Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

Oncology > Chapter 2: Carcinogenic agens, DNA repair and predispositions (Book §2.3-§2.6) > Flashcards

Chapter 2: Carcinogenic agens, DNA repair and predispositions (Book §2.3-§2.6) Flashcards

1
Q

What is the common mechanism of action for chemical carcinogens?

A

An electrophilic (electron deficient) form reacts with nucleophilic sites (sites that can donate electrons) in the purine and pyrimidine rings of nucleic acids

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

True/false: Chemical carcinogens only act directly on DNA

A

Not true, although they can act directly, some have to be metabolized, forming ‘ultimate carcinogens’

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

A family of enzymes is involved in the metabolism of chemicals in the liver and is important in the activation of carcinogens to ultimate carcinogens. How is this family called?

A

Cytochrome P450 enzymes

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

Carcinogens can be segregated into ten groups, but we will be discussing the four major classes here. What are they?

A
  • Polycyclic aromatic hydrocarbons (PAHs)
  • Aromatic amines
  • Nitrosamines
  • Alkylating agents
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

How do carcinogens exert their effects?

A

By adding functional groups covalently to DNA. Chemically modified bases, called DNA adducts, mask the identity of the base or distort the DNA helix, causing replication errors. The resulting mutations initiate cancer

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

True/false: PAH must be metabolized by P450 to become an ultimate carcinogen

A

True

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

Where can PAHs be found?

A

E.g. coal and cigarette smoke

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

How are heterocyclic (aromatic) amines formed?

A

By cooking meat

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

Where are nitrosamines and nitrosamines found?

A

In tobacco, or are formed when preservative nitrites react with amines in fish/meat during smoking

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

What is an exmample of an alkylating agent?

A

Mustard gas

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

Retroviruses are also oncogenic. How do they cause cancer?

A

Many cause cancers by encoding mutated forms of normal genes (i.e. oncogenes) that have a dominant effect in host cells. But the mechanism can differ and will be further discussed in Chapter 4 and 13

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

In addition to carcinogens, endogenous cellular reactions can generate mutations. How is this done?

A

Production of ROS (by oxidative respiration and lipid per oxidation) that can react with DNA and lipids to produce oxidized products

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

True/false: ROS are equally harmful when produced by radiation and respiration (endogenous reactions)

A

False, radiation produces extremely reactive hydroxyl radicals immediately and randomly within a cell, while respiration produces the less reactive superoxide radical immediately and only at specific locations within the cell

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

Endogenous chemical reactions also contribute to the formation of mutations. What is the most common? (+ explain what happens) example endogenous chemical reaction: hydrolysis of glycosidic bond between a base and deoxyribose, producing an abasic site

A

Deamination of cytosine to form uracil (uracil removed -> abasic site -> DNA pol. inserts an A -> transition from C to T)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

A family of cytidine deaminases play a role in the immune response that protects against retroviruses but also deaminate cytosines in the host genome. How is this family called?

A

APOBECs (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

Fill in: Clusters of TC -> TT transitions on the same strand of DNA and within localized regions from APOBEC activity is one mechanism for the formation of…..

A

kataegis (= a pattern of localized hypermutations identified in some cancer genomes, in which a large number of highly-patterned basepair mutations occur in a small region of DNA)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

DNA repair is an important line of defense against mutations caused by carcinogens/endogenous mechanisms. What are the five types of DNA repair systems?

A
  1. One-step repair
  2. Nucleotide excision repair (NER)
  3. Base excision repair (BER)
  4. Mismatch repair
  5. Recombinational repair
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

What is one-step repair? Explain the enzyme involved

A

The direct reversal of DNA damage. The repair enzym alkyltransferase directly removes an alkyl group form the O6 atom of guanine after exposure of DNA to alkylating carcinogens. In this case, a methyl group is transferred to a cysteine residue on the alkyltransferase and the alkyltransferase becomes inactive

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

Where is nucleotide excision repair (NER) used for?

A

Helix-distorting lesions such as pyrimidine dimers and bulky DNA adducts induced by UVB and PAHs respectively

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

Briefly describe the mechanism of NER

A

The lesion, along with some (24-32) adjacent nucleotides, is excised out by endonucleases, and DNA polymerase is used to fill in the gap using the opposite strand as a template

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

Which inherited disorder is characterized by a defect in NER?

A

Xeroderma pigmentosum (XP). They are hypersensitive to the sun and have a 1000x increased risk for skin cancer

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

Where is base excision repair (BER) used for?

A

They target chemically altered bases (e.g. 8-oxoguanine) that are induced mostly by endogenous mechanisms. If this repair is not done, there will be a point mutation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

We have discussed this before, but can you briefly explain how 8-oxoguanine can cause a mutation?

A

The 8-oxoguanine lesion can mimic T and form a stable 8-oxoguanine:A base pair, bypassing detection of replicative DNA polymerases. Failure to remove 8-oxoguanine results in a G -> T transversion mutation.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
24
Q

What is the first step of BER and which enzyme plays a role here?

A

The first step is carried out by a family of DNA damage-specific glycosylases (e.g. OGG1/MUTYH) which scan millions of base pairs per second for 8-oxoguanine lesions. The glycosylases flip the lesion outside of the helix and cleave the base from the DNA backbone, creating an abasic site.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
Q

What is the second step of BER and which enzymes play a role here? (reminder: the 8-oxoguanine is removed, creating an abasic site)

A

An endonuclease cleaves the DNA strand at the abasic site and DNA polymerase II replaces the nucleotide and ligase fills the gap.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
26
Q

Poly (ADP-ribose) polymerase (PARP) interacts with single strand break intermediates formed during BER and synthesizes a poly (ADP-ribose) chain. What does this lead to?

A

This poly (ADP-ribose) chain signals to other DNA repair proteins and also leads to modification of histones and relaxed chromatin structure for increased DNA accessibility

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
27
Q

Fill in: Mutation in the MUTYH gene that encodes a DNA glycosylase responsible for the removal of mismatched adenines paired with 8-oxoguanine may be the principal cause of ….

A

multiple colorectal adenoma syndrome

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
28
Q

What do mismatch repair mechanisms correct?

A

They correct replication errors that have escaped editing by polymerases. It includes repair of insertions and deletions produces as a result of slippage during the replication of repetitive sequences, as well as nucleotide mismatches

29
Q

What are the molecular events/steps of mismatch repair?

A
  1. Recognition of the mismatch is carried out by proteins hMSH2/6 and hMSH2/3 hMLH1/hPMS2 and hMHL1/hPMS1 are recruited
  2. The newly synthesizes strand is identified (flagged by the replication machinery)
  3. Endomucleases and exonuclease remove the nucleotides around, and including, the mismatch
  4. DNA polymerases resynthesizes a newly replicated strand
30
Q

Which cancer syndrome is associated with a germline mutation in hMLH1 or hMSH2 (who recognize mismatch)?

A

Hereditary non-polyposis colorectal cancer (HNPCC) Half of the patients have that mutation, which leads to loss of function

31
Q

What are the two types of recombinational repair that mend double-strand DNA breaks?

A

Homologous recombination and non-homologous end-joining

32
Q

The recombinational repair is shown in this figure. Can you explain what you are seeing steps a-h?

(globally understand the process, don’t learn by heart oc)

A
  • a) A double-strand break activates the ataxia telangiectasia mutated (ATM) kinase.
  • b) The RAD50/MRE11/NBS1 complex (a substrate of ATM) uses its 5’-3’ exonuclease activity to create single-stranded 3’ ends.
  • c) BRCA1/2 aids in the nuclear transport of RAD51 (gray circles).
  • d) RAD52 facilitates RAD51 binding to these exposed ends to form a nucleoprotein filament.
  • e) RAD51 can exchange a homologous sequence from a single strand within a double-stranded molecule (shown in red) with a single-stranded sequence.
  • f) The sequences from the double-stranded molecule are then used as a template sequence for repair.
  • g) Resolvases restore the junctions formed s a result of homologous recombination, called Holliday junctions.
  • h) Two copies of intact DNA molecules are produces with rarely any errors.
33
Q

Which inherited syndrome is associated with a mutation in the ataxia telangiectasia mutated (ATM) kinase? What are they sensitive to and what risk do they have?

A

Ataxia telangiectasia, patients are sensitive to X-rays and have an increased risk of lymphoma

34
Q

What do patients with gremlin mutations in the BRCA1 and BRCA2 gene have an increased risk for?

A

Breast- and ovarian cancers (those who develop cancer show that they acquired a second mutation later in life and illustrate that BRCA1/BRCA2 act as tumor suppressor genes)

35
Q

Can loss of function of BRCA1 and BRCA2 also occur in sporadic tumors?

A

Yes

36
Q

What can non-homologous end joining possibly result to (a failed attempt to repair)?

A

Chromosomal translocation (it is more error-prone than homologous)

37
Q

Before we delve into the different types of conventional (chemo- and radiation-) therapies. Can you roughly explain what the different mechanisms are. (this will be discussed later, don’t learn but understand the concept)

A

Several conventional therapies aim to induce extensive DNA damage in order to trigger apoptosis, and paradoxically include agents classified as carcinogens. Other conventional therapies inhibit DNA metabolism in order to block DNA synthesis in the rapidly dividing cancer cells. Still other drugs interfere with the mechanics of cell devision

38
Q

What are the three types of chemotherapy?

A
  • Alkylating agents and platinum-based drugs
  • Antimetabolites
  • Organic drugs

(note: in the lecture alkylating agents and platinum-based drugs are considered different groups, but since the mechanism is similar, by some they are considered the same group)

39
Q

How do alkylating agents work?

A

They form DNA adducts by covalent bonds via an alkyl group

40
Q

How do platinum-based drugs work?

A

By forming covalent bonds via the platinum atom (the DNA damage triggers apoptosis)

41
Q

What do bi-functional alkylating agents (type of alkylating agent) do? (not discussed in lecture)

A

These are compounds with two reactive groups that form intra-strand and inter-strand cross-links in DNA that alter the conformation fo the double helix or prevent separation of the DNA strand and interfere with DNA replication

42
Q

What are two common alkylating agents?

A

Chloroambucil and cyclophosphamide (last one has to be metabolized)

43
Q

What are two common platinum-based drugs?

A

Cisplatin and carboplatin

44
Q

What are antimetabolites and how to they work?

A

Antimetabolites are compounds that are structurally similar to endogenous molecules (e.g. nitrogenous bases of DNA) and therefore can mimic their role and inhibit nucleic acid synthesis

45
Q

What are two examples of antimetabolites?

A

Fluorodeoxyuridylate (F-dUMP) and methotrexate (MTX) See the figure for how similar they look

46
Q

How does f-dUMP work? (not discussed in lecture, really unsure if you should know this)

A

F-dUMP competes with the natural substrate dUMP for the catalytic site of thymidylate synthase, the enzyme that produces deoxythymidylate (dTMP). F-dUMP forms a covalent complex with the enzyme and acts as a suicide inhibitor, generating an intermediate that inactivates the thymidylate synthase through covalent modification. As a result, the dTMP and dTTP pools are depletes; dUMP and dUPT accumulate, and DNA synthesis is rapidly dividing cells is severe compromised.

47
Q

How does methotrexate (MTX) work? (not discussed in lecture, really unsure if you should know this)

A

IT targets an accessory enzyme of the same reaction as f-dUMP. As an analog of dihydrofolate, MTX is a competitive inhibitor of dihydrofolate reductase, the enzyme used to regenerate tetrahydrofolate. Tetrahydrofolate produces N5N10 methylenetetrahydrofolate that is required in the thymidylate synthase reaction

48
Q

An example of an organic drug is doxorubicin. What does this do?

A

Doxorubicin is a microbial anthracycline antibiotic that inhibits topoisomerase II, an enzyme that releases torsional stres during DNA replication, by trapping single-strand and double-strand DNA intermediates. It can also form DNA adducts and intercalate into DNA.

49
Q

What is a serious side effect of doxorubicin? (not discussed in the lecture, unsure if you should know this)

A

Cardiac damage. However new compounds have been found that can block cardiac toxicity

50
Q

What are two opposing strategies that can be used to disrupt the mitotic spindle? (not discussed in the lecture, unsure if you should know this)

A

The plant alkaloids vincristine and vinblastine (from the Madagascar periwinkle plant) bind to tubular and prevent microtubule assembly, in contrast to the drug paclitaxel (taxol) which binds to the ß-tubulin subunit in polymers and stabilizes the microtubules against depolymerization.

51
Q

Is ionizing or non-ionizing radiation used as treatment to tumors?

A

Ionizing radiation

52
Q

What happens in the cell because of radiation?

A

Radiation reacts with water inside cells to generate ROS that damage DNA. Apoptosis will be induced in cells that contain large amounts of DNA damage

53
Q

Fill in: The supply of … affects the potency of ionizing radiation and is thought to be caused by the generation of ROS

A

oxygen (extra info: and can assist in making radiation-induced damage permanent)

54
Q

There are more double-strand breaks in irradiated cells in presence of oxygen than cells irradiated in absence of oxygen. What does this mean for the treatment of a (solid) tumor?

A

The number of zones of hypoxia within a solid tumor influences the outcome of radiation treatment

55
Q

What is the major obstacle in achieve long-term effects with chemotherapy?

A

Drug resistance (this can be intrinsic or extrinsic)

56
Q

Cancer cells, as part of a large tumor mass, will receive different doses of treatment, depending on the location of individual cells within the mass. Explain

A

Cells deep within the tumor, and therefore furthest from blood supply, will receive lower doses than cells on the surface of the tumor. (cells within the same tumor may have acquired different mutations, some that lead to drug resistance)

57
Q

Fill in: Cells within the tumor that are classified as cancer stem cells are intrinsically/extrinsically resistant to the therapies

A

Cells within the tumor that are classified as cancer stem cells are intrinsically resistant to the therapies

58
Q

There are several mechanisms that a cancer cell may utilize to become resistant to chemotherapy. Explain the processes by use of this figure

A

The cells may become resistant by increasing the efflux of the drug, decreasing the intake of the drug, increasing the number of target molecules within the cell, or altering drug metabolism or DNA repair processes.

59
Q

The multi-drug resistance gene (MDR1) codes for a member of the ATP-dependent transporter family that is involved in the movement of nutrients/molecules across the membrane. Explain why a mutation in this gene can cause drug resistance. (this was not discussed in the lecture, don’t learn please, just understand a little)

A

This protein, normally a chloride ion efflux pump can bind a variety of chemotherapeutic drugs (doxorubicin, vinblastine, taxol). Upon binding (via conformational change) the drug is released extracellularly. A mutation in the pump can cause an increase in efflux.

60
Q

Fill in: Other drugs utilize specific transporters to enter cells. Mutations in these receptors may render them nonfunctional and decrease influx/efflux of the drug.

(this was not discussed in the lecture, don’t learn please, just understand a little)

A

Other drugs utilize specific transporters to enter cells. Mutations in these receptors may render them nonfunctional and decrease influx of the drug.

61
Q

What are two ways drug resistance of methotrexate (MTX) can occur? (this was not discussed in the lecture, don’t learn please, just understand the process)

A

(1) Resistance to MTX commonly occurs by mutation of the folate transporter or (2) by an increase in the number of drug target molecules by gene amplification

62
Q

The DHFR gene is amplified in some cancer cells. An increase in the efficiency of DNA repair, such as increased alkyltranferase activity, can give rise to resistance from alkylating agents such as… (this was not discussed in the lecture, don’t learn please, just understand the process)

A

doxorubicin

63
Q

What is synthetic lethal strategies?

A

It involves interactions whereby inhibiting the function of one gene is cytotoxic only in the presence of an additional mutation

64
Q

We are now going to delve in at the development of poly-(ADP-ribose) polymerase (PARP) inhibitors for use in tumors with BRCA1/2 mutations as an example of a synthetic lethal strategy

A

If you already understand this topic and feel no need to go in depth about it, you can finish this deck here :) It was discussed in the lecture but this will be very detailed!

65
Q

What are PARPs and what do they do?

A

PARPs are enzymes that are key in base excision repair (single-strand breaks). These enzymes synthesize poly (ADP-ribose) polymers that rapidly bind to DNA strand breaks to amplify the DNA damage signal and recruit DNA repair proteins

66
Q

What does inhibition of PARP. cause?

A

Impaired base excision repair and the accumulation of single-strand breaks (can lead to double strand breaks)

67
Q

The synthetic lethal strategy takes advantage of the characteristic DNA repair defect caused by mutations in tumors in some cases of inherited breast cancer. Explain how this works

A

Some of these patients carry a germline mutation in either tumor suppressor gene, BRCA1 or BRCA2 and acquire a somatic mutation in the other BRCA1/2 allele later in life. This results in a tumor that is deficient in homologous recombination and double-strand repair. The non-tumor cells in the patient do not carry the homozygous BRCA1/2 mutated genotype and retain the homologous recombination DNA repair pathway

68
Q

Which cells are targeted with PARP inhibitor?

A

Tumor cells that lack BRCA1/2 function are treated with PARP inhibitors have impaired homologous recombination and base excision repair pathways. These characteristics are lethal. Healthy cells treated with PARP inhibitors have a functional homologous recombination pathway and are viable.

69
Q

Some interesting information that you can read and skip

A

A PARP inhibitor (olaparib) is approved for patients with ovarian cancer with BRCA1/2 mutations. The approval of olaparib with its companion diagnostic for treatment in BRCA-positive ovarian cancer is a great stride for personalized cancer therapy. Additional PARP inhibitors are tested for other cancer types, such as prostate (which shows synthetic lethality)

Oncology (18 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions