oncology v1.0

Upload: arnold23456

Post on 05-Apr-2018

224 views

Category:

Documents


0 download

TRANSCRIPT

  • 7/31/2019 Oncology v1.0

    1/85

    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

    Oncology Page 1

  • 7/31/2019 Oncology v1.0

    2/85

    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

    Oncology Page 2

  • 7/31/2019 Oncology v1.0

    3/85

    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

    Oncology Page 3

  • 7/31/2019 Oncology v1.0

    4/85

    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

    Oncology Page 4

  • 7/31/2019 Oncology v1.0

    5/85

    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:

    Oncology Page 5

  • 7/31/2019 Oncology v1.0

    6/85

    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.

    Oncology Page 6

  • 7/31/2019 Oncology v1.0

    7/85

    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

    Oncology Page 7

  • 7/31/2019 Oncology v1.0

    8/85

    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

    Oncology Page 8

  • 7/31/2019 Oncology v1.0

    9/85

    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

    Oncology Page 9

  • 7/31/2019 Oncology v1.0

    10/85

    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

    Oncology Page 10

  • 7/31/2019 Oncology v1.0

    11/85

    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

    Oncology Page 11

  • 7/31/2019 Oncology v1.0

    12/85

    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?

    Oncology Page 12

  • 7/31/2019 Oncology v1.0

    13/85

    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

    Oncology Page 13

  • 7/31/2019 Oncology v1.0

    14/85

    Also inhibits thymydilate synthase (TS) as increased DHF building up in

    the cell will actually inhibit TS

    Inhibits dihydrofolate reductase (DHFR)

    Stops the conversion of dihydrofolate to tetrahydrofolate to stop the

    production of all nucleotides

    Countered by the cancerous cells by increasing efflux transporters (such as

    P-gp)expressed on the surface of the cell to remove MTX, or due to 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

    6-MP is metabolised by TPMT (Thiopurine methyltransferase)

    Oncology Page 14

  • 7/31/2019 Oncology v1.0

    15/85

    Slow metabolisers will accumulate 6-MP leading to toxicity

    This is the enzyme which is inhibited by allopurinol

    6-MP tends to be given to patients who need allopurinol to combat tumour

    lysis syndrome

    Adjust dose of 6-MP down to compensate

    6-MP is also metabolised by xanthine oxidase

    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 forma 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

    Oncology Page 15

  • 7/31/2019 Oncology v1.0

    16/85

    Experimental therapy which has drugs which produce reactive oxygen species

    when exposed to light

    Looks like iron contained within a polyphoryn ring

    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

    Attaches to tubulin, which makes up microtubules

    Oncology Page 16

  • 7/31/2019 Oncology v1.0

    17/85

    Both classes of drugs lead to peripheral neuropathy

    Also important for intracellular trafficking of chemicals with vesicles

    Vinca alkaloids bind to the positive end of beta tubulin to prevent polymerisation

    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

    Oncology Page 17

  • 7/31/2019 Oncology v1.0

    18/85

    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

    Oncology Page 18

  • 7/31/2019 Oncology v1.0

    19/85

    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)

    Oncology Page 19

  • 7/31/2019 Oncology v1.0

    20/85

    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

    Oncology Page 20

  • 7/31/2019 Oncology v1.0

    21/85

    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

    Oncology Page 21

  • 7/31/2019 Oncology v1.0

    22/85

    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

    Oncology Page 22

  • 7/31/2019 Oncology v1.0

    23/85

    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

    Oncology Page 23

  • 7/31/2019 Oncology v1.0

    24/85

    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

    Oncology Page 24

  • 7/31/2019 Oncology v1.0

    25/85

    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:

    Oncology Page 25

  • 7/31/2019 Oncology v1.0

    26/85

  • 7/31/2019 Oncology v1.0

    27/85

    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

    Oncology Page 27

  • 7/31/2019 Oncology v1.0

    28/85

    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

    Oncology Page 28

  • 7/31/2019 Oncology v1.0

    29/85

    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

    Oncology Page 29

  • 7/31/2019 Oncology v1.0

    30/85

    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

    Oncology Page 30

  • 7/31/2019 Oncology v1.0

    31/85

    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

    Oncology Page 31

  • 7/31/2019 Oncology v1.0

    32/85

    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 periodsBevacizumab is used in colorectal cancer, antiangiogenic as well

    Oncology Page 32

  • 7/31/2019 Oncology v1.0

    33/85

    Activates the immune system to kill the cancer

    Therapeutic vaccines

    Prepares the immune system to prevent cancers, generally targeting a factorwhich is implicated in cancers, like viruses

    Prophylactic vaccines

    There are two types of vaccines against cancer:

    Human Papilloma Virus (HPV) vaccine

    Prophylactic vaccines against the HPV virus has been shown to decrease the

    chances of getting cancer

    Gardasil works against four strains of the virus which have a high risk of causing

    cancer

    Because it doesn't protect against all strains, it doesn't completely prevent cancer

    Mostly mild effects were seen (local injection pain etc) Some severe effects were rarely seen, but they were not specifically linked

    to the vaccine

    Considered to be safe

    Requirements for a therapeutic vaccine

    The host tends to be immunocompromised either due to the cancer or due

    to the treatments

    So they don't have enough immune function to respond to the vaccine

    Host must be able to respond to the vaccine

    Tumours tend to suppress the immune system to keep themselves going So we cut them out to reduce the suppression

    Plus this generates inflammation, which kicks off the immune system again

    Need to be able to overcome tumour induced immunosuppression

    Easy immune target

    Could be easy, because the cancer can produce some weird antigens due to

    their damaged state

    Could be easy to target just one, but there's a lot of targets

    Could be difficult, because the cancer isn't just one type of cell, many

    different cells could exist, displaying a range of antigens

    The tumour needs to express antigens on its MHC molecules

    Adoptive T cell therapies

    We give the patient premade cells /antibodies

    Their immune system doesn't do much while we do the work

    We then introduce our specially made T cells from the lab, and sicc them on

    the tumour cells

    Passive therapy

    Harder to get (need a biopsy of the region near the tumour

    Expected that these cells have at least some activity against the

    tumour

    Near the tumour

    Easier to get

    Get more cells

    Peripheral blood

    We can get T cells from:

    Then we have two culture methods:

    Cancer vaccines

    Oncology Page 33

  • 7/31/2019 Oncology v1.0

    34/85

    The T cells are only exposed to one antigen isolated from the tumour

    Growth factors are added to stimulate the clonal expansion of the cells

    which are specific against that antigen only

    So we've got a lot of cells which are similar as they all attack the same

    antigen

    Takes a lot of growth and exposure cycles to get a decent amount of

    cells (6 weeks)

    Antigen-specific stimulation

    Take all the T cells and stimulate all of them to grow

    Remove regulatory T cells while growing them

    Cause a bit of genetic modification to get a wide range of T cells

    formed

    After a shorter period, we get enough cells (10 days)

    Not all the cells are effective against the tumour, we haven't

    grown them specifically against tumour antigens. We're just

    grabbing a bunch and hoping they're active against the tumour

    Some of the T cells will actually trigger an autoimmune reaction,

    as autoreactive T cells would normally be kept under anergy. Butsince we've stimulated them in the lab, they are activated, and

    ready to cause some havoc

    But there are problems with this method:

    Polyclonal stimulation

    Individualised for the patient

    Low toxicity compared to harsh chemo drugs

    Advantages

    Need to collect cells and pieces of the tumour

    Chance of autoimmunity

    Very high cost

    Not yet proven to be effective

    Disadvantages

    Cell based therapies

    The patient needs their immune system to mount a response (compared to

    passive where it just sits back and does nothing)

    Active therapies

    Take the cells from the person, grow them a bit, and break them open and

    inject them back into the patient as a vaccine

    Pump the area full of IL-2 to try and overcome anergy

    Autologous- from self, hard to get a proper response because it's still

    showing self antigen

    Allogenic- from someone else, tends to work better because it's recognised

    as foreign instead

    Don't need to define tumour antigens, just grab a bunch of cells and

    mash them up

    Individualised against that person's tumours

    Advantages

    Need to get a piece of tumour, which again requires a biopsy of the

    region

    Autoimmunity can result, because the tumour cells still display self-

    antigen Hard to get a good immune response

    Disadvantages

    Whole cell vaccines

    Take the tumour and a few dendritic cells, get the dendritic cells to display

    antigens from the tumour, and put them back into the patient, where the

    Dendritic cell vaccines

    Oncology Page 34

  • 7/31/2019 Oncology v1.0

    35/85

    Make sure you put in some danger signals as well to help activate the

    immune system.

    dendritic cell will cause the host's immune system to start attacking the

    tumour

    Exactly the same advantages and disadvantages as above

    Cell free therapies

    Active therapy as well

    Quite a popular type of vaccine, as it's used for other organisms, like antiviral

    vaccines

    Sub-unit vaccines

    Need a good delivery system and immunogenic substance

    Not immunogenic either, because it's just pieces of peptide

    It is safe and cheap

    But not individualised (hard to find a specific target against the tumour) and we're

    not sure if they work.

    Attenuated bacteria or viruses (weakened) Virus like particles, which are assembled viruses without the DNA

    Biological delivery systems

    Emulsions (o/w)

    Liposomes (balls of membrane)

    Chemical delivery systems

    We have some delivery systems

    Cytokines

    Cytokines reaching the tumour causes signalling within the tumour to

    induce apoptosis TNF is one such cytokine

    Directly against tumour

    IL-2 again is another cytokine which triggers the immune system

    Triggers the immune system against the tumour

    Immunotherapy either:

    Dosing is too frequent

    Cytokines have a naturally short half-life as a natural safety mechanism

    Tends to be pryogens, cause hypotension and shock etc.

    Has systemic toxicity, need to target specifically against the tumour

    Immune stimulants

    Remember: the environment around a tumour is immunosuppressive Toxins which are used to trigger danger signals to cause an immune reaction

    CpG is a bacterial component which binds to the Toll-like receptor of phagocytic

    cells (like dendritic cells) to cause a danger signal, and kick start the immune

    system in that region

    Antibodies

    Quite specific against the tumour cells

    We can form specific antibodies against tumour targets

    They can circulate around the body for months, requiring infusions just a fewtimes a year

    They are also great in terms of half-life

    Mouse or chimeric antibodies aren't like human ones, they will be attacked

    But the antibodies themselves tend to be toxic somewhat due to the immune

    reactions they are able to cause

    Oncology Page 35

  • 7/31/2019 Oncology v1.0

    36/85

    by the immune system leading to anaphylatic symptoms

    They also tend to be bulky, so they get stuck in small capillaries, so they might not

    be able to reach the tumour

    And they are still really expensive

    Targets the HER-2 receptor in many ways:

    HER2 is able to become cleaved in the membrane, that can cause signalling.

    The cleaving is blocked once herceptin binds

    HER2 is able to dimerise with other HER receptors , which activatessignalling. Herceptin prevents dimerisation

    Immune cells which are able to detect the presence of herceptin on the cell

    will trigger apoptosis of the tumour cell, as it's been coated with this

    antibody (remember: antibodies are involved in opsonisation, marking cells

    out for the immune system)

    The cancer cell will recognise the HER2 receptor is faulty due to this

    attached antibody, it will destroy its own HER 2 receptor

    Signals for proliferation, mobility (metastasis) and survival

    Plus it codes for VEGF, a known angiogenesis agent

    Why is blocking signalling so important?

    Herceptin- CANCER target

    CTLA-4 is sometimes expressed by T cells when communicating to an APC

    cell

    If CTLA-4 is expressed, then T cell activation is cancelled

    So if we blocked CTLA-4, then we would increase the immune system, as it

    relieve the inhibition

    Anti-CTLA-4 antibodies can lead to autoimmune disease, the patient

    needs to discontinue if symptoms of an autoimmune disease appear

    Only problem is, CTLA-4 is there for a reason, normally used to prevent

    autoimmune diseases

    Anti-CTLA-4 IMMUNE system target

    Oncology Page 36

  • 7/31/2019 Oncology v1.0

    37/85

    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

    Oncology Page 37

  • 7/31/2019 Oncology v1.0

    38/85

    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

    Oncology Page 38

  • 7/31/2019 Oncology v1.0

    39/85

    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

    i.e. they don't attack the same targets.

    In theory, both could be given at the same time if their cancers expressed both

    the HER2 receptor and the estrogen receptor

    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:

    Oncology Page 39

  • 7/31/2019 Oncology v1.0

    40/85

    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):

    Oncology Page 40

  • 7/31/2019 Oncology v1.0

    41/85

    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:

    Oncology Page 41

  • 7/31/2019 Oncology v1.0

    42/85

    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 li