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Oncology > Chapter 2: Radiation and Chemical Carcinogenesis (Lecture 2) > Flashcards

Chapter 2: Radiation and Chemical Carcinogenesis (Lecture 2) Flashcards

1
Q

What is radiation?

A

Radiation is energy, which causes ionization of an atom, resulting in emission of an electron.

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2
Q

During radiation, a molecule can be hit, and thus an electron is lost. Does it become a positive or negative charged molecule?

A

A positive one! (since it loses an electron, which has a negative energy)

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3
Q

What is the main target of radiation?

A

The DNA molecule

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4
Q

True/false: The electron can only cause direct damage to the DNA

A

False, it can also indirectly cause damage, via production of Reactive Oxygen Species (ROS)

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5
Q

What % of damage to the DNA is done by direct and indirect radiation?

A

Direct: 30%, indirect: 70% (by radiolysis)

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6
Q

What ROS is formed after radiolysis?

A

OH· (hydroxyl radical)

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7
Q

What fixates the damage of an OH· (hydroxyl radical)?

A

Oxygen: R· + O2 -> RO2· –> ROOH (so funny enough, oxygen induces, but also fixes the problem)

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8
Q

The radiation units that are used are Gray and Sieverts. Can you briefly explain (the difference)?

A
  • Gray (Gy): absorbed dose in tissue, used in radiotherapy
    • 1 Gy = energy deposit of 1 Joule/ kg tissue
  • Sievert (Sv): Equivalent dose, unit for biological damage, used in radiation protection and radiation risk estimates
    • = absorbed dose in Gy multiplied by a factor relating to LET (= 1 for photons, 20 for alpha particles)
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9
Q

What does LET stand for and what is it?

A

Linear Energy Transfer = the average energy per unit distance deposited by a charged particle [keV/µm]

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10
Q

You can have low LET and high LET. Explain the differences between the two and how they look

A

The most important aspect is that high LET creates more damage than low LET

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11
Q

Fill in: The biological effect depends on … type and … deposit

A

The biological effect depends on radiation type and energy deposit (LET)

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12
Q

What are examples of radiation particles?

A
  • Alpha (2 protons + 2 neutrons)
  • Deuteron (proton + neuron)
  • Beta (electrons)
  • Neutrons
  • Protons
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13
Q

What are examples of electromagnetic radiation?

A

Photons: X-rays and gamma-rays

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14
Q

Fill in: The higher the LET, the *more/less* cell kill per Gy

A

More. This can also be depicted in the following figure

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15
Q

What can an alpha-particle (helium nucleus) be stopped by?

A

A piece of paper Note: it is not so dangerous for your body, unless you e.g. swallow it, it can cause harm

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16
Q

What can a beta-particle (electron) be stopped by?

A

A few mm of aluminium

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17
Q

What can a gamma-particle (photon) be stopped by?

A

Only by lots of e.g. lead (dutch: lood) Note: this is why they build bunkers when radiation is emitted

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18
Q

What is the most common/dangerous DNA alteration because of radiation?

A

DNA double strand breaks

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19
Q

True/false: DNA double strand breaks cause malignant transformation or cell death

A

Partly true. If the damage is excessive and/or irreparable, this is the case (there is malignant transformation/cell death). However if the amount and type of damage in the DNA can be handled, correct DNA repair can occur and there is cell survival.

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20
Q

Radiation carcinogenesis is a multi-step process. Explain the steps and their characteristics.

A
  • Initiation: DNA damage, chromosomal damage, > 1 mutation
  • Promotion: Cell proliferation, influenced by intercellular processes, growth factors, hormones and environmental factors
  • Progression: Invasion, migration, metastasis of cells because of mutations in cancer associated genes (proto-oncogenen en tumorsuppressor genes) and DNA repair genes, angiogenesis
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21
Q

Fill in: *Activating/Inactivating* mutations of tumorsuppressor genes is the most probable mechanism of radiation induced cancer, leading to malignant growth.

A

Inactivating

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22
Q

What are the benefits and risks of controlled exposure to radiation for diagnostics and therapy?

A

Benefits: therapy (cure, palliation, diagnostic information)

Risks: tissue/organ injury, teratogenic, genetic and carcinogenic effects

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23
Q

To give an indication, what percentage of secondary tumors is attributable to radiotherapy (in case of treatment)?

A

8%. So there is a 8% chance that someone will get a secondary tumor after radiotherapy. However you should consider that radiotherapy is not something that is done quickly, this is usually done in an advanced stage

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24
Q

Just a little info on radiotherapy that you do not have to learn:

A
  • There are 115.000 new cancer patients per year in the Netherlands
  • 50% of all cancer patients receive radiotherapy with curative or palliative intent (alone or combined with surgery/chemo)
  • 7x as many patients are cured by radiotherapy as by chemotherapy
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25
Q

For illustration, how much Sievert will you get on a plane and how much will you get for radiotherapy for a tumor?

A

Plane: 0,037 mSv Tumor: 20-100 Sv

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26
Q

Explain, due to an example of crossing the street, how low- and high dose have changes of inducing cancer

A

If you only cross the street once, you have a certain change of being hit by a car If you cross the street multiple times, you have an increasingly higher chance of being hit by a car. The same works for low- and high dose of radiation. There is always a chance to induce cancer

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27
Q

Information about carcinogenic effects on radiation is obtained via epidemiological studies of exposed population(s). What are some examples of these populations?

A
  • Patients treated with radiotherapy
  • Radiation workers
  • Victims of nuclear accidents/ activities
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28
Q

From different groups we observed that they have a specific susceptibility to certain types of cancer. Can you name which cancers are related to: A-bomb survivors, Ra-dial painters (radium), early radiologists, mine workers (radon) and exposure in nuclear accident?

A
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29
Q

In the lecture several examples of radiation in the past have been presented. Experiments with X-rays resulting into skin cancer, madame curie developing leukemia, how radium was thought to be a cure/miracle

A

However you do not have to know this

30
Q

What requirements do you need to study carcinogenic risk estimation

A
  • Large radiation exposed population
  • Non-exposed control group
  • Long follow-up time
  • Individual dosimetry data
31
Q

Children are much more sensitive to radiation-induced cancer than adults. Can you explain this due to the results that were found in the studies>

A

At a younger age cells proliferate faster and there is a longer lifespan to develop cancer. Therefore children are more susceptible than adults

32
Q

What is the latent period?

A

The period between exposure to radiation and manifestation of a tumor

33
Q

What is the risk period?

A

The period during which the risk to die from cancer is increased (generally between the minimal and maximal latent period)

34
Q

How does a graph look where on the y-axis there is a death risk and on the x-axis years after exposure for both leukemia and solid tumors? Do they look the same?

A

Latent period = period between expose to radiation and manifestation of a tumor

35
Q

A life span study was done on the atomic bomb survivors on the solid cancer incidence. It is very hard to find a study group.. why is this population so good?

A
  • Large radiation exposed population (>80.000 persons)
  • Non-exposed control group (>25.000)
  • Long follow-up time: 64 years/ongoing
  • Individual dosimetry data are available
36
Q

What were the most important findings of the life span study regarding the atomic bomb survivors?

A
  • Leukemia is the most frequent ionizing radiation-induced cancer.
  • Risk of solid cancer increase with dose in a linear fashion.
  • Age at exposure is important: children are the most sensitive to radiation.
37
Q

What are the factors determining the carcinogenic risk of radiation? (you don’t have to know this, for illustration)

A
  • Exposed volume
  • Total dose, dose rate and dose per fraction
  • Organ/ tissue specific sensitivity for cancer induction
  • Host susceptibility (genetic predisposition, immunodeficiency)
  • Biological factors (e.g. hormonal status, tissue repopulation rate)
  • Shape of the dose-cancer risk incidence curve: organ specific
  • Gender
  • Age at exposure
  • Environmental factors
  • Other biological/ physical factors
38
Q

How many deaths as a result of exposure to radiation in Fukushima?

a. 1
b. 100
c. 1.000
d. 10.000
* This is for illustration*

A

a. 1 (most people died of the blast)

39
Q

This figure shows the elctromagnetic spectrum. The orange line depicts from which point is ionizing and non-ionizing radiation. On which side is which?

A

Left: non-ionizing radiation

Right: ionizing radiation

40
Q

Fill in: Ionizing radiation is … radiation with high frequency

A

electromagnetic

41
Q

Of all the non-ionizing radiation, which are/is carcinogenic? (electric and magnetic fields, radio waves, microwaves, infrared, ultraviolet, and visible radiation)

A

Ultra Violet (UV) light from the sun

42
Q

Where do microwaves come from?

A

Microwave

43
Q

Where does electromagnetic radiation come from

A

Smart phone

44
Q

What are characteristic DNA damages of ionizing radiation? And non-ionizing radiation?

A

Ionizing radiation:

  • single strand DNA breaks
  • double strand DNA breaks
  • base damage

Non-ionizing radiation (UV)

  • Pyrimidine dimers (leading to point-mutations)
45
Q

What is the most sensitive cell cycle phase and why?

A

The S phase, there is replication ongoing, meaning there are twice as many DNA molecules. (also G2/M are sensitive)

46
Q

There are three types of UV light, name and shortly explain them all

A
47
Q

So the most carcinogenic UV radiation is UVB. What is a typical mutation and what does this lead to?

A

Cytosine and other pyrimidine dimers -> it is recognized as a thymine -> mutation -> skin cancer

48
Q

What are genotoxic and non-genotoxic compounds?

A
  • Genotoxic compounds: inducers of DNA damage (directly/indirectly)
  • Non-genotoxic compounds: tumor promotors
49
Q

What are the most important genotoxic DNA-damage inducing carcinogens?

A
  1. Polycyclic Aromatic Hydrocarbons (PAHs)
  2. Aromatic amines
  3. Nitrosamines and nitroamides
  4. Alkylating drugs
50
Q

What happens during DNA adduct formation?

A

An electron deficient group binds covalently to an electron rich group of the DNA (e.g. amino, hydroxyl, sulphhydryl group)

51
Q

What happens because of DNA adduct formation?

A

DNA adducts disturb the DNA structure and replication (mostly after enzymatic activation by cytochrome P450-dependant enzymes such as CYP1A1, which act as catalisator) If this is not repaired -> carcinogen specific mutation

52
Q

Earlier, we discussed inducing carcinogens (PAHs, aromatic amines, nitrosamines and nitroamides, alkylating drugs). An example of a nitrosamine is alkylnitrosoureas that is found in tobacco. This causes methylation of guanine. What does this look like and what happens because of it?

A

Fig p52. A methyl group is added as can be seen by the red box. This means the guanine will be recognized as an adenine and a base pair transition will take place (AT instead of CG)

53
Q

Another endogenous carcinogenic reaction is oxidative carcinogenesis (ROS). What permanent DNA damage will occur because of ROS?

A

Oxidation of nucleotides

54
Q

How can you be protected from ROS?

A

By glutathione, vitamins A, C and E. They inactivate ROS

55
Q

What are different type of drugs that can be used for chemotherapy?

A
  • Alkylating agents
  • Platinum-based drugs
  • Antimetabolites
  • Organic drugs
56
Q

In the lecture she discussed very briefly the different drugs for chemotherapy. Therefore, it will be discussed swiftly in here as well (more info will be in the book flashcards)

A

However, if you want a little more explanation (like me) on how these therapeutics work… I loved this video: https://www.youtube.com/watch?v=t7QDJOXeux4 Pharmacology - Chemotherapy agents (MOA, Alkalating, antimetabolites, topoisomerase, antimitotic ) Armando Hasudungan

57
Q

What do alkylating agents do?

A

They form DNA adducts via alkyl group

58
Q

What are examples of alkylating agents?

A

Chlorambucil, cyclophosphamide (require metabolic activity)

59
Q

What doe platinum-based drugs do?

A

They cause crosslinking of DNA as monoadduct, interstrand crosslinks, intrastrand crosslinks or DNA protein crosslinks (just remember: interstrand crosslink!)

60
Q

What are examples of platinum-based drugs?

A

Cisplatin and carboplatin

61
Q

What do anti-metabolites do?

A

They mimic the role of endogenous molecules, but inhibit nucleic acid synthesis

62
Q

What are examples of anti-metabolites?

A

Methotrexate (MTX) or 5-fluoro-uracil

63
Q

Examples of organic drugs are doxorubicin and vincristine/vinblastine. What do these drugs do?

A

Doxorubicin: topoisomerase II inhibitor Vincristine/vinblastine (microtubili inactivator)

64
Q

Can you match each molecule (a-d) to the correct names? Carboplatin=1, chlorambucil=2, cisplatin=3, cyclophosphamide=4

A

a=2, b=4, c=3, d=1.

65
Q

True/false: alkylating agents have a direct action without metabolization

A

True

66
Q

There can be intrinsic radiation/chemotherapy resistance. What are the different categories for this?

A
  • Location of cells in a tumor
  • Tumor cell heterogeneity
  • ‘Acquired’ drug resistance
67
Q

What is meant by resistance because of the location of the cells in a tumor?

A

Distance from blood vessels and vascular density: hypoxic cells are radio-resistant and drug delivery is abolished.

68
Q

What is meant by resistance because of the tumor cell heterogeneity?

A

Differences in radiation – drug sensitivity due to mutations. Cancer stem cells are generally more radio-chemo resistant because they are in G0 (yeah I don’t understand that either, please message me if you do)

69
Q

What is meant by resistance because of ‘acquired’ drug resistance

A

A cell can amplify the effect of a drug by the four ways depicted in the figure.

70
Q

The induction of pyrimidine dimers in DNA is typical after:

a. X-rays
b. Oxidative damage
c. UV radiation
d. Polycyclic aromatic hydrocarbons (PAH)

A

c. UV radiation

Oncology (18 decks)

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