Oncology v0.2
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Transcript of Oncology v0.2
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Understand the difference between enteral and parenteral nutrition
Plus it's really expensive (to produce and administer because it's sterile ANDneeds to be given with a needle)
Can even lead to intangible costs, like psychological changes
It's annoying to the patient (invasive)
And complications can arise, like phlebitis (inflammation of veins) or infections
etc.
Important point: Use the gut if you can, or as soon as possible. If the gut is partially
working, use it as much as possible. This is to prevent loss of function in the gut.
Terminology (might want to skip this and read this as a summary)
Parenteral nutrition is nutrients given from a route outside the gut (see below)
Total Parenteral nutrition (TPN) is where the patient gets 100% of their nutrients,
needs to be a large volume and is completely water soluble. We will preparethese quite frequently
Peripheral nutrition is smaller volumes delivered via a peripheral vein
Nutritional support is delivering a constant stream of nutrients to the blood (can
be either enteral or parenteral) for special cases like cystic fibrosis (can't get
enough nutrients quickly due to thick mucus layer)
Basic differences
Basically, enteral means through the gut (GI system), while parenteral is
anywhere but the gut
Orally
Different tubes (e.g. nasogastric tubes)
Stoma (piece of gut is exposed to the environment)
Enteral could be given:
Generally more suitable for larger volumes which are not iso-
osmolaric
Therefore, can be used for long-term Total Peripheral Nutrition (TPN,
where all their nutrients are delivered this way)
Patients may have protracted diarrhoea, chronic obstructions (orpseudo obstructions) of the GI system, or short bowel syndrome (too
much GI system cut out due to surgery, think about inflammatory
bowel conditions like Crohn's disease or ulcerative colitis)
Central line- Jugular or subclavian vein, but it's inserted via the arm
Generally suitable for smaller volumes, but must be iso-osmolaric
Therefore, used for short terms (like after surgery)
Peripheral line- out in the arm
Parenteral is generally giving via IV (can also be IM or IC) which can be at two
different sites
OVERALL: the goal is to get nutrients into the bloodstream of the patient. The gut
processes larger molecules into smaller ones, while parenteral nutrition focuses
on getting these nutrients directly into the bloodstream to bypass the gut
Aseptic Dispensing
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Contents of nutrition liquids
Both types of liquid will contain all the components of the food we normally eat,
such as carbohydrates, fats and amino acids, trace nutrients etc.
Enteral formulations are quite simple, being made from more complex moleculeslike proteins and long chain carbohydrates
In addition, because it's being added centrally, we need to make sure it's
compatible with the blood
Which means the fats need to be suitably water solubilised (as a
suspension) and the osmolarity may need to be adjusted.
Parenteral formulations need to have these complex molecules to be broken
down to simple molecules, BECAUSE the gut is being bypassed (remember: the
gut is normally responsible for the important function)
Understand the importance of adequate nutrition in debilitated patients whether in
hospital or in the community.
You need to eat, it's kinda important.
Effects of malnutrition
So obese people are technically malnorished due to a lack of balance
Malnutrition is where a proper balance of nutrients isn't achieved
Leads to breakdown of various proteins and organ failure
Patients can be in a catabolic state, where their body is breaking down
proteins because the person isn't getting enough nutrients
Leads to tiredness, exhaustion and death
Patients could be in a normal metabolic state, but might not be getting
enough energy
There are two types of malnutrition we can look at
Costs of malnutrition
Slower healing times (longer visits are more expensive)
Increased chance of infection
Other complications, like muscle wasting (catabolic state)
Costs of product and production (aseptic production is costly)
Tangible
Psychological
Non-tangible
Refeeding syndrome
Arnold Lee
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Insulin secretion is tied to several electrolytes, such as potassium intake
into cells and phosphate
Leads to a reduction of electrolytes inside cells
After a long time of starvation, the body will adapt slowly to changes, such as
reducing the insulin secretion
Causes death due to a multitude of problems
If a person is suddenly fed a lot of food after this state, insulin secretion will kick
in and cause electrolyte imbalance (especially blood phosphate decreases due to
absorption into cells)
Appreciate the role of the pharmacist in an Aseptic Production Unit (APU) with regard
to parenteral nutrition
Aseptic versus Sterile
VERY important difference
Usually achieved with autoclaving or high temperatures etc.
Sterile is an absolute, a black or white state where the product contains no
contaminants whatsoever.
Does not guarantee sterility, but it's hoped it's sterile
i.e. this definition isn't as black and white when it comes to contaminants
Aseptic production is where a product is prepared from sterile products in a very
clean (aseptic) workplace.
Examples are bacteria, viruses or even fungi
Viable contaminants are able to grow and give someone an infection (can
lead to death by sepsis)
Examples are bits of glass or dustFILTERS ARE IMPORTANT, they keep them out to prevent this issue
Non-viable contaminants can't grow, but still cause problems, such as
occlusion of blood vessels or may be pyrogens
Contaminants come in viable and non-viable flavours
TPN bags
May be divided into three compartments (glucose, amino acids and fat
compartment) for enhanced stability. Must be combined before use
Note: after combination, inspect bags for creaming of the lipid suspension
(this is where the suspended lipids gather together to form larger particles,
might kill your patient if given)
TPN bags contain a liquid for TPN
TPN bags can generally be purchased and given in that state
Gives a lot more flexibility, tailoring it to specific patient requirements, but
this is very costly due to running the APU and hiring a pharmacist to make
it.
But they can be individualised within an aseptic production unit (APU)
Understand the principles behind aseptic preparation AND Be familiar with basic
aseptic manipulation
Skin particles carry stuff
We could cough or sneeze stuff outTherefore, we need to wear appropriate protective equipment
We are the number one source of contamination
Regularly checked to see if it's clean (taking swabs to see if anything will
grow)
Within the APU is a clean room
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Air is filtered
Everything is flush against the wall (no overhangs or anything)
Horizontal cabinets blow air towards you, protects the product only (which
means it can blow nasty chemicals like cytotoxics in your face)
Vertical flow cabinets will blow air downwards, protecting both the product
and the operator.
A laminar air flow cabinet is in these clean rooms
Generally speaking, these points are where the liquid is going to touch theequipment
This includes needle/syringe/filter tips, the inner ribs of the syringe etc.
Make sure you don't touch critical points
Reconciliation is where the products taken into the clean room are
matched with what's leaving the clean room.
This is in addition to other standard operating procedures, error reports,
GMP requirements etc.
Make sure the paperwork gets done
There's a window which allows you to observe and check on the tech.
NOTE: the person in the clean room might be a technician. Therefore, we are
responsible for anything they do
Why is safety important?
These cytotoxics are carcinogenic/toxic so we need to protect the people
handling these compounds
Protect staff
Prevent complications
Protect patients
Administration
Short infusions for cytotoxics (or peripherial nutrition) need to be
controlled specifically by a pump
Advantage is this allows for greater mobility, can let them go home
instead, saves the hospital money.
Longer infusions (such as for TPN) can also be controlled by a pump, or
they may use an elastomeric pump, which uses rubber to push liquids at a
slow rate.
TPN or cytotoxics are usually not delivered by the pharmacist, but they need totell these people how to.
Potentially fatal mistake with vesicants (blistering agents)
"Not for intrathecal (spinal)" use is NOT acceptable. Use "For IV use
only"
Be as specific as possible
Be careful to check it's the right patient, dose etc.
Because we need to tell how these medicines are used, we need to be very clear
when writing labels
This is where the IV fluid leaks out into the surrounding tissues (so it's
called being 'tissued' by nurses)
Patients need to be told to report discomfort or pain ASAP
In the case of vesicants (blistering agents) this can cause massive necrosis.
Be wary of extravasation
Intrathecal drugs tend not to be given very often, so the pharmacist incharge will personally deliver it to prevent mistakes
Also, you can only give a few millilitres via the intrathecal route (larger
volumes are used for IV route), so the size difference should tip off the
nurses as well
Note: For intrathecal drugs
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Patient Information
Such as for extravasation
Or if the elastomeric pump breaks at home
How to counter side effects (like anti-emetics for vomiting)
Need to tell the patient what to do
Can vary greatly between patients and within patients
e.g. changing organ function, reduced effect or tolerance etc.
Doses
Biological (contamination)
Chemical (reactions occurring)
Physical (precipitation or light sensitivity)
Stability
Allergies
Pregnancy (debatable, risks to foetus need to be considered)
Contraindications
Check for:
We need to know what can happen, and may have to advise on how tocounter them
Important information is the side effects which will affect the patients
Adverse reactions
Note: REMEMBER, the cytotoxics will usually affect growing cells. These side effects are
usually caused by affecting dividing cells like the bone marrow or mucosal surfaces etc.
Oral and GI mucosal damage due to cytotoxics affecting their regeneration
and repair
Oral hygiene becomes much more important
Patients need to report abdominal pain or bleeding
Mucositus
White blood cells and platelets are reduced by cytotoxics
Must report bleeding due to reduced platelets
Can also cause neutropenic sepsis (means low neutrophils plus infection)
where temperature is high, chills, sore throat, pain on urination etc.
Myelosuppression/immunosuppression
Lysis of tumour cells releases calcium, uric acid and potassium
This can lead to gout, need to treat with allopurinol and keep hydrated
Tumour lysis
Hair grows back wavy
Usually temporary and not harmful, but don't let the patient be surprised
Alopecia
Be competent at calculations
Sometimes we might be adding extra nutrients or electrolytes to the TPN bags for
specific requirements for the patient. So we need to be able to make calculations.
Generally, we already have these electrolytes in a solution, so we need to know what
volume of these liquids we're adding.
Try to understand why the calculations/formula works. Saves you from having to
rote learn AND helps to pick up on any mistakes
Potassium ions can be supplied by potassium dihydrogen phosphate or
Watch out for other sources of electrolytes!
General tips:
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So when you're adding phosphate, you have to add potassium
potassium chloride
The TPN bag might come with some electrolytes, make sure you take away
these electrolytes from your calculations
Premade TPN bags can generally hold 20% more fluid /)^3^(\
In other words, adding calcium gluconate just after potassium dihydrogenphosphate (or vice versa) will lead to calcium phosphate formation
This is VERY BAD, because calcium phosphate is insoluble, it will block your filter
or piss off your patient with phlebitis if you don't kill them first
Don't replace filters, they can cost $5US per filter
To avoid this problem, just use another solution first (like sodium chloride if you
have to add it) OR just rinse with water for injection
Important consideration: Calcium phosphate WILL form if calcium ions are in contact
with phosphate ions
Example calculation
A patient needs 68mmol potassium ions and 40mmol phosphate ions in the TPN bag.
The TPN bag already contains 48mmol potassium and 20mmol phosphate. You havethe following solutions available:
Potassium chloride 2mmol/mL (contains 2mmol/mL of potassium)
Potassium dihydrogen phosphate 1mmol/mL (contains 1mmol/mL of potassium and
phosphate)
What must you do to fulfil the prescription?
Start off by calculating how much of each electrolyte you need. In this case, the TPN
bag already contains some of the electrolytes, so we need to subtract them:
Potassium: 68mmol - 48mmol = 20mmol
Phosphate: 40mmol - 20mmol = 20mmol
We can see both are short by 20mmol, but we have two solutions we can use.
We can't use potassium chloride, otherwise we'd have an excess once we try to add the
phosphate because the phosphate solution also has potassium in it.
Lucky for us, the shortage is a 1:1 ratio, so we can just use the potassium dihydrogen
solution only to make up the 20mmol shortage.
Now, we know each 1ml of the solution contains 1mmol of both potassium andphosphate, but we need 20 mmol of both, so we divide 20mmol by 1mmol/mL
20mmol / 1mmol/mL = 20mL
Notice how the units will fit (mmol will cancel each other out, and since the ml is on the
bottom, it gets flipped up after division), showing you did the right type of calculation
So the answer is we need to add 20mL of potassium dihydrogen phosphate to the TPN
bag to fill the prescription.
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Objective: Understand the biological basis of cancer
Tightly regulated with several checkpoints
Cell division occurs through the cell cycle
The process is called oncogenesis
Suppressor genes
Proto-oncogenes/ Activator genes
Associated with two families of genes
Cancer occurs because cell growth becomes unregulated
Inherited
Chemical
Physical
Infectious
Several factors are known to damage cells to cause them to have their growth
unregulated
Summary
The cell cycle
G0- "Growth 0" phase. The cell is at rest, no division is occurring (lots of cells are
like this in the body, as they are terminally differentiated)
The instruction can be from a hormone, growth factor, a change in local
conditions etc.
G1- "Growth 1" phase. The cell prepares to divide, BECAUSE it's received an
instruction to divide. As a result, it will now synthesise proteins and enzymes
required for division
Antimetabolites, such as methotrexate will work here
S- "Synthesis" phase. The cell will now replicate DNA. This is the longest stage
clocking in at 6-8 hours.
G2- "Growth 2" phase. The cell has two copies of DNA, and it will now produce
proteins required for mitosis to occur. Takes 2-3 hours.
Oncogenesis
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Antimotility agents, such as paclitaxel will work here
M- "Mitosis" phase. The cell will now split, taking one copy of the DNA, to
produce two identical cells. This is the shortest phase, clocking in at 1 hour. The
cell will now return to G0 phase, and can re-enter the cycle if stimulated.
A homeostatic mechanism exists in the body to keep things under control
Cells will be killed off due to apoptosis over time
While other cells will be triggered to grow to replace these dying cells
Normally, we would expect the number of dying cells to equal the number of
cells created to keep the number of cells in the body constant
So the cell cycle is tightly regulated to stop this from happening
If the homeostatic mechanism fails, then we get cancer.
Cell division checkpoints
DNA damage is harmful to cells, as it can cause a loss in function, which includes
not making a correct protein, or it could even become cancerous.
Once that mutation passes down through the cell cycle, it becomes fixed
into the DNA permanently, because the cell doesn't have an original copy
of the DNA to check against.
Therefore, cells have defence mechanisms against mutations from being passed
down during mitosis
G1 arrest- the cell cannot enter the cell cycle
G2/M arrest- the cell cannot enter mitosis
If the cell fails to pass the checkpoint test, the cell cycle is immediately
halted to allow for repairs to occur before continuing:
If the DNA cannot be repaired, the cell will undergo apoptosis
So the cell cycle has several 'checkpoints' where the integrity of the DNA is
checked to stop mutations from occurring.
p53 is especially important, as it is a part of the G1 checkpoint, can induce
DNA repair and induce apoptosis if needed
Therefore, many tumours will have p53 deactivated
p53 and the Rb (retinoblastoma) genes are important in cell cycle control, as they
will regulate the cell cycle.
Telomeres are straight pieces of DNA at the end of a chromosome
The straight ends cannot be perfectly copied, so they shorten with each cell
division
Once the telomeres are short enough, the cells are triggered to undergo
apoptosis
The reason for this is to make sure cells have an automatic 'expiry date' to
prevent them from accumulating too many mutations, and becoming
cancerous.
Therefore, it's also another common mutation seen in cancers
To counter this, a cancerous cell can activate telomerase, which increases
the length of the telomeres to prevent apoptosis from being triggered
Another important mechanism is the use of telomeres
Oncogenesis
Remember: the cell cycle is tightly regulated, so the cell has quite a few
barriers which it needs to overcome to become cancerous
For example, to become cancerous, the cell would have to ignore apoptotic
signals (p53), grow independent from growth factors, have factors to
promote angiogenesis (production of blood vessels), avoid the immune
An important fact is one mutation is not enough to cause cancer
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system etc.
But if the checkpoints are non-functional (either inherited or mutated),
then it's much easier for these mutations to occur, so it's easier for the cell
to become cancerous
REMEMBER: normally a person will carry two copies of the gene, both must
be broken to get cancer ('dominant' gene, so hetrozygous people are still at
higher risk of getting cancer as a result)
Normally, these mutations will be prevented by the checkpoints put in place
If you live long enough, by chance you will accumulate enough mutations
Because the cell needs multiple mutations to become cancerous, cancer is adisease which is concentrated in the elderly
Suppressor genes
Activator genes (proto-oncogenes)
Also, there are two main groups where mutations will cause cancer, as they are
important for regulation of cell growth:
p53 is again an important suppressor gene, as it contains apoptosis genes
If BRCA is mutated, the incidence of breast cancer shoots through theroof
BRCA is an important suppressor gene as it is involved in double stranded
DNA repair
Anything inhibiting growth, such as growth regulator genes are important
Contact inhibition genes- normally these will stop cells from dividing if they
are in contact with each other, as it indicates there's no space to grow.
Suppressor genes will work to prevent cancer, so these should be kept ON
Angiogenic genes are very important in tumours, as the tumour must be
able to get a blood supply set up to grow properly. Otherwise the tumours
will be small and most likely unsuccessful.
Some genes will allow cells to escape immune surveillance, or be
immunosuppressive
Others will help them survive outside the tumour, which allows distant
metastasis to occur (surviving outside the original tumour is quite difficult)
Activator genes are also called proto-oncogenes, as normally they are not
cancerous, but if mutated, will cause cancer. Therefore, to prevent cancer, these
should be kept 'INACTIVATED' (not completely off, normal body function might
need them, like healing)
How do we get cancer?
As stated before, you need functional suppressor and non-activated
activator genes to NOT have cancer.
Sometimes, people will inherit a non-functional copy (or copies) orsuppressor genes
Or receive one (or two) copies of an activated activator gene
Think about it as they've already accumulated mutations required for
cancer.
Therefore, these people are at a higher risk of getting cancer
Inherited
Carcinogens are chemicals which will cause damage to DNA (either directly
or indirectly through metabolites/breakdown products)
Again, these mutations need to hit a suppressor or activator/proto-
oncogene.
Chemical
Direct damage to DNA
Ionising radiation
Non-ionising radiation
Physical
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Damage via production of radicals
Either will cause DNA damage, which might give you cancer if the wrong
genes are turned on/off (see above)
Quite a range of viruses can do this
Why? Because p53 can trigger apoptosis and ruin their plans
Human Papillomavirus (HPV) and Epsein-Barr virus
Can inhibit p53
This is probably why hepatitis B and C cause liver cancer
Cause increased division, which leads to more chances of being mutatedand causing cancer
Yeah this can only end badly
Seen by retroviruses (can enter the host's DNA) like HTLV-1 or HIV
Insertion into oncogenic gene
Infectious agents
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Chronic inflammation can cause cancer
The immune system can kill cancerous cells
Can be thought of having a role before AND after cancer
The immune system has a role in cancer (surprise!)
Chronic inflammation and oncogenesis
Inflammation produces some reactive oxygen species which may damage
DNA, causing activation/inactivation of genes
Inflammation also encourages division of some cells (especially immune
cells) which can lead to cancer
It appears chronic inflammation can cause cancer
NSAIDs have some effect for protecting against cancer
Therefore, anti-inflammatory cytokines or chemokines may be used to prevent
cancer.
Immune response AGAINST cancer
Destroys the infectious agent which can cause cancer
Kills any cancerous cells before becoming a tumour
How is the immune system protective against cancer?
Neutrophils, macrophages and dendritic cells
Detect foreign cells, and abnormal body cells (due to infection or
cancer) to trigger an immune response (produce cytokines and stuff),especially trigger the acquired immune response
Slow down the infection long enough for the acquired immune
system to kick in
Innate immune response is the first-line protection mechanisms
T Lymphocytes for a cellular immune response, B lymphocytes for a
humoural (antibody) response
Produces more effective killing cells (natural selection, where
lymphocytes with the best receptor against the antigen is stimulated
more)
Produces memory cells to prevent long term recurrence
Acquired immune response is the killing blow
The requirement of a danger signal will also prevent any self-reactive
cells from being activated as well
Self-reactive cells are killed off during thymic selection to protect the bodyagainst auto-immune reactions
Recap: innate immune response vs acquired immune response
All nucleated cells are able to get cancerous
But all nucleated cells must express MHC-I
The MHC-I is continuously recycled from displaying an antigen and being
drawn back into the cell to find a new antigen to display
Normally, the immune cells will see all the MHC-I receptors displaying
normal body antigens
But if the cell becomes cancerous, it might start producing antigens the
immune system can't recognise
This will lead to an immune response, and destruction of the cancerous
cells
So How does that help against cancer?
The role of the immune system in cancer
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Because it's MHC-I, it needs the CD-8 co-receptor to stimulate CD8 T
cytotoxic cells
Therefore, the immune response will be mainly carried out by CD8 T
lymphocytes (cellular response)
What kind of immune response?
Well, it's not the same as the diseases we've seen in the pastTumours will make 'Tumour specific antigens' (TSA) which are the mutated
proteins the immune system can't recognise
In addition, they might also make 'Tumour associated antigens' (TAA) ,
which is where the tumour produces proteins which shouldn't belong in
that part of the body
Lastly, an infectious agent can be causing cancer, these cells will display
viral antigens to become a target for the immune system as well.
Don't we have to worry about auto-immune reactions?
Danger signals can come from infected cells at least
Also, if a tumour does form, then the centre of the tumour may becomenecrotic due to reduced blood supply to the region. The immune system
will respond to necrosis with inflammation.
If cells are kept in anergy, how do we activate them against cancer?
Plus they are more likely to be subject to mutations due to
inactivated suppressor genes.
Tumours will be subject to natural selection, because vulnerable
cancerous cells will be killed off easily, leaving cells which are
resistant to immune attack
They can look normal to the immune system by expressing normalantigens on MHC-I
They can shut down antigen presentation (however, see below)
They can produce an environment which can be immunosuppressive
Maybe but cancers can have immune defences
Immunosuppressed due to drugs, infectious agents or radiation
Plus as people get older, their immune system strength decreases
Or the person just can't mount a response
The immune system decides to induce tolerance against the tumour
cells, preventing any immune cells from attacking it
Or the tumour cell or supporting cells will produce
immunosuppressive factors like cytokines
So one important result of treatment (radiation, chemo or surgery) is
to kill off these immunosuppressive cells and let the immune system
clean up
Or the person produces the wrong response
So our immune system should work against cancer effectively right?
It's one method to prevent the immune system from noticing
But Natural Killer (NK) cells will be able to detect if a cell is missing MHC-I
NK cells are always set to kill, so they need an inhibitory signal to prevent
the cell from being killed
MHC-I provides the inhibitor signal, so cells with MHC-I will survive
Cells which do not produce display MHC-I cannot send the inhibitory signal,and so they will die.
What if the cell stops producing MHC-I?
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Why is it difficult to treat cancer?
Narrow therapeutic range due to targeting the same pathways used by our
healthy cells
We can counter this by combining several drugs at lower doses to prevent
extreme toxicity
The amount of cells we can kill is limited by toxicity
Leads to increased drug resistance
Use multiple drugs to help to prevent increased resistance
Cells are rapidly dividing, and the genomes are prone to mutation due to damaged
repair/error checking mechanisms
Brain and testes
They can escape to safe sites in the body, where it is hard to get drugs or immune
involvement in
Therefore, we need to apply chemotherapy as soon as possible
By the time we're treating the cancer, it's already growing slowly, and is less
receptive to chemotherapy
Combination therapy
Again, results in better response (synergy) and reduced side effects and a lowered
chance in gaining resistance
Each drug should work against the cancer
Each drug should have a different mechanism of action
Drugs should avoid overlapping toxicities
AND include a few which are non-cycle specific
Reason for this is because only a certain portion of the cancerous cells
will be in the part of the cell cycle, combining the two leads to a better
outcome
Target different stages of the cell cycle
There are a few principles you should keep in mind:
Infusion over time or frequent dosing
Think of it like the time-dependant kill antibiotics, a long period of
time is preferred
Cell cycle specific drugs need to achieve high concentrations over a long
period of time, as different cells will enter that specific part of the cell cycle
at different times.
One fast infusion
Think of it like the concentration-dependant kill antibiotics, where the
highest concentration needs to be achieved
While non-specific agents just need to be given in one single high dose
The dosing of a cell cycle specific vs. a non specific agent is different:
Surgery causes injury which stimulates cells to come out of G0
Therefore, can hit more of the cancerous cells
Cell cycle specific drugs should be coordinated with surgery
Allows the body's normal tissues to recover from the chemotherapy
But the waiting time between treatments is short enough to prevent the
cancerous cells from
Drugs are given in treatment cycles
Pathways for antimetabolite drugs to target:
Pharmacology of cytotoxic drugs
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Inhibits dihydrofolate reductase (DHFR)
Stops the conversion of dihydrofolate to tetrahydrofolate to stop the
production of all nucleotides
Countered by the cancerous cells by increased efflux or a mutation or
upregulation in DHFR
Methotrexate (MTX)
Inhibits Ribonucleotide reductase (RR)
Stops the conversion into deoxyribonucleotides, as that's the form needed
to be incorporated into DNA
Hydroxyurea
Inhibits IMP dehydrogenase (IMPDH)
Stops purines from being made (A as AMP and G as GMP)
6-Mercaptopurine (6-MP)
Inhibits thymidylate synthase
Prevents the conversion of dUMP to dTMP to cause a thymineless death (a
pyrimidine)
5-Flurouracil (5-FU)
Not shown above
Inhibits DNA polymerase
Stops nucleotides from being added to DNA to stop production
Cytarabine
Azathioprine and 6-MP metabolism
Azathioprine is metabolised to 6-MP
Highly polymorphic
Fast metabolisers will produce too much toxic side products
Slow metabolisers will accumulate 6-MP leading to toxicity
6-MP is metabolised by TPMT (Thiopurine methyltransferase)
This is the enzyme which is inhibited by allopurinol
6-MP is also metabolised by xanthine oxidase
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6-MP tends to be given to patients who need allopurinol to combat tumour
lysis syndrome
Adjust dose of 6-MP down to compensate
Folinic acid
Not to be confused with folic acid
Folinic acid can be converted by another enzyme to several different forms, like
THF or MTHF, which can readily be used by the cells of the body
If it is used with 5-FU, it enhances the cytotoxic effect, as MTHF, a cofactor for the
thymidylate synthase enzyme is required for binding and inhibition
Methotrexate depletes useable folate reserves (as THF) as dyhydrofolate
reductase has been inhibited
i.e. stops DHF from being recycled into THF
Cancerous cells are too damaged by this point to be saved by this
folinic acid rescue
Folinic acid rescue after methotrexate use will allow healthy cells of the
body to produce nucleotides to prevent side effects
BUT it could also be used with methotrexate.
Mitotoxicity hypothesis
DNA damage in normal cells will lead to apoptosis
Therefore, the point of using of agents is to try and stimulate the cancerous cells
to undergo apoptosis
p53 induces apoptosis, it is a part of the G1 checkpoint of the cell cycle
These cancers are responsive to treatment, as p53 induces apoptosis
Leukemias and lymphomas
Some cancers will keep a normally functioning copy of p53 (wild type)
Minimally responsive to treatments
Lung, pancreatic and colon cancers
Other caners will get a mutation in p53, apoptosis isn't easily induced
Problem is, it depends on the function of certain genes/proteins like p53
Telomeres
2-30 kilobases which repeats 'TTAGGG'
A 50-300 base single stranded section will loop back onto the DNA and form
a stable loop (t-loop)
Caps at the end of chromosomes
DNA polymerase isn't able to copy this section perfectly, it shortens with each
replication
Therefore, old cells which may have gained a lot of mutations won't be
allowed to grow anymore
Once it reaches a critical length, p53 steps in and prevents the cell from passing
the G1 checkpoint, forcing the cell into senescence (remain in G0 forever)
Inactivated version of p53 and
Activation of telomerase, which is an enzyme which adds to the length of
telomeres, making them grow again.
But cancer cells can get around this:
These two mutations will cause a cell to become immortal
Photodynamic therapy
Experimental therapy which has drugs which produce reactive oxygen species
when exposed to light
Looks like iron contained within a polyphoryn ring
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When struck by light, the iron will catalyse the production of free radicals
Allows for some targeting to specific sites of the body
DNA repair systems
Caused by natural errors
Mutations can lead to colorectal cancers
Mismatch repair
Single strand breaks (caused by alkylating agents and irinotecan)
BRCA1 and 2 are slower as they are made for double strand breaks
PARP1 repairs these, but if it is inhibited, BRCA1 and 2 can take over
Base excision repair
Addition of substances (such as alkylating agents)
Nucleotide excision repair
Double strand breakages (topoisomerase inhibitors and bleomycin induces
this, along with cross-linked DNA due to alkylating agents)
Homologous recombination repair assisted by BRCA is the best bet, which is
where the sister chromatid (remember you carry two copies) lends its
information to help join the two strands together
Non-homologous end joins is less safe as there's nothing to check against
Double strand break repair
Topoisomerase I inhibitor- irinotecan
Relieves coiled tension within the DNA strand (double helix)
Topoisomerase I is involved in uncoiling the DNA prior to replication
The enzyme will separate the two strands of DNA
Cuts one strand
Unties the strand by passing it over the other strand
Joins the two cut pieces together to complete the unwinding
Current model for inhibition is:
Actually is metabolised into SN-38 which is 1000x more active, but it's highly
protein bound and has a very short half life
It is cleared by UGTA1, which is lacking in Gilbert's syndrome. Stops the
SN-38 from clearing, leading to severe myelosuppression
Irinotecan will stop the ends from being joined together, leading to a single strand
breakage
Topoisomerase II inhibitors
Relieves coiled tension BETWEEN DNA strands (not within the strand)
Relieves supercoiling of DNA
Cuts both sides of the DNA strand
Passes the strand past another strand to relieve the supercoiling
Joins the two ends back together
Similar action to above
Some drugs like anthracyclines will allow the double strand breakage, but won't
allow it to come back together
Anti-mitotic drugs
Important during the M phase to pull apart and drag the chromosomes
Both classes of drugs lead to peripheral neuropathy
Also important for intracellular trafficking of chemicals with vesicles
Attaches to tubulin, which makes up microtubules
Vinca alkaloids bind to the positive end of beta tubulin to prevent polymerisation
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of the chain
Taxanes on the other hand will bind to the side of beta tubulin. It allows
polymerisation, but not depolymerisation (so it become stuck)
HER2 and Imatinib (and other signalling pathway blockers)
Some cancers will have unregulated growth due to expressing growth receptors
We can block these receptors to prevent growth
Use Herceptin (trastuzumab)HER2 is a receptor which can be expressed in breast cancer
Imatinib blocks a tyrosine kinase associated receptor to prevent growth in Chronic
Myeloid Leukaemia
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Intro
Otherwise, the chemo can kill the patient before it kills the cancer
We want to specifically kill cancer cells over normal cells (selective toxicity)
Compared to antibiotics, which exploit differences in biochemical pathways
between us and them
Problem is, cancerous cells tend to use the same biochemical pathways as normalcells, which is why it's very toxic
Some normal cells are rapidly dividing (gut, bone marrow, liver) so they are
affected by chemo
But some cancerous cells won't divide rapidly, so chemo won't work well
against them
So we tend to target rapidly dividing cells to target the cancer
Leads to more drug resistance and treatment failure
Rapidly dividing cells are bad for treatment, because they tend to accumulate
more mutations
But it's limited by the toxicity of the drugs
We want to maximise kill count (hopefully on a log scale)
Oral forms are desired
Finally, we also want to have them in a form which is easy to administer
Vesicant- a substance which is able to cause blistering. Quite a few chemo drugs tend to
be vesicants. This is why patients need to be told to look out for redness, swelling,
discomfort or pain around the infusion site.
Alkylating agents
Can't copy or transcribe information from DNA
Trigger apoptosis due to damage
Guanine is generally targeted due to its nucleophilic properties (see below)
Designed to interfere with DNA function
Guanine is alkylated, so there's this massive group attached to it
This can lead to the elimination of the group as well (the base comes
off the DNA, see below)
Either way, the DNA can't work this way, so excision repair enzymes
are activated, to cut the DNA to replace these faulty bases
Because repairs can be made, this isn't effective
Modification of DNA bases (mono-alkylation)
See below for the structure a sulphur mustard
Notice it has two chlorines, so it can alkylate twice
Between chains
Within chains (more common)
It can form covalent bonds either:
This will prevent the DNA from coming apart normally for normal
function
Effective
Cross-linking within and between DNA strands (di-alkylation)
Normally, we'd except A goes with T and C goes with G in DNA
But alkylated G can go with T, which is a mistake
This will lead to mutations
Which can lead to a malfunctioning cell, and apoptosis
Nucleotide mispairing
How does it work? (mode of action):
Medchem of cytotoxic drugs
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Janus is the Roman god of doors. He has two heads, one pointing inside, and
the other pointing out.
People may have secondary tumours which are completely different
to the original tumour after a few years of treatment
Why is this important? Because alkylating agents will kill cancerous cells BUT
because they interfere with DNA, they can also CAUSE cancer.
Exhibits a 'Janus' effect
Below is a sulphur mustard, where there's a two carbon bridge between theS and the chlorines. THIS IS IMPORTANT. RECOGNISE THIS.
Sulphur mustards are gases, due to low intermolecular bond strength (they
don't H-bond to each other) so they are too dangerous to work with
So nitrogen mustards were investigated, because they can H-bond to each
other, so it's not a gas anymore, so it's safer to handle
The alkylating agents will always have a specific moiety
The two nitrogens in the right side ring presents a electron rich regionThis makes it nucleophilic, attacking the alkylating agent (seen as R)
Can lead to the ring opening which permanently binds the agent to
the base
Or can cause the entire group to come off as a leaving group from the
DNA
This addition will lead to a positive charge on the nitrogen, which needs to
be removed.
But remember: monoalkylation (shown below) can easily be repaired
Why is guanine (N7 nitrogen) targeted specifically?
The electronegative chlorine atoms will draw electrons towards itself,
causing the adjacent carbons to become slightly positive
Chlorine is a good leaving group as it comes of neutral with respects to
acid-base chemistry (i.e. even though it's negatively charged, it
doesn't have acid base chemistry)
The non-bonding electron pair (NBP electrons) on the nitrogen is attracted
to the positive charges, leading to intramolecular nucleophilic attack (SNi)
The mechanism of action of alkylating agents is all the same (and we need to
memorise it)
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Bond angles are strained (at 60 degrees instead of normal 108)
Both carbons are positively charged
The SNi leads to the formation of the aziridium ion, which is a highly reactive
electrophile (i.e. susceptible to nucleophilic attack)
Remember: the molecule is bifunctional as it has two carbons, so it
can crosslink DNA (deals more damage)
After nucleophilic attack with the nucleophile (which is likely to be guianine),
the base is now alkylated.
Forms the aziridium ion too easily then, which will just react with all the cells
it comes into contact with
So we need to tie up those NBP electrons to stop forming the aziridium ion
as easily to reduce toxicity, to reduce side effects
If the nitrogen mustard shown above had an aliphatic R group, it is too toxic to use
in people
Alkylating agents- examples
Mephylan
The NBP electrons on the nitrogen are partially taken up into the aromatic ring
It's actually L-phenylalanine (amino acid) attached to the mustard
The sterochemistry on the carbon is R
But it's still actively taken up by all cells, leading to side effects
They thought the phenylalanine would allow the drug to be taken up into growing
cells because it's an amino acid
If the phenylalanine comes off, it's still active because the mustard is intact
If the amino or carboxylate groups are metabolised, again, the mustard is
still intact and it's still active
This drug has some activity, because the NBPs are somewhat available
This is the really important one because we use it quite often
Cyclophosphamide
R
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It is a prodrug, it must be metabolised first:
In fact, the structure shown on the right can be further broken down to form
just a bare nitrogen mustard, which is thought to have most of the activity
The NBP electrons in Cyclophosphamide are completely taken up into resonance,
so no aziridium ion formation can occur, so there is no alkylation.
Need to co-administer with Mesna and make sure to keep the patient very
well hydrated with IV fluids and oral fluids
Mesna (pictured top left below) has a sulfate group purely for solubility and
salt formation, while the active area of the molecule is the thiol (SH) group,
which acts as a nucleophile to bind with the acrolein to form a non-toxic
compound
Problem with cyclophosphamide is acrolein is a side-product which is toxic
Some cancer cells produce a great amount of glutathione (GSH)
Remember: thiol is a nucleophile, the active aziridium ion form is very
attractive
GSH has a thiol group, which can react with the alkylating agent before it
reaches the DNA to deal damage
Therefore, these cells will be resistant to treatment
Thiol groups could also be a hindrance to treatment though
An alkylating agent may be conjugated to a steroid to help it get into specific
cells
It is only effective in cells which have low ALDH (aldehyde
dehydrogenase), which are the well-differentiated blood cells, while
the stem cells of the blood are quite high in ALDH, so they tend to be
protected
Cyclophosphamide is actually quite targeted if you think about it
Lastly, some forms are slightly selective
Alkylating agents- Methansulfonates
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The oxygens are strongly electronegative, causing a great positive charge on
the sulfur and adjacent carbon
Busulfan has two methanesulfonate groups (the two sulfur containing groups on
the sides)
The methanesulfonate group is a good leaving group, so the carbon with thepositive charge is able to attack guanine as well
But because it's got two groups, its able to cross link DNA
Alkylating agents- nitrosoureas
These are the drugs which tend to end in 'mustine'
Very useful for brain cancers, as they are lipophilic enough to pass through the
BBB
Because the non-bonding pairs of electrons on the nitrogen are completely
taken up into resonance, so the aziridium ion can't be formed
Although they look like normal alkylating agents, they don't have the same
mechanism
Instead, through a complicated mechanism, it breaks down to form two positively
charged carbocations which are the active molecules
Platins (alkylating-like agents)
These are not alkylating agents, but shows some similar action (crosslinking of
DNA)
The classical one is cisplatnin
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Cisplatnin is a square planar molecule, with 2 amine and 2 chloride groups in
a cis configuration:
This is because of this equilibrium reaction:
Interestingly, cisplatnin is formulated in normal saline (0.9% NaCl)
If the concentration of chlorine is high (as it is in the blood and in normal saline),
then the equilibrium lies to the left, which is the inactive form
Therefore, platnins are prodrugs
However, if cisplatnin moves into the cells, the chloride concentration is much
lower, the equilibrium moves to the right, and the activated 'aquated' form is
produced (pretty much water chucked on)
The H2O ligand is a very good leaving group
The aquated form is active, because the platinum atom can now attach to the N7
atom of guanine (just like alkylating agents)
However, this is a intra-strand (within strand) crosslink.
This will cause the DNA to have a 90 degree kink due to the shape of
cisplatnin (square planar)
This irregular shape means the DNA is now useless
Because there are two chloride groups, the same process will happen again, whichcauses DNA to become cross-linked
GSH will also bind to platnins to make them useless
We can try to shield the platnin with a bulky group, but this is ineffective
Again, another huge problem is with glutathione
Therefore, we have newer, second generation platnins which are less
reactive/toxic but still just as effective
Cisplatnin is too reactive, it is quite toxic
It has a bi-dentate ligand instead of the two chorines
This slows down the aquation of the platinum, leading to reduced toxicity
Pictured above is oxaliplatnin, a second generation platnin
Antimetabolites
Self directed learning
Up to now, we've looked at compounds which deliberately damage DNA
But antimetabolites will cause DNA damage by preventing the synthesis of DNA,
either by producing false metabolites, or interfering with the enzymes responsible
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Therefore, this class of drugs are S phase specific for the cell cycle
for production
Responsible for producing thymine from uracil, uses tetrahydrofolate (THF)
as a co-factor
Disruption will mean thymine synthesis cannot occur, and the cell will
apoptose due to a thymineless death
The primary target enzyme is thymidylate synthase
Antimetabolites- 5-fluorouracil
5-flurouracil has a strongly electronegative group on the 5 position, which makes it
quite attractive to the enzyme
Note: he doesn't think it's a prodrug, because prodrugs tend to be
catabolised (broken down) to its active form. 5-FU is anabolised (built up) to
its final form due to the addition of ribose and phosphate
It is a prodrug (even though Schmerer disagrees), it must first be converted to its
deoxyribonucleotide form (pretty much just attach some phosphates to it to makeit look something like a nucleotide)
Normally the THF would react with the uracil to form thymine, but this can't
happen due to electrical repulsion between the fluorine and the nitrogen 10
of THF
When it enters the thymidylate synthase enzyme, it causes the formation of a
false complex with tetrahydrofolate (THF) and thymidylate synthase
This effectively prevents thymidylate synthase from being regenerated, which
stops thymine production
This causes the elongation of DNA to be stopped, leading to apoptosis
Additionally, these false nucleotides may also be incorporated into the DNA and
RNA
Anti-metabolites- folate metabolism
As stated above folate (as THF) is an important co-factor for thymidylate synthase
It needs to be reduced back to THF to be used again
After thymine is produced from uracil, the THF is oxidised to dihydrofolate (DHF)
It is able to be inhibited
Also causes a thymineless death
May be used as a synergistic drug with 5-FU, as they both target the same
process
The enzyme folate reductase is responsible for this function
Increases the electron density on the nitrogen at the bottom of the
ring, which is essential for binding
Therefore it will be able to outcompete folic acid
Better substrate compared to the endogenous substrate, folic acid due to
the amine group
Methotrexate will inhibit folate reductase
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Bleomycin
This is a problem, as it is hard to scale up to get large yields
Massive molecule which is synthesised by bacteria
Although a part of the molecule is cut off, DNA binding sites lie to the right
of the molecule shown below. However, it is unable to intercalate with DNA
due to too much 3D structure (need to be flat to intercalate)
The important bit is the iron in a square planar structure
Notice how the oxygen is bound to the iron, it displaces the carbamate
group
The oxygen is reduced to oxygen free radicals, which then damage the DNA
The action of bleomycin is to bind to the DNA and cause DNA breakages
The molecule is enzymatically cleaved by hydrolase, which reduces DNA binding
and damage
The copper is removed to inactivate the molecule to reduce toxicity (it will
find iron to chelate to in the body)
Normally, it comes as a blue copper complex (the copper sits where the iron is
sitting below)
It is amazing to see such a large molecule being able to enter the nucleus. The
sugars may be used as a recognition site to gain access to the nucleus
Because it converts oxygen into free radicals, the compound is associated with
oxygen toxicity, leading to pulmonary fibrosis. Need to monitor patients carefully
Actinomycin
Flat ring system which isn't fully aromatic. It is still able to intercalate to the
DNA
Composed of three basic parts:
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Two large lactones made of 5 amino acids, they may differ or be the same
Planar rings allow pi-stacking
Lactones will bind via hydrogen bonding (contains amino and carboxyl
groups) and Vander Waals' forces (because it's big)
The entirety of the molecule will be able to bind to the DNA, causing it to bend out
of shape completely
Bending it out of shape this badly prevents topoisomerase II from unwinding the
DNA properly, so the cell can't replicate or transcribe DNA, leading to death
Anthracyclines
Doxorubicin
Epirubicin
There are a few anthracyclines in use e.g.
Although they have 4 rings, they are not tetracyclines
Tip: rubor is redness, can't forget it's red now
They are red coloured compounds, and they are renally excreted, causing urine to
go red
Note: formaldehyde naturally formed by the body will attack the sugar,
which can cause covalent bonding of the anthracycline to the DNA
That is a good thing
The 4 flat rings allow for intercalation into the DNA, while the daunosamine sugar
(seen at the bottom of the image) will aid with binding to the DNA
Prevents transcription and duplication of DNA
After intercalating with the DNA, it stabilises the interaction of topoisomerase II
with the DNA, preventing it from doing anything else
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Causes free radical formation, which does have some effect against DNA,
but the problem is it also occurs in the cytosol of cells
This is why it might be causing cardiotoxicity, as the cells of the heart cannot
divide to form new cells, so the cells will take gradual damage over use
Therefore, there is a maximum cumulative lifetime dose for all the
molecules in the anthracycline family
They are also a target for reductase enzymes, this is a major issue
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Importance of targeted systems for chemotherapy
Chemotherapy drugs are generally not targeted at specific against cancer cells as
we don't have many biochemical differences between cancer cells and normal
cells.
Remember: treatments tend to be dose-limiting due to toxicity
Increasing dose due to better targeting leads to better outcomes
Reduced toxicity as the drugs won't affect normal cell function
Increased efficacy as more of the drugs will hit the cancerous cells
Therefore, if we were able to produce a targeted form, it would be better due to:
Levels of drug targeting
Broadest targeting
Targeting to the capillary bed of the desired organBetter than nothing
First order targeting
Targets at a cellular level
Hit specific cells within a region or in the body
Second order targeting
Targets a specific part of the cell
In our case, we want to target the nucleus of the cancerous cells to deal the
greatest amount of damage to DNA
Third order targeting
Physicochemical properties of the carrier/drug will help the drug reach its
target
In other words, the body won't active move the drug, it needs to be
designed to get there on its own
Analogous to passive diffusion
Examples are modifying pH or particle size
Passive targeting
Manipulate the body to actively take the drug to where it's needed
Analogous to active transportExamples are antibody based systems
Active targeting
To get these levels of targeting, we can consider two types of systems:
Ideal properties of a carrier
Non-toxic
Cheap
Specific targeting to the desired cells
Doesn't leak the drug while moving to the site of action (might be a liposome)
Drug must get to the site
Drug must be released at the site (otherwise the carrier will prevent it from
having its action)
Drug must remain at the site for as long as possible
Nano-particulates- encapsulates the drug to carry it to the site of action
Generally, there are two types of carriers:
Targeted Drug Delivery systems
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Liposomes- small spheres of phospholipid membranes which has drugs
inside (inside is a hydrophilic solvent)
Emulsions- small spheres of lipids which has the drugs in the lipid
compartment (inside is a lipophobic environment)
See case 1
Polymers
Proteins (make sure it's human protein to prevent an immune reaction)
Both of these have long half-lives to give it enough time to reach the site
See case 2
Drug-conjugates- drug is attached to the carrier to be enzymatically released at
the site
Barriers to drug delivery
Tumours are able to cause angiogenesis (required for growth larger than
1-2mm), but they can't produce a drainage lymphatic system
The blood vessels formed in tumours are very leaky due to increased gaps
between the tight junctions of the cells of the endothelium, this allows
liquids to move out
Liquids tend to be kept in the center due to a thicker extracellular
matrix in the core
Pressure tends to be highest at the middle of the tumour, pushing liquids
from the core outwards
Our drug can be pushed outwards due to this pressure, so chemotherapy is
most effective around the outside of tumours
High interstitial pressure in tumours
Perfusion is greatest on the outside of tumours where the growth is
occuring, while it is lowest at the core of the tumour, which may be
hypoxic and necrotic
Our drugs are delivered by the blood, so again, the surface of the tumour ismore affected than the core
Non-uniform perfusion
The membrane tends to keep bulky or polar substances from entering the
cell, so it's hard for our drug to get in
To make matters worse, the membrane is studded with efflux transporters
like P-gp which kicks out the drugs as soon as they enter
Cell membrane barriers
Glutathione- contains a thiol group (-SH) which is very attractive for
alkylating agents as it is also a good nucleophile. So our alkylating agents
will attack glutathione instead of attacking the DNA
DNA repair enzymes- if the cell can repair the damage the drugs arecausing, then it will be resistant to attack
Intracellular inactivation
Enhanced permeability and retention effect
Although the lack of a lymphatic system in tumours causes an increased pressure
within tumours, this is also an advantage to us
The enhanced permeability and retention effect means our drug is able to enter
the tumour easier, because the gaps between the tight junctions are wider
(remember, these carriers tend to be quite big)
And since there's no lymphatic system, the drug can't be washed away due to
lymphatic drainage, so it stays in the tumour for longer
Overall, this effect counteracts the increased pressure from the tumour
Case 1: doxorubicin in PEGylated liposomes
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Normal liposomes use phosphodialcholine to create the phospholipid bilayer
seen in liposomes
PEGylated liposomes will use a phospholipid with PEG (polyethylene glycol)
polymer attached to the polar end of the phospholipid
What happens is the PEG will be on the outside of the liposome, surrounding it
with this polymer
Low CmaxLow AUC
High clearance
Short half-life
Large volume of distribution
Normal liposomes will generally be ineffective, due to their poor
pharmacokinetic variables
PEG prevents the cells from detecting and phagocytising the liposomes
PEG prevents opsonisation, so it can't be picked up as a foreign component
PEGylated liposomes have much better pharmacokinetic variables, as they are
able to evade the reticuloenothelial system (macrophages and monocytes),
which is what causes the poor performance of liposomal compounds
Case 2: Doxorubicin-polymer conjugates (PK1)
Doxorubicin is attached to a polymer through an amino acid spacer
Too large to enter through normal tight junctions, but small enough to
enter through the leaky tight junctions of the tumour
Allows some targeting, as normal cells won't be able to take up this
conjugate easily
The polymer makes the particle size very large
Once the conjugate has reached the tumour, a tumour cell will take it up via
pinocytosis ('cell drinking')
Once it is inside the cell, the endosome (the vesicle formed from pinocytosis) will
be fused with a lysosome
The enzymes in the lysosome, together with the acidic environment of the
endosome will cause cleavage of the amino spacer between the doxorubicin and
polymer to be cleaved, releasing the free drug
The free drug is now free to move around the cell and cause damage as required
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Background
In adults it's important for healing and endometrial growth in females In embryos, it's important to produce vessels from vasculogenesis (the
production of blood vessels from nothing)
Angiogenesis is the process where new blood vessels are formed FROM PRE-
EXISTING vasculature
Tumours need a supply of oxygen and nutrients which are delivered by the
blood
Can't get too big if there aren't any blood vessels supporting it
Tumours cannot grow any larger than 1-2mm if angiogenesis cannot take place
Therefore, antiangiogenic treatments are being researched
Mechanism
These factors are peptides, not other hormones
Wounded areas will produce angiogenic factors, like vascular endothelial growthfactor (VEGF)
These factors will bind to receptors on the endothelial cells of the blood vessel
Growth factors are then required to bind to other receptors to really kick off
angiogenesis by activating the endothelial cells
Activated cells will break down the basement membrane of the blood vessel to
form holes for new blood vessels to poke out of
The endothelial cells will then divide and poke out of the holes to travel towards
the injury site using adhesion molecules to drag themselves forwards
They then roll up to form a tube
Smooth muscle cells will then support the newly made blood vessel for structuralsupport
How does this apply to secondary cancers?
Tumours will produce an angiogenic factor to produce blood vessels
Luckily, this stops any secondary tumours from carrying out angiogenesis
But once they get big enough, they also secrete angiostatin, a natural inhibitor of
angiogenesis, normally used to prevent unnecessary angiogenesis
Once the initial large tumour is removed, this secretion of angiostatin is also
stopped
The concentration of angiostatin drops, which allows smaller tumours to grow,as they are able to form blood vessels now
Thalidomide
Mechanism of action is unknown
Has antiangiogenic effects
May be used in multiple myeloma as a last resort
Need to have effective contraception, as it is present in semen
Hormonal contraception/IUD or surgery PLUS condoms/diaphragm
Make sure no one can get pregnant
However, it is strongly teratogenic
Pregnant women
Women who are able to have children but are unwilling to use
contraceptive methods
Therefore is contraindicated in:
Antiangiogenic treatments
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Ditto for men
Monoclonal antibodies
Because it binds so tightly, it stops normal factors from attaching to
prevent angiogenesis
Cetuximab has a high affinity for the epidermal growth factor receptor, which is
used in angiogenesis
Expected side effect: reduced healing, irregular periods
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Intro/Glossary
Cure
Removal of all cancerous cells from the body. Ideally, the patient will now have the
same life expectancy as someone who doesn't have cancer.
Remission
Reducing the cancer, even to below detectable levels. However, the cancer is not
completely removed, and may return at any time.
Adjuvant chemotherapy
Additional therapy given with the main method of treatment. For example, adjuvant
chemotherapy is chemotherapy given in addition to surgery (the main treatment).
Adjuvant therapy may also include radiation as well. All this is done to decrease the
chances of reoccurrence of cancer
Neo-adjuvant chemotherapy
Chemotherapy given BEFORE the main treatment, for example, chemotherapy may be
carried out to reduce the size of a tumour before surgery, which can reduce the
amount of tissue to cut, reduce the vasculature (that's a good thing, means you'd lose
less blood during surgery) and make it shrink away from healthy tissue to save that
tissue.
NOTE: Remember, chemo is more effective on the outer edge of solid tumours, which
causes the shrinkage.
Palliative chemotherapy
By this point, we know the cancer can't be cured, so chemo is given to reduce thetumour sizes to relieve symptoms. PLUS it can be used to extend life. Just remember,
we can't cure them by this point, make them more comfortable and live a bit longer.
TMN staging system
T= size of the initial tumour, higher the number, bigger it is
N= number of lymph nodes or extent of spread along lymph nodes, higher the number,
it's spread more throughout the lymphatic system
M= indicates if it has metastasized, where 0 is no, 1 is yes.
e.g. T2N1M0 means it's a medium sized tumour with little regional node infiltration and
no distant metastasis.
Metastasis
Bone (leads to bone pain)
Liver (leads to jaundice)
Brain (leads to mental changes)
Lungs (leads to difficulties in breathing)
Cancer cells are able to split off and travel around the body to for new tumours at
different sites of the body. There are four main sites they will go to, leading to a
common set of symptoms:
Disease templates
Breast cancer
The most common cancer in females. However, it does occur rarely in males. The
disease is also more common in older people, which is common for cancers.
Workshop 1- Solid tumours
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Age
Family history
Race
BRCA1 and BRCA2 double strand DNA repair mechanism genes are faulty in a
high number of cases. This mutation can be passed down, leading to somewomen developing breast cancer quite early in life
Early menarche (menstruating from a young age)
Not having children
Increased exposure to estrogen
Pathophysiology is common to most cancers, where the genetic material of cancerous
cells is damaged, leading to unregulated growth. However, there are some specific risk
factors:
Solid, hard
Irregular
Non-tender
Solitary
90% of the time, a small painless lump can be felt
10% of the time, stabbing or aching pain can occur
Sometimes, it can become tender, and a discharge can be seen
Regular screening is recommended
Mammograms and ultrasounds are used to detect them
Very, very curable if picked up early
Signs and symptoms:
See above for symptoms if the cancer is advanced.
See common treatment goals
Now days a partial removal (breast saving surgery) is recommended
Mastectomy (removal of the breasts)
Note: may be just as effective as mastectomy in some cases
Radiation therapy (instead of surgery)
Non-pharmacological treatments:
Pharmacological treatments (see 'Mechanisms of action' and 'side effects' below for
details):
5-flurouracil
Epirubicin
Cyclophosphamide
Adjuvant therapy with FEC is common:
Notice how the above combo has two drugs which are not specific for any parts
of the cell cycle, and 5-FU is specific for the S-phase. This makes them synergistic
as the treatment will work regardless of what stage the cells are in.
Early stage- focus on cure
Paclitaxel
Taxanes
Therefore, avoid use.
CAUTION: anthracyclines have cumulative cardiotoxicity. In other words, if you
used Epirubicin during adjuvant therapy, you can't use it again or anything else in
that family (like doxorubicin).
Late stage- focus on palliative care
Endocrine therapy only if the cancer carries estrogen receptors
Misc
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Tamoxifen- a estrogen receptor antagonist. Normally, the estrogen
stimulates the growth of the tumour.
Trastuzumab AKA Herceptin is only good for HER-2 positive cancers only
Long acting formulation + short acting for breakthrough pain
Also give laxatives to prevent constipation
Opioids like morphine are the gold standard
Paracetamol can work
NSAIDs can be useful for bone pain
Bisphosphonate for bone pain
Pain
Ondansetron plus dexamethasone
Lorazepam for anticipatory nausea due to anxiety
Nausea
Non-cancer
Prostate cancer
The most common cancer in males, again it is more common in older people. For
obvious reasons, it cannot occur in females.
Age (old)
Race (African Americans are more affected)
Family history
It has been linked to:
Generally little to no symptoms if locallised
Urgency and dribbling if it's starting to spread (the urethra passes through the
prostate gland, so if it's starting to grow, it will block it, so you can't piss as easily)
Can result in back pain plus other generalised symptoms if advanced
Symptoms are:
Only carry it out if symptoms are present, or if the person has a high risk
PSA assay has a low diagnostic value, some people without cancer have increased
PSA, while people with cancer can have a low PSA
Can confirm cases quite easily and quickly
Digital Rectal Examination (DRE) has good diagnostic value, but people aren't
very keen on having them.
Imaging allows points of interest to be mapped out and biopsied (with a
needle) to check for cancerous cells, helps to grade the cancer.
Transrectal ultrasound
Population wide screening is not implemented, but there are some ways to diagnose
prostate cancer:
Gleason score should be taken, which is where the cancer cells are checked to see if
they form glands (well differentiated cells) or not (undifferentiated cells).
Undifferentiated cells will cause a worse prognosis.
Importantly, we need to know how hormones affect the tumour:
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LH-RH (also known as GnRH or gonadotropin releasing hormone) will stimulate
the pituitary gland to release LH (Lutenizing hormone) and FSH (follicular
stimulating hormone)
LH and FSH will stimulate the testes to release testosterones which will stimulate
the prostate to grow, making the cancer worse
We need to target this pathway for a specific treatment (see below)
Surgery to remove the prostate is well recommended for a complete cure at early
stages (this is the main treatment, and what we're aiming for)
It depends on what side effects the patient prefers
However, radiation is just as effective (external beam therapy, where radiation is
fired at the prostate)
Plus old people are not candidates for this treatment, need to use a
pharmacological treatment
At later stages, surgery to remove the testes (orchidectomy) can be performed
(not very popular though)
Or for some patients, it's better for their life if they just waited and watched the
tumour carefully. This is because these people tend to be old, so it might not be
worth dragging them through treatment to make the rest of their lives miserable.
Non pharmacological treatments:
GnRH agonist, will attempt to over-stimulate the pituitary gland, and cause
the receptors to desensitise to reduce the downstream production of
testosterone
Occurs because at the beginning of treatment, the GnRH receptors
haven't desensitised, so there's a lot of testosterone being produced
downstream
Causes 'tumour flare', which causes an increase in symptoms arising from
the tumour, plus hot flushes, decreased impotence and tender breasts
Goserelin injections- depot of goserelin injected monthly
Non-steroidal testosterone receptor antagonist
Prevents testosterone from binding to the receptor, mainly to counteract
the tumour flare effect
Causes the same side effects as goserelin, but can also cause bone loss
(osteoporosis)
Flutamide tablets- given daily for a short period of time
If non-responsive, need to focus on palliative care and maybe some other
Pharmacological treatments (advanced cancers):
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Surgery is not an option, because it's metastasized
Make sure the chemotherapy agent is compatible with the patient
conventional chemotherapy drugs e.g. vincristine etc.
Colorectal cancer
Very common cancer overall in the population
Age is the main one (again)
Low fibre-high fat diet
Sedentary lifestyle
Hereditary (family history)
Inflammatory bowel conditions (especially Ulcerative colitus, Crohn's disease to a
lesser extent)
Risk factors:
Changes in bowel motions (chronic constipation)
Weight loss
Abdominal pain and cramps
Malaena, tarry stools with blood
Bloating
Signs and symptoms:
Most commonly, a barium enema can be used to check for growths
A colonoscopy may also be used
May be anemic, due to blood loss
A DRE can be used to rule out haemorrhoids as the cause of symptoms
Diagnosis:
Remove the tumour and surrounding tissue to make sure to remove all the
traces of cancer for a total cure
Colostomy will be performed just after the surgery, which is where one
part of the bowel will be open to the outside world to allow food in. Later
on, after the ends have healed, the GI tract is put back together.
Again, surgery is first line treatment for non-metastasized cancers, with adjuvantchemotherapy (FOLFOX)
Adjuvant therapy for local invasion of some tissues
Radiation is more effective for rectal cancers
Radiation is not as effective here
Nutritional support to reverse weight loss
Non-pharmacological treatments:
Not for 'rescue use' as for methotrexate
Instead, it improves the action of 5-FU on thymidylate synthase
Folinic acid
5-Flurouracil
Oxaliplatin
FOLFOX (first line treatment):
Capecitabine (prodrug of 5-FU) if not responsive or at late stage
5-FU
Folilic acid
Topoisomerase inhibitor
SEVERE diarrhoea
Irinotecan (instead of Oxaliplatnin)
FOLFIRI
Pharmacological treatments:
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Good for late stage cancers
Bevacizumab is an antibody which prevents the angiogenesis of metastatic
growths, preventing them from growing
Common treatment goals
Generally speaking, at earlier stages of cancer, the tumour is small, encapsulated (i.e.
cells are completely surrounded and cannot leave) and has not invaded any other
tissues. Therefore, a complete cure is possible if the tumour is cut out, with some
adjuvant chemotherapy to make sure there aren't any cancer cells left.
However, in later stages, palliative care is more important, trying to reduce the sizes of
the tumour and distant metastasis. A multitude of drugs can be given, and surgery is
less important because it wouldnt achieve a cure.
Also, we have to weigh up between treating the cancer and preserving the life quality
of the patient. For example, if the person is old and has advanced cancer, then it might
not be worth giving them chemotherapy because it would severely reduce their life
quality without much of an impact on the life expectancy. See prostate cancer for more
examples.
Mechanisms of action
Specifically targets the S-phase of the cell cycle (because it stops DNA
replication)
Pyridine analogue which gets incorporated into the growing DNA strand.
Because it has a fluorine on the 5 position, it stops any more nucleotides
from being added to the molecule, stopping synthesis of DNA.
Also blocks thymidylate synthase
5-flurouracil
Antimetabolites
Prevents DNA and RNA from being made
G2 cell cycle specific
Can trigger apoptosis
Intercalates between bases in DNA to inhibit topoisomerase II and stabilise
topoisomerase II once the DNA has been cut
Cumulative Cardiotoxicity
WARNING: take care with people with ischemic heart disease
Also generates free radicals. However, this is not important to its action,
but it results in some side effects
Doxyrubicin, epirubicin
Anthracyclines
Not cell cycle specific
Can also lead to apoptosis
Binds to nucleophiles, the pyridine bases of DNA, causing alkylation, cross
linking within or between strands of DNA
Causes haemorrhagic cystitis (bleeding in bladder)
Need to co-administer with Mesna and plenty if IV fluids to counterthis
Side product, acrolein, is produced. It causes inflammation of the bladder
Cyclophosphamide
Alkylating agents
Taxanes
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Anti-mitotic agent, inhibits microtubule formation by attaching to the actin
subunit
Prevents the M phase (where they build microtubules to split the genetic
material between nuclei)
Constiaption is common as a result
Strong peripheral neuropathy
Paclitaxel
Also prevents mitosis by inhibiting microtubule formation by attaching to
the actin subunit
Attaches at a different site compared to taxanes
Prevents the M phase
Monitor symptoms
Can cause constipation due to reduced gastric motility
Extreme peripheral neuropathy
VincristineVinca alkaloids
Binds to DNA (crosslinking between strands)
DNA becomes unusable
Causes extreme peripheral neuropathy (monitor symptoms)
Causes sensitivity to cold, avoid cold drinks/ice
May cause deafness and renal toxicity
Consider amifostine administration to protect against nephrotoxicity, it
contains thiol to prevent damage
Monitor renal as well
Increase fluids to prevent renal toxicity
MONITOR: peripheral neuropathy
Oxaliplatin
Platins
Serotonin 5-HT3 receptor antagonist
Antiemetic effect
Ondansetron
Glucocorticoid
Enhances the effect of Ondansetron
Dexamethasone
Non-cancer agents
Side effects
General side effects and how to avoid them:
Fluid from infusion can seep out into surrounding tissues
Incredibly dangerous as some drugs are vesicants (blistering agents)
May be caused by poor circulation (due to incorrect line site, use a central
line, which has good flow compared to a peripheral line)
Patients must be told to report discomfort or pain at the infusion site so it
can be stopped and an antidote can be administered.
Extravasation (immediate effect)
Caused when the drug is detected by the chemoreceptor zone in the brain,
triggers nausea and vomiting
Ondensetron and Dexamethasone are commonly used
Nausea and vomiting (immediate effect)
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Will also damage oral linings as well as the rest of the GI tract, leading to
diarrhoea
Occurs because the mucus membranes contain rapidly dividing cells, and
they too are affected by treatment
Good oral health and nystatin (anti-fungal drug) are given to prevent oral
issues, while loperamide (anti-diarrhoeal) will be given for GI symptoms.
Mucositis and diarrhoea (delayed effect)
Reduced white blood cells and platelets, leading to increased bleeding or
susceptibility to infections
Again, the bone marrow contains rapidly dividing cells, leading to a
shortage in these cells
Worst suppression occurs 7-14 days after infusion
Need to monitor blood cell counts weekly
If neutrophils are very low, they must be put into isolation
gCSF (granulocyte Colony-Stimulating Factor) can be given to stimulate
white blood cells to grow
Sore throatPain on urination
Feeling pretty shit
Fever may be present
WARNING: must tell patients to look for symptoms of infection:
Myelosuppression/neutropenia (delayed effect)
Again due to hair follicles containing rapidly dividing cells
Use a government subsidised wig or just buy a scarf
Hair loss and alopecia (delayed effect)
Specific side effects have been listed with the specific drug
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Intro
The last clinical workshop dealt with solid tumours. This workshop deals with tumours
which do not form solid masses (as they are in the blood). These tumours are diffuse
tumours.
Acute Lymphoblastic Leukaemia (ALL)
There shouldn't be any detectable in the blood
Blast cells, which are immature cells of the circulatory system are present in large
amounts in the blood
Therefore, most of the symptoms we encounter are from a lack of
functioning blood cells (e.g. anaemia)
Due to the high volume of blast cells, normal haematopoiesis (production of
blood cells) can't occur
B and T lymphocytesIn ALL, a large amount of lymphocytes are being produced
The most common age is 5 years old (best prognosis between 2-9)
Pale, tired
Also shows reduced haemoglobin in the blood
Anaemia
Due to thrombocytopenia (lack of platelets)
Can also be seen as petechiae (purple spots on skin due to minor
haemorrhage on the surface of the skin)
Easily bruised/ bleeds easily
Enlarged lymph nodes, liver and spleen
Weight loss
May have a cold as a result
Even though number of white blood cells are increased in blood test results
(because these cells are useless at fighting off infection)
Highly susceptible to infections
Shouldn't be present in the blood
Blood tests will also show blast cells in the blood
May have Philidelphia chromosome (see below), which indicates a worse
prognosis
Signs and symptoms
Treatments
Bulk of the cells will be killed off here
Anti-gout medication
Required to prevent tumour lysis syndrome, which is where
cells release uric acid on death
Generally required for diffuse cancers due to the sheer numberof cells being killed
Allopurinol
Vinca alkaloid
Antimitotic drug
Vincristine
Drugs are:
Induction
Split into three phases:
Workshop 4- Diffuse tumours
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Severe peripheral neuropathy (loss of feeling and constipation,
consider docusate)
Asparginine is an amino acid which can't be synthesized in
lymphoblasts (but is produced everywhere else)
This enzyme will reduce the amount of circulating asparginine
to retard the growth of the cancerous cells
Watch out for anaphylactic shock (reaction against enzymes)
and hyperglycaemia
L-asparginase
Glucocorticoid which causes immunosuppression
Although it doesn't kill many cells, it's given to stop any further
growth
Can cause restlessness or increased aggression
Prednisone
Administered intrathecally (into the spine)
Anti-folate drug
Used to destroy cancerous cells in the CNS, as the other drugs
can't cross the BBB
Caution: may cause seizures, monitor carefully
Methotrexate
Mixups are avoided as the pharmacist personally delivers the
dose
The volume which can be delivered intrathcally is small (3-5ml)
compared to 100s of ml for IV
Caution: do NOT get mixed up with vincristine, as intrathecal
vincristine is fatal
Approximately 3 months after remission
Can use the same drugs at a higher doseAggressive ch