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Year 1 Semester 2 > Oncology > Flashcards

Oncology Flashcards

1
Q

Describe epigenetics

A
  • Heritable modifications of DNA that do not alter the primary sequence
  • Result: altered gene expression
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2
Q

Describe DNA methylation

A
  • Covalent modification of a methyl group to cytosine at position C5 to make 5-methylcytosine
  • Most genes have GC rich areas of DNA in their promoter regions - CpG islands
  • Methylation of the C residues within the CpG islands leads to gene silencing
  • Little or no detectable DNA methylation in yeast and Drosophila
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3
Q

What are characteristics of Prader-Willi syndrome?

A
  • Mental retardation

- Obesity

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4
Q

What are characteristics of Angelman syndrome?

A
  • Mental retardation
  • ‘Happy puppet’ syndrome
  • Jerky movements + inappropriate laughter
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5
Q

What causes AS and PWS?

A

Defects in imprinted genes of chromosome 15 of the mother (AS) or the father (PWS)

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6
Q

Describe heterochromatin

A
  • Highly condensed in interphase
  • Transcriptionally inactive (contains few genes)
  • Replicates late in S phase
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7
Q

Describe euchromatin

A
  • Organised in 30nm fibre during interphase
  • Transcriptionally active
  • Replicates early in S phase
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8
Q

What is the position effect?

A

Spreading of heterochromatin into euchromatic regions causes cell to cell variability in gene expression

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9
Q

Explain X-chromosome inactivation

A
  • Discrepancy of 1 X-chromosome in males (XY) but 2 X-chromosomes in females (XX)
  • Solution: females need to silence one X-chromosome - X-chromosome inactivation
  • Mechanism of silencing is initiated by Xist - X-inactive-specific-transcript ‘marks’ inactive X: only expressed from inactive X-chromosome and codes for an RNA. No protein product and RNA remain in the nucleus. Followed by DNA methylation
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10
Q

Describe genomic printing

A
  • ~200 imprinted genes on autosomes
  • Imprinted genes only expressed from one allele
  • Dependent on parental origin
  • Imprinting resets on passage through germline
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11
Q

What are autosomes?

A

The chromosomes that are not involved in sex determination ie not X or Y

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12
Q

What are the four stages in the mechanism of chemical carcinogenesis?

A
  • Initiation
  • Promotion (reversible)
  • Progression (irreversible)
  • Malignancy
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13
Q

Describe initiation of carcinogenesis

A

Initiation event involves cellular genome mutations in tumour suppressor genes and oncogenes

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14
Q

Describe promotion of carcinogenesis

A

Promotion stimulates proliferation and causes both mutated and normal cells to proliferate

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15
Q

Describe progression of carcinogenesis

A

Irreversible enhancement/repression of gene expression. Selection of neoplastic cells for optimal growth genotype/phenotype in response to the cellular environment

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16
Q

What happens if there is a high dose of carcinogen?

A

Tumours develop (carcinogen acts as both initiator and promotor/accelerator)

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17
Q

What happens if there is a low dose of carcinogen?

A

No tumours develop (no initiator)

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18
Q

What happens if there are multiple doses of promoter?

A

No tumours develop (requires initiator)

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19
Q

What happens if there is a low dose of carcinogen + promotor?

A

Tumours develop

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20
Q

What happens to 2-naphthylamine in the liver?

A
  • Converts 2NTA to carcinogenic metabolite 2-amino-naphthol

- This is then detoxified to glucuronide (not carcinogenic)

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21
Q

What happens to glucuronide in the bladder?

A
  • Human urothelial cells express beta-glucuronidase

- Converts glucuronide to a carcinogen

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22
Q

What is asbestosis?

A

Formation of scar tissue in the lung as a result of exposure to asbestos

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23
Q

What does asbestosis more commonly predispose?

A

Bronchogenic carcinomas

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24
Q

What does exposure to blue asbestos fibres carry a risk of?

A

Mesothelioma

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25
Q

What is the latent period of mesothelioma?

A

25-45 years

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26
Q

What is another factor that increases chance of asbestos related cancer?

A

Smoking

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27
Q

Describe asbestos fibres

A
  • Asbestos is a fibrous silicate substance
  • When inhaled, the needle-like fibres become coated in proteins (asbestos bodies) and their presence excites a macrophage and giant cell response, rather like silicosis
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28
Q

What two genes are most frequently mutated in smoking-related lung cancers?

A
  • K-Ras

- p53

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29
Q

What is the active carcinogen in tobacco smoke?

A
  • 3,4-benzpyrene

- It is a polycyclic aromatic hydrocarbon

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30
Q

Describe the process that causes cancer due to the chemical in tobacco

A

3,4-benzpyrene is converted by aryl hydrocarbon hydoxylase into benzpyrene diol epoxide that binds to DNA forming damaging adducts

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31
Q

Describe glutathione S transferase (GSTM1)

A
  • Detoxifies carcinogens
  • Some individuals have null genotype so no GSTM1 protein is detectable
  • GSTM1 is polymorphic in the population, being null in about 30-50% of individuals depending on the ethnic group from which they come
  • Homozygous null individuals have an increased risk of lung cancer and smoking-induced bladder cancer
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32
Q

Will all heavy smokers develop lung cancer?

A
  • No

- In some smokers, AHH may not be expressed therefore DNA-binding epoxides are not generated

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33
Q

Describe carcinogenesis following chemotherapy

A
  • Rare
  • Secondary carcinogenesis can occur from the use of alkylating agents in chemotherapy
  • Risk of secondary tumours following cancer treatment
  • These result from DNA-damage inflicted on surviving normal somatic cells during treatment
  • DNA strand breakage and base damage induced
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34
Q

Why are nitrites and nitrates in our diet carcinogenic risks?

A
  • Gut bacteria convert nitrites and nitrates into nitrosamines
  • These are carcinogens that can lead to cancers of gastro-intestinal tract and liver
35
Q

How do nitrites and nitrates get into our diet?

A
  • Food additives

- Fertilisers that enter drinking water

36
Q

What is aflatoxicosis?

A

Aflatoxicosis is poisoning, especially of the liver, that results from ingestion of aflatoxins from contaminated food

37
Q

How can UV radiation be dangerous?

A
  • Non-ionising (causes excitation of atoms)
  • Damages DNA
  • Form pyrimidine dimers but can also break DNA by indirect mechanisms
  • Caucasians susceptible to melanoma and basal cell carcinoma
38
Q

What does neoplasm translate to?

A

New growth

39
Q

Describe a tumour

A

Usually one cell type with supporting tissue structures

  • Neoplastic cells
  • Stroma (connective tissue, fibroblasts, blood vessels, immune cells)

Autonomous
-Response to physiological stimuli lost or abnormal allowing unregulated growth

40
Q

What is the main risk for all adult cancers?

A

Age

41
Q

Describe benign tumours

A
  • Well circumscribed
  • Slow growth
  • No necrosis
  • Non-invasive
  • No metastasis
42
Q

Describe malignant tumours

A
  • Poorly circumscribed
  • Rapid growth
  • Often necrotic
  • Invasive
  • Metastasis
43
Q

What are some clinical effects of benign tumours?

A
  • Do not invade or metastasise
  • Space occupying effects - obstruction, epilepsy, conduction abnormalities
  • Haemorrhage - pulmonary, gastrointestinal
  • Hormone production - pituitary, adrenal, endocrine pancreas
44
Q

What are some ways that tumours spread?

A
  • Directly invade locally
  • Via the lymphatics
  • Via the bloodstream (haematological)
  • Through body cavities (transcoelomic)
45
Q

What are some microscopic features of benign cells?

A
  • Resemble tissue of origin
  • Well circumscribed
  • Well differentiated
  • Minimal nuclear pleomorphism
  • Mitotic figures normal
  • No necrosis
46
Q

What are some microscopic features of malignant cells?

A
  • Variable resemblance
  • Poorly circumscribed
  • Variable differentiation
  • Variable pleomorphism may be anaplastic
  • Mitotic figures abnormal
  • Necrotic
47
Q

What are some cytological features of malignancy?

A
  • High nucleo-cytoplasmic ratio
  • Nuclear hyperchromasia
  • Nuclear pleomorphism
  • Abnormal chromatin structure
  • Abnormal mitotic figures
48
Q

What do the letters stand for in TNM staging?

A
  • T - tumour size
  • N - degree of lymph node involvement
  • M - extent of distant metastases
49
Q

Explain the nomenclature of tumours

A
  • All end in -oma
  • Benign epithelial tumours are either papillomas or adenomas
  • Benign connective tissue tumours begin with term denoting cell of origin e.g lipoma
  • Malignant epithelial tumours are carcinomas
  • Malignant connective tissue tumours are sarcomas
50
Q

Describe teratomas

A
  • Contains elements of all three embryonic germ cell layers
  • Of germ cell origin
  • Benign and malignant forms
  • Ovarian - almost always benign
  • Testicular - more often malignant
51
Q

What are onocgenes?

A

-Drivers of neoplastic behaviour

52
Q

How do oncogenes work?

A
  • Direct stimulation of cell cycle dependent transcription
  • Increased/activation of growth factor receptors
  • Increased growth factor
  • Interference with intracellular signalling
52
Q

How do oncogenes work?

A
  • Direct stimulation of cell cycle dependent transcription
  • Increased/activation of growth factor receptors
  • Increased growth factor
  • Interference with intracellular signalling
53
Q

What do gatekeepers do?

A
  • Inhibit proliferation or promote the death of cells, especially those with DNA damage
  • Send negative signals to the cell
54
Q

What do caretakers do?

A
  • Maintain integrity of the genome by promoting DNA repair
  • Nucleotide excision repair
  • Mismatch repair
  • DNA double strand break repair
55
Q

What is an example of a protein that acts as a gatekeeper and caretaker?

A

p53

56
Q

What does p53 do?

A
  • Cell cycle arrest
  • DNA repair
  • Block of angiogenesis
  • Apoptosis
57
Q

Is BCL-2 pro or anti apoptotic?

A

Anti-apoptotic

58
Q

How does a proto-oncogene become an oncogene?

A

A single mutation

59
Q

What are the 7 deadly sins relating to metastasis?

A
  • Self-sufficiency in growth signals
  • Insensitivity to growth-inhibitory signals
  • Evasion of apoptosis
  • Defects in DNA repair
  • Limitless replicative potential
  • Sustained angiogenesis
  • Ability to invade and metastasise
60
Q

What causes cancer?

A

Mutations in DNA resulting in production of altered cells which have changes in proliferating mechanisms

Changes in the DNA caused by covalent modification:

  • spontaneous or genetic predisposition
  • ionising radiation or UV radiation
  • chemical carcinogens
61
Q

What are the 3 main approaches to dealing with established cancers?

A
  • Surgical excision
  • Radiotherapy
  • Chemotherapy
62
Q

What are the four types of agent traditionally used to treat cancer?

A
  • Alkylating agents
  • Antimetabolites
  • Cytotoxic antibiotics
  • Plant derivatives
63
Q

Describe alkylating agents

A
  • Most commonly employed anticancer drug
  • These are compounds which have the property of forming covalent bonds with suitable nucleophilic substances in the cell under physiological conditions
  • Causes intrastrand crosslinking of DNA
64
Q

How do alkylating agents cause DNA crosslinking?

A
  • Normally guanine residues in DNA exist predominantly in the keto tautomer
  • This allows them to readily make Watson-Crick base pairs by hydrogen bonding with cytosine
  • When the 7 nitrogen of guanine is alkylated it becomes more acidic and the enol tautomer is formed
  • This modified guanine can mispair with thymine residues during DNA synthesis creating a mutation
65
Q

How do alkylating agents treat cancer?

A

The mutation that it causes result in DNA damage which triggers cell death by apoptosis

66
Q

What are the major groups of alkylating agents?

A
  • Nitrogen mustards
  • Ethylenimines
  • Alkylsulphonates
  • Hydrazines and triazines
  • Nitrosoureas
  • Platinum based compounds
67
Q

Give an example of a nitrogen mustard

A

Cyclophosphamide

68
Q

Give an example of an alkylsulphonate

A

Busulphan

69
Q

Give an example of a nitrosoureas

A

lomustine or carmustine

70
Q

Give an example of a platinum based compound

A

Cisplatin

71
Q

What are the major groups of the antimetabolites?

A
  • Antifolates - e.g methotrexate
  • Antipyrimidines - e.g 5-FU, gemcitabine
  • Antipurines - e.g mercaptopurine, thioguanine
72
Q

Describe methotrexate

A
  • Folate analogue
  • Usually given orally but can also be given intramuscularly, IV or intrathecally
  • Low lipid solubility so does not cross the blood brain barrier easily
  • Polyglutamated which means it can be retained within cells for weeks
73
Q

What does methotrexate inhibit?

A

DHFR

74
Q

Describe the antipyrimidines

A
  • Fluorouracil (5-FU) interferes with thymidylate synthesis (DTMP)
  • It is converted into a fraudulent nucleotide FDUMP. Cannot be converted into DTMP
  • Cytarabine is an analogue of cytosine but has arabinose and not ribose attached
  • Undergoes phosphorylation to give cytosine arabinoside triphosphate
  • This inhibits DNA polymerase
  • Gemicitabine is an anologue of cytarabine
75
Q

Describe the antipurines

A
  • Mercaptopurine, thioguanine, fludarabine
  • Mercaptopurine is converted to 6-mercaptopurine-ribose-phosphate called lethal synthesis
  • 6-mercaptopurine-ribose-phosphate inhibits a number of enzymes in the de novo synthesis of purines
  • Fludarabine in its triphosphate form inhibits DNA polymerase
76
Q

What are some cytotoxic antibiotics?

A
  • Anthracyclines
  • Dactinomycin
  • Bleomycin
  • Mitomycin
77
Q

Describe anthracyclines

A
  • The main anticancer anthracycline antibiotic is doxorubicin. Others are daunorubicin, idarubicin, epirubicin, aclarubicin and mitoxantrone
  • It binds to DNA and inhibits both DNA and RNA synthesis
  • Its main cytotoxic action appears to be mediated through an effect on topoisomerase II the activity of which is markedly increased in proliferating cells
78
Q

What are some plant derivatives used to treat cancer?

A
  • Spindle poisons - affect microtubule function and prevent mitotic spindle formation
  • Vinca alkaloids
  • Taxanes
  • Camptothecins
  • Etoposide
79
Q

What are some other anticancer drugs?

A
  • Hormones (hormone inhibitors)
  • Monoclonal antibodies
  • Protein kinase inhibitors
  • Miscellaneous agents
80
Q

What are the main drawbacks of chemotherapy of cancer?

A
  • Target cell proliferation not the more lethal properties of invasiveness and metastasis
  • Non-specific cell killers rather than being aimed at the particular changes which make a cell malignant
  • The development of resistance, particularly multidrug resistance, to anticancer drugs
  • Leaves some remaining cells
81
Q

Describe tumour lysis syndrome

A
  • An acute side-effect of chemotherapy and a metabolic emergency
  • Occurs due to rapid cell lysis and large amounts of cell metabolites in blood
  • It is characterised by hyperuricaemia, hyperphosphataemia, hyperkalaemia and hypocalcaemia
  • If untreated can lead to acute renal failure, cardiac arrest and death
  • Risk assess patients prior to chemotherapy
  • Monitor and respond to deranged urea and electrolytes/fluid balance: dialysis may be required
82
Q

Describe the bone marrow side effect of chemotherapy

A
  • Myelosuppression - reduced production of cells which provide immunity, oxygen transport and clotting common with many chemotherapy agents
  • Only actively dividing cells in the bone marrow are affected
  • Monitor full blood count prior to then daily during treatment cycles
  • Occasional use of recombinant human granulocyte-colony stimulating factors recommended to reduce incidence/duration of myelosuppression
  • Cells with shorter life span are more affected
83
Q

What are some gastro-intestinal side effect of chemotherapy?

A
  • Nausea and vomiting
  • Loss of appetite
  • Constipation
  • Diarrhoea

Year 1 Semester 2 (26 decks)

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