molecule inhibitors - enter cells to
block kinase’s enzymatic function inside cells
Switch off downstream pathways that control
proliferation, survival, growth and migration
Imatinib & CML
unusual leukaemia in which almost 100% of cases
are driven by a single molecular event → reciprocal
translocation Chr9q:Chr22q
produces a unregulated ‘fusion protein’ kinase →
white cell (myeloid) proliferation
a drug was designed to target
the unregulated Abl kinase
Imatinib switches off Abl
kinase signalling
like a key in a lock
dramatic ↓ in CML mortality
Trastuzumab (Herceptin®)
HER2 gene is amplified in 15-20% of breast cancers
Trastuzumab is a humanised antibody directed to the
HER2 protein’s extracellular domain
Antibodies are proteins → must
be administered IV
Given in combination with traditional chemotherapy
Significantly ↑ survival in a type of breast cancer
previously associated with a very poor prognosis
Even with late-stage, metastatic disease
But targeted therapies usually don’t
work for very long
Imatinib and Trastuzumab are unusually successful kinase targeting drugs
Other kinase inhibitors often dramatically reduce a cancer’s size initially
then they stop working and the cancer grows back again very quickly…
… because cancers develop mechanisms to overcome the drug → resistance
e.g. cancer cells acquire new mutations that block access of the drug to the
catalytic pocket of the kinase enzyme
i.e. if a drug ‘key’ can’t get into
the lock, it can’t ‘lock’ the protein
additional approaches are
needed immunotherapies
…target immune checkpoint molecules
T cells that kill cancer cells are called cytotoxic T cells
their activity is tightly controlled so they
are switched on only when needed
too much cytotoxic T cell activity in the
body leads to damage of normal cells
controls exist to keep activation in check
→ immune checkpoint control
mechanisms, e.g. PD-1 receptor on T cells
Cancers alter the immune checkpoint balance:
e.g. they suppress cytotoxic T cell activation by
expressing PD-1’s ligand → avoid elimination
Immunotherapy
Immune checkpoint inhibitor drugs:
Nivolumab - blocks PD-1 so PD-L1 on cancer cells
can’t interact with PD-1 on cytotoxic T cell
Cytotoxic T cells reactivated → kill cancer cells
Ipilimumab is another type of checkpoint inhibitor
Immune checkpoint inhibitors
produce long term results
Some patients with metastatic
melanomas and kidney cancers
have been ‘cured’ of their disease
Treating Cancer - Summary
Cancers develop and progress in a step-wise manner through
accumulation of mutations that overcome intrinsic cellular defence
mechanisms
Traditional chemotherapies target highly proliferative cells to:
cure cancers in many patients
cause significant side effects by also affecting normal cells
Targeted therapies have specific tumour cell molecular targets:
oncogene-driven cancers, e.g. BCR-Abl in CML, HER2 in breast cancer
Immunotherapies have specific immune cell molecular targets:
exhausted immune cells (T cells), e.g. nivolumab, ipilimumab
