Cancer2,3,4 Flashcards
what are cytotoxic chemotherapy
the use of cytotoxic agents to treat cancer.
how do cytotoxic chemotherapy work
they target the mechanisms by which cells divide and grow.
how do they work ? systemically or localised?
they are systemic treatment via blood stream, so it affects the entire body, hence the side effects
do cytotoxic chemotherapy distinguish between cells
NO. they kill both cancerous cells and normal cells
when is the tumor no longer palpable and when is no longer visible by xray
<10^9 - no longer palpable
<10^7 no longer visible
what is the hypothesis for the growth of cancer cells
> cancer cells grow exponentially
on the x axis is time, y axis is number of cancer cells in the body
as the tumour grows, the rate of its growth increases too, and the time it takes for it to double in size gets shorter and shorter
however, once tumour reaches large size, the rate of growth falls
this is probably due to the lack of blood supply and oxygen
this has implications for chemotherapy, because the bigger the tumour, the fewer cells will be in th growth phase.
what is the log kill hypothesis
- that a specific dose of drug kills a constant fraction of cells rather than a specific number.
- the log kill is usually proportional to dose, which in turn is limited by toxicity of the drug
how are chemotherapy scheduled
- the highest dose that can kill the highest possible fraction of cancer cells without intolerable side effect,
- with the shortest interval before the next cycle, to avoid regrowth
- and time given between for recovery of side effects
- with each cycle, fraction of cancer cells reduces
how do you know treatment end point since you can’t see the tumour
using TNM system that have been developed through clinical trials.
what are the types of tumours
- Haematological tumours which affect the blood , bone marrow and lymph nodes.
such as leukaemia, lymphoma, myeloma - solid tumours
describe solid tumours
outside area - closest to blood and oxygen supply so are in growoth phase
inside area - necrotic interstitium .
Cells outside are replicating, therefore getting bigger and bigger. bigger cells = impact surrounding tissue and compresses blood vessels. low blood supply to cells in the middle of the cancer = they die.
so outer layer are growth, inside layer are dead cells.
what is the best way to kill solid tumour
combination of cell cycle specific and cell cycle non specific
how do growing tumours impact drug delivery
these cells impact blood supply travelling through the tumour so it is difficult to deliver drugs.
what does neoadjuvant mean
used to shrink tumour before surgery
how are cytotoxic chemotherapy administers
- intravenously - most common
- oral - most common
- intramuscular injection
- subcutaneous injection
- intracavity
- intrathecal
what are the examples of intravenous administration of cytotoxic chemotherapy and explain them
> cannula =
PICC line = inserted peripheral vein and tip of line sits above right atrium of heart
Hickman line = tunnelled lines under skin of chest, inserted in the central vein w tip sitting above right atrium of the heart.
porta Cath= small chamber buried underneath skin
describe solid tumours
outside area - area of apoptosis (Cell death) #
inside area - necrotic interstitium .
Cells outside are replicating, therefore getting bigger and bigger. bigger cells = impact surrounding tissue and compresses blood vessels. low blood supply to cells in the middle of the cancer = they die.
so outer layer are growth, inside layer are dying.
why are solid tumours difficult to treat
- poor blood supply
- composition of tumour interstitium
- several layers of tissue
- high tumour interstitial pressure that impacts the movement of drug into the tumour
how do growing tumours impact drug delivery
they compress blood vessels, decreasing blood supply to the cells. therefore it is difficult to administer the drugs as they reach tumours through blood supply
what happens when cytotoxic drugs work on the outer layer of the solid tumour
they kill the cancerous cells on the outer layer. the inside cells that had low blood supply and low oxygen levels can now access these nutrients and start to divide.
what are the side effects of cytotoxic chemotherapy for HEAD
- Hair loss
- mood changes, poor concentration / fatigue
what are the side effects of cytotoxic chemotherapy of MOUTH
taste changes
mucositis - inflammation of gut / mouth / Gi tract
> causes speech/swallowing/eating difficulties
what are the GI side effects of cytotoxic chemotherapy
- nausea and vomiting
- poor appetite
- diarrhoea
- constipation
what are the side effects of cytotoxic chemotherapy of hands, feet and skin
- dry skin
- nail changes
- peripheral neuropathy
what are the GENITAL side effects of cytotoxic chemotherapy
- loss of libido
- sterility
how is sterility treated
- storage of eggs
- sperm banking
what are the side effects of cytotoxic chemotherapy of BLOOD
- damage to hemopoietic system (bone marrow toxicity ) - bone marrow is responsible to producing blood cells. chemotherapy damages bone marrow leading to reduction in RBC, WBC (neutrophils), platelets
what are the impacts of toxicity to hemopoietic system
Myelosuppression
less WBC = poor immune system = more risk of infections such as fungal / viral .
pt must be on antifungal /antiviral
how is myelosuppression reduced
- treatment: fractionating dose instead of giving bolus to minimise peak height and assoc toxicity
- timing of doses / hemopoietic monitoring
- transfusions
- CSFs - prevention
- avoid exposure to infections so avoid infected people / large crowds
-watch hygiene especially kitchen
what are the side effects of cytotoxic chemotherapy of ORGANS
- pulmonary toxicity
- cardiotoxicity
- hepatoxicity
- nephrotoxicity
- bladder toxicity
how is nausea and vomiting induced in patients on cytotoxic chemotherapy
CTZ (chemotherapy trigger zone) is activated.
which antiemetics are used
Ondansetron,
which drug is renal toxicity a side effect of
cisplastin
how is the renal toxicity side effect treated
mannitol diuresis
which drug is haemorrhagic cystitis a side effect of
ifosfamide
cyclophosphamide
how is the haemorrhagic cystitis side effect treated
diuresis
which drug is cardiotoxicity a side effect of
doxorubicin
Carcinogenicity of chemotherapy
- many cytotoxic agents are mutagenic especially akylating agents
- appear 10 -15 years later
which cancers can develop later on as a result of chemotherapy
neoplasia’s often leukaemia’s
what are the mechanism of drug resistance. t
- improved proficiency in repair of DNA
- reduced drug activation
- increased drug inactivation
- reduced cellular uptake of drug
- increased reflux of drug
- alternative biochemical pathways
- alterations in target enzymes
how do you combat the mechanism of drug resistance
by giving 2 or more drugs in combo with 4 different mechanisms as the likelihood for a tumour having 2 or more diff mutation is less likely
Describe the mechanism for multi drug resistance
amplified gene product (MDR - 1 gene
which codes for transmembrane p glycoprotein (P170) whose job is to pump out (efflux) chemotherapy drug
how do you combat this multi drug resistance
by giving pump blockers that inhibit these channels
what is chemotherapy drugs didved into
- cell cycle (phase) specific
- cell cycle (phase) non specific
what is the difference between cell cycle specific and non specific
specific: can work at a specific phase of cell cycle
- schedule dependent
non specific: kill any cells at any phase of the cell cycle
- non specific are dose dependent. activity depends on dose
which cell cycle specific drugs work for G1
- HORMONAL DRUGS
- ANTINEOPLASTIC ENZYMES
which cell cycle specific drugs work for S phase
- topoisomerase-1 inhibitors
- ANTIMETABOLITES
> FOLATE ANALOGS
>PURINE ANALOGS
>PYRMIDINE ANALOGS
which cell cycle specific drugs work for G2
- Epipodophyllotoxin derivatives
- blemomycin
which cell cycle specific drugs work for M
Vinca alkaloids
how are chemotherapy used in combo
> use of specific and specific together
avoid overlapping mechanisms of actions and toxicities
alternate myelosuppressive and non myelosuppressive drugs
what are the different classes of chemotherapy
- alkylating agents
- antimetabolites
- topoisomerase inhibitors
- antimitotic
what are alkylating agents
- they are cell cycle non specific agents, are very effective any cells that are rapidly dividing - best for phase G1, and S
how do alkylating agents work
they affect transcription and suppress protein synthesis.
how do alkylating agents kill cancer cells
they alkylating agents that attach that bind covalently to nucleophilic groups through an alkyl group
- N7 and O6 of guanine (G is 7th letter, 6 is next o 7)
- N1 and N3 of adenine (A = 1)
- N3 of cytosine (C=3rd letter)
They can cause intra strand linking and cross-linking of DNA strands, abnormal base pairing, or DNA strand breaks, thus preventing the cell from dividing.
what do alkylating agents undergo to perform alkylation
compound CH3CH2CL. The chlorine disaggregates , forming intramolecular cyclisation. this cyclic structure then opens out to form CH2+ which covalently binds to the N on Guanine etc.,
how does the MOA of alkylating agents affect DNA replication
They can cause
+ intra strand linking : so 2 Gs on the same strand which leads to adduct
+ cross-linking of DNA strands = stops strand separation as DNA is covalently bound together instead of hydrogen bonding
+ abnormal base pairing
+ DNA strand breaks
+ De-purination = strand cleavage
+ tautomeric mutation - i.e G pairs with T
thus preventing the cell from dividing.
therefore, cell undergoes dna repair or apoptosis
are alkylating agents mono or bi functional
they can be either mono or bifunctional. so bifunctional means that it can link 2 bases (guanine) together
which base position is most critical for alkylating agent action
Guanine N7
when are alkylating agents using in combo
solid and lymphatic tumours
what is one limitation of alkylating agents
they are mutagenic and carcinogenic
what are the side effects of alkylating agents
Extravasation damage
N & V
Mucositis
Myelosuppression
Alopecia
Depressed gametogenesis
Increased risk of non-lymphocytic leukaemia
Drug handling/waste handling
what are nitrogen mustards
they are a sub group of alkylating agents - the only ones we need to know
what was the first nitrogen mustard, and is it still in use
- mechlorethamine IV - it is very unstable and reactive so it is less used
- reactivity and extravasation at injection site
it has all of the side effects
what regime was mechlorethamine given as part of
MOPP
Mechlorethamine
oncovin
prednisolone
procarbazine
which nitrogen mustards are the standard drug of choice, and their formulation
cyclophosphamide - oral but can be given via IV, Im
ifosfamide - IV
what are kind of drugs are these 2 drugs
they are prodrugs that are activated by P450 into a variety of metabolites.
what are the side effects of these
same as what we’ve put down before
what are the use of cyclophosphamide and give examples
used singly or in combo for a variety of neoplastic diseases such as
- Acute lymphoblastic leukaemia
- breast cancer
-Burkitt’s lymphoma and other lymphomas
where does resistance occur from in p450 nitrogen mustards
increased dna repair
increased production of thiols (glutathione)
what are the other nitrogen mustards to know
chlorambucil
melphalan
uramustine
oestramustine
chlorambucil, it’s formulation and use
Oral admin for lymphocytic leukaemias – esp CLL
what is melphalan and it’s formulation and use
- Phenylalanine as a carrier targets to melanoma
- Oral admin for myeloma and ovarian
do nitrogen mustards cross the BBB? what has been developed to counteract this?
No as they’re to polar
Nitrosoureas have been developed
what are nitrosoureas
bendamustine
Carmustine
Nimustine
