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18. radiotherapy and chemotherapy Flashcards

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1
Q

what is clinical efficacy?

A

the ability to produce the desired effect

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2
Q

when someone has cancer, what are clinicians trying to do?

A

not necessarily cure the disease, but to expand lifespan

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3
Q

what do many cancer treatment target and what sort of cells may resist this?

A

proliferating cells

>cancer cells that are quiescent during the treatment

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4
Q

curves can be plotted showing lethality of this dose to cancerous tissue and normal tissue, how is the dose determined?

A

want to cause maximum lethality to cancerous tissue without harming normal tissue too much, killing 10% of normal cells is clinically acceptable

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5
Q

why is there a difference between how cancerous tissue and normal tissue react to treatment?

A

cancer cells have mutated genomes and so they are more susceptible to some things and less susceptible to others

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6
Q

in terms of treatment, what can substantially harm normal tissue?

A

the wrong dose, for the wring amount of time

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7
Q

what does radiotherapy rely on?

A

cytotoxicity

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8
Q

what is the general concept of radiotherapy?

A

blast tissue with radiotherapy and cause damage in that tissue

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9
Q

how does the radiotherapy does have to be delivered and why is this? and is this ideal?

A

in factions
>tumours need to be blasted with a certain amount of energy in order to kill them, but if this was given all at once it will kill the patient very quickly
>this is not ideal

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10
Q

what is the typical radiotherapy dose?

A

60-80 Gy total in 2 Gy fractions for a solid tumour

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11
Q

what is the unit for radiotherapy?

A

Gray (1 Gy = 1 J/kg)

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12
Q

name the three types of radiation and which is most commonly used in radiotherapy?

A

alpha, beta and gamma radiation

most radiotherapy relies on beta particles

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13
Q

what are the properties of alpha radiation?

A

helium nuclei, they are not very penetrative but are strongly ionising

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14
Q

what does strongly ionising mean?

A

they strip the electrons off things that they collide with

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15
Q

what are the properties of gamma radiation? (4)

A

> electromagnetic radiation
very penetrative
can be stopped with a thick layer of lead
not very ionising as they do not collide with much

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16
Q

how big is gamma radiation wavelength and what else can be used in radiotherapy?

A

very short

>X-rays can also be used

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17
Q

what are the properties of beta radiation?

A

> fast electron
come out of atom fast or slow depending on radioactive decay of the atom
relatively penetrative
can be stopped with thin sheet of aluminium

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18
Q

what three properties make beta radiation the best for radiotherapy?

A

> they can penetrate tissue
they are quite ionising
they can be easily stopped

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19
Q

what was the first isotope used for radiotherapy and why was it not ideal?

A

Radium 226
>long half life so isotopes needed to be collected after
>primarily emits alpha which is not very penetrative
>radium decays to radon - radioactive gas that it not easily contained

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20
Q

name three more favourable isotopes now used and what do these all have that is different and so you need to tailor the therapy around? how are they all similar? when are they used?

A

Caesium 137, Iridium 192 and Gold 198
>they have different half-lives
>they all emit beta particles
>they are each used in different settings

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21
Q

what sort of exposure do you normally want with radiotherapy and why is gold good for this?

A

> quite short exposure

>it has a short half life

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22
Q

Caesium 137, Iridium 192 and Gold 198 all emit beta particles, how are these particles different ?

A

they all have different energies of emission of beta particle

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23
Q

what is a bad property of caesium 137? and how can we get around this?

A

it very reactive and so will react with water to give toxic productions
>encase it in something inert so that it cannot react with tissue

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24
Q

what can iridium 192 be used for a why?

A

tumour that are close to the source
>it is low emission and not very penetrative
>using this will avoid damaging healthy tissue far from the source

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25
what is a bad property of gold 198 and how can we get around this?
it decays to toxic mercury and so needs to be encased to stop mercury poisoning
26
what two types of radioactive source can be used in radiotherapy?
external and internal sources
27
describe an external radiotherapy source
put the source outside the body and let it irradiate what it shines one
28
describe an internal radiotherapy source
source can be implanted into the tumour mass itself and allow it to irradiate the tumour from the inside
29
what is systemic therapy and give an internal and externally delivered example
>when the treatment is spread throughout the body | >irradiate whole body from the outside >inject radiotherapy into circulatory system
30
what is targeted therapy and give an internal and externally delivered example
>when the treatment is targeted at a certain location >irradiate a certain location >implant material into tumour mass
31
in addition in internal, external, systemic and targeted, what else can the radiotherapy source be?
sealed or unsealed
32
what is usually used to generate an external radiotherapy source?
particle accelerators or X-ray generators to provide a beam of radiation
33
to target a certain location of the brain in radiotherapy, what is made?
a head cast with a hole where the radiotherapy can shin through to treat tumour material
34
what three factors are there to chose between in terms of internal radiation?
>sealed or unsealed >transient or implant >systemic or targeted
35
give an example of when an internal source of radiation is used
>in prostate cancer >pellets of iridium 192 or Gold 198 are implanted into the tumour >constantly irradiating the tumour at low dose >pellets can be left in indefinitely as long as gold pellets are encased
36
if internal radiotherapy source is implanted and has a long half life, what needs to happen after treatment?
it needs to be removed
37
name the radiotherapy can be delivered systemically but localises to what part of the body?
iodine 131 | thyroid
38
what hormone does thyroid tissue produce and what is important about this in regard to thyroid cancer radiotherapy?
>triiodothyronine hormone | >it contain 4 iodine molecules
39
when iodine 131 is injected into a patient what happens? and why does this happen?
it enters circulation and very rapidly concentrates at the thyroid >no other tissue in the body uses iodine
40
what is the half life of radioactive iodine and how long does it last in a patient and what happens if it is not concentrated at the thyroid?
8 days | clears out the body in 4 days - if it doesn't concentrate at the thyroid then it is excreted
41
why do people receiving radioactive iodine treatment need to be isolated?
they are excreting radioactive iodine
42
what has lead on from the idea of reactive iodine radiotherapy?
that we can use the biology of the tissue to get therapy to concentrate in a certain tissue
43
when tumour cells are exposed to radiotherapy what are we hoping this will result in?
we hope that damage to the tumour cells will induce a death response
44
how many different types chemotherapeutic agents are there?
>50
45
what are the three broad types of chemotherapeutic agents?
>DNA damaging agents >anti-metabolites >agents that interfere with microtubules
46
most of our cells are post mitotic, name the two main places where proliferation still occur in humans?
>hair follicles | >blood
47
why do people loose their hair during the course of chemotherapy?
proliferating cells are targeted
48
what do proliferative cancer cells require in order to undergo mitosis?
microtubules
49
what do microtubules effects do?
they interfere with microtubule dynamics
50
describe microtubule dynamics
>microtubules grow at the plus end at the GTP cap. | >they shrink rapidly by catastrophe where they lose subunits from one end and the microtubule shrinks.
51
what happens to microtubules when they segregate chromosomes?
they undergo catastrophe and shrink, pulling chromosomes to opposite side of the cell
52
what are taxanes?
high affinity microtubule binding drug that stabilises polymerised microtubules and so stop them from de-polymerising
53
why are taxanes hard to synthetically produce?
they are highly stereospecific
54
where did taxanes originally come from and how are they obtained now?
they originally came from trees | >they are obtained for chemotherapy from cultured tree cells
55
if chromosome segregation can not occur, what is not generated? and what happens to cells?
daughter cells | >conflicting signals telling cells to go through M phase and not being able to will trigger cell death
56
where do taxenes bind microtubules? and what does this cause?
the interior cavity of microtubules | >a slight conformational change that stabilises microtubules
57
name another compound similar in function | to taxanes, what do they do at low and high doses? which dose it used clinically?
Vinca Alkaloids >stabilise microtubules are very low doses >at higher doses they lock tubulin monomers in their monomeric state and stop them from polymerising >low does
58
where do Vinca Alkaloids bind microtubules? and how many molecules are needed to stabilise microtubules?
towards the end | >one or two
59
most therapies rely on microtubule effectors in combination with other things, give an example
DNA damaging agents
60
give examples of DNA damaging agents (3)
alkylating agents platinum compounds anti-metabolites
61
what are alkylating agents based on?
nitrogen mustard formulation based on compound used as a gassing agent in WWI >nitrogen mustard has a nitrogen instead of sulphur
62
what is a widely used alkylating agent treatment for multiple myeloma?
Melphalan
63
what do alkylating agents cause?
potent DNA damage
64
describe the structure of nitrogen mustard?
Cl- - - Nme - - - Cl
65
describe the basic mechanism of nitrogen mustard action
>lone pair on N kicks Cl off one side >reactive intermediate with unstable nitrogen reacts with N-7 of guanine >lone pair on N kick off second Cl >reactive intermediate attracts second guanine and forms cross links between DNA bases
66
what type of DNA damage can mustard cause? and what implication does this have on cells?
guanine inter and intra strand cross links >these are hard things for cells to repair, especially when strands are linked - lots of repair cuts out bases and replaces with correct bases, this is much harder is you need to cut out from two strands
67
what do alkylating agents rely on?
cancer cells have impair their DNA damage mechanism >at correct does normal cells should be able to correct this damage >this is good as we only want to cause death to cancer cells
68
what is Mitomycin C? and what can it be used in combination with?
an alkylating agent produced from bacteria >it forms cross links in DNA but attacks different position of guanine that mustard agent - and so it can be used in combination with this in order to cause lots of damage
69
what is a pro-drug?
a drug that is given in an inactive form and is activated once inside the body
70
what is temozolomide and what does it do?
a pro-drug that spontaneously hydrolyses and decomposes to active state in physiological pH >its an alkylating agents which adds a methyl group to guanine at oxygen 6
71
what enzyme removes methyl from damaged bases? and what happens after this? and what implication does this have on therapy?
MGMT >methyl group is irreversible attached to a cysteine residue in the enzyme >causing enough damage will exhaust this enzymes repairing capability
72
why is temozolomide an even better damaging agent for some tumours?
MGMT is lost an mutated in some cancers
73
when methyl-guanine accumulates in cells, what happens?
when cells go through replication methyl-guanine pairs with thymidine instead of cytosine and will hopefully disable cells
74
why is temozolomide useful in terms of treating neurological tumours?
it can cross the blood brain barrier
75
platinum DNA damaging compounds are widely used, give an example of one and why this can kill parts of tumours that other agents cant?
cisplatin | >its oxygen independent and so can kills parts of the tumour that are poorly oxygenated
76
what does cisplatin form of on DNA?
intra and inter-stand adducts
77
what happens when you cross link two platinum centres?
this gives greater ability to cause cross links between strands
78
what synergies well with low doses of cisplatin in low does?
radiation
79
give two example of anti-metabolites and what are they analogues of
5-flurouracil is an analogue of uracil | difluorodeoxycytidine is an analogue of cytidine
80
what is the function of 5-flurouracil?
a thymidine synthase inhibitor - an enzyme required to make thymine based nucleotides
81
what happens to difluorodeoxycytidine when it is taken up by cells?
it can be phosphorylated up to three times
82
what does diphospho-difluorodeoxycytidine do?
this inhibits ribonucleotide reductase - an enzyme that is important for producing nucleotides for S phase
83
what does triphospho-difluorodeoxycytidine do?
>it is incorporated into growing DNA strand >replication machinery adds next base onto DNA >machinery realises its made a mistake and dissociates from strand >this is called masked termination
84
what is replication machinery not very good at repairing?
the second last base it has just added onto growing strand
85
what two functions does difluorodeoxycytidine have?
it blocks replication and stops nucleotide synthesis
86
when therapies synergise, what does this mean
they work together
87
what is the first intervention done with a tumour? and what is used to mop up cells that the surgeon may have missed?
surgery | chemotherapy and radiotherapy
88
if metastasis has occur what can no longer be used?
radiotherapy | >as you don’t want to radiate the whole body
89
what is used for metastatic cancers? and what does this do?
chemotherapy | >prolong lifespan
90
what happens when cisplatin and radiotherapy are used in combination?
cisplatin adducts and strand breaks in close proximity to each other and this is much harder to repair >this leads to greater levels of death than either treatment alone
91
give 4 other example of how chemotherapy and radiotherapy can be synergised
1. use a chemo that will inhibit a certain DNA repair enzyme and this will enhance radiations ability to cause cell death 2. target cancer cells and stroma cells that are helping the cancer cells with two different agents 3. use chemo agents that inhibit cells survival pathways 4. can use chemo to restrict cells to more sensitive phases of cell cycle
92
what phases of the cell cycle are more sensitive to radiation damage? and what can be used to get cancer cells into these phases?
G2 and M phase | >taxanes
93
what is radioresistance? and how does this vary between cells?
this is the level of ionising radiation that organisms are able to withstand. >different cells types of differentially sensitive to radiation damage.
94
what type of non-tumour cells are most sensitive to radiation? and what implication does this have on therapy?
bone marrow stem cells >we need to be aware of this when deciding what dose to give a patient, we also need to direct the radiation away from these areas of the body
95
what three factors can affect how sensitive a tumour is to radiation?
oxygen tension, tumour size and individual variation (i.e. there is heterogeneity in the population, some people are more sensitive to others)
96
why would it be useful to know how susceptible someone is to radiotherapy before treatment?
to decide what does to give the patient: | you don’t want to induce more damage than can be repair in other tissue and lead to further tumorigenesis
97
how can tumour size affect effectiveness of radiotherapy?
if the tumour is localised and concentrated then it is easier to treat. when it is spread throughout the body it is less easy to treat with radiotherapy
98
in terms of oxygen tension, what type of tumour cells are more sensitive to radiation?
anoxic (high levels of oxygen)
99
what do tumour cells upregulate in order to resit chemo? and what can be used to combat this?
transporter proteins to pump chemical out of their cells >chemo cannot accumulate in cells and so significant DNA damage is not caused >pump inhibitors - this results in more DNA when cells have these pumps
100
what do mechanisms that detoxify cells rely on? and what do they do? and how is this implicated in cancer?
P450 superfamily >they conjugate drugs with a small molecule to prevent their activity in >these enzymes are often upregulated in cancer and are good at inactivating chemo
101
chemotherapy and radiotherapy are very selective ways to treat cancer, TRUE or FLASE?
FLASE
102
better ways to target tumours need to be established, what is one way that the field is moving?
>individual tumour profiling prior to therapy >next gen sequencing to identify oncogenes to target >this will make for much more selective treatment
103
what will still be required with these more selective therapies?
chemo and radiotherapy

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