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Biology of Cancer > Seminar 11 - Chemoprevention > Flashcards

Seminar 11 - Chemoprevention Flashcards

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1
Q

How do tumour cells overcome the hallmarks of cancer?

A
  1. Evading growth suppressors - loss of RB suppressor
  2. Enabling replicative immortality - turned on telomerase
  3. Activating invasion and metastasis: inactivation of E-cadherin
  4. Tumour-promoting inflammation: COX over expression
  5. Avoiding immune destruction: infiltrating tumour-promoting inflammatory cells
  6. Genome instability and mutation: increased mutation rate
  7. Inducing angiogenesis: production of VEGF
  8. Resisting cell death - production of IGF survival factors
  9. Deregulating cellular energetics - increased glycolysis
  10. Sustaining proliferative signalling - activation of Ras oncogenes
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2
Q

List the main environmental factors that can be attributed to cancer development.

A
  1. Tobacco
  2. Diet - fruit/veg, meat, fibre, salt
  3. Occupation
  4. Alcohol
  5. Overweight and obesity
  6. Infections
  7. UV - Radiation
  8. Radiation - ionising
  9. Physical exercise
  10. Post-menopausal hormones
  11. Reproductive - breast feeding
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3
Q

Outline the WCRF/AICR Expert 2007 recommendations.

A
  1. Be as lean as possible without becoming underweight
  2. Be physically active for at least 30 minutes every day
  3. Avoid sugary drinks. Limit consumption of energy dense foods - particularly processed foods high in sugar, or low in fibre or high in fat
  4. Eat more variety of vegetables, fruits, wholegrains and pulses such as beans
  5. If consumed at all, limit alcoholic drinks to 2 for men and 1 for women a day
  6. Limit consumption of red meats and avoid processed meats
  7. Limit consumption of salty foods and foods processed with salt (sodium)
  8. Don’t use supplements to protect against cancer
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4
Q

Define therapeutic prevention of cancer.

A

The use of natural or synthetic compounds to reverse, delay, prevent or suppress carcinogenic progression to invasive cancer

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5
Q

What are the ideal properties of a therapeutic chemopreventive agent?

A
  1. High efficacy
  2. Low or no toxicity
  3. Known mechanism(s)
  4. Acceptance by humans
  5. Low cost
  6. Oral formulation
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6
Q

Define the main 2 types of cancer preventive therapies.

A

Blocking agents: compounds which inhibit carcinogenesis by preventing carcinogens from being generated, or from reaching, or reacting with, critical target sites in tissues

Suppressive agents: compounds which act after carcinogenic exposure by suppressing the expression of neoplasia

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7
Q

State the putative mechanisms of prevention by blockade mechanisms.

A
  1. Scavenging free radicals
  2. Antioxidant activity
  3. Induction of phase II drug metabolising enzymes
  4. Inhibition of phase I drug metabolising enzymes
  5. Induction of DNA repair
  6. Blockade of carcinogen uptake
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8
Q

State the putative mechanisms of cancer prevention by suppression.

A
  1. Altering gene expression
  2. Induction of apoptosis of preneoplastic lesions
  3. Inhibition of cell proliferation and clonal expansion
  4. Induction of terminal differentiation, senescence
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9
Q

Outline the ways signal transduction can be modulated via suppression.

A
  1. Inhibition of ornithine decarboxylase activity
  2. Induction of phosphatases
  3. Inhibition of tyrosine kinase activity
  4. Inhibition of the arachidonic acid cascade
  5. Modulation of hormone/growth factor activity
  6. Induction of gap junction communication
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10
Q

Outline an example of tertiary cancer prevention.

A

SERMs for prevention of breast cancer recurrence and metastases

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11
Q

State examples of secondary cancer prevention.

A
  1. Topical diclofenac for prevention of skin cancer in patients with actinic keratosis
  2. Bladder cancer prevention using valrubicin for patients with carcinoma in situ
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12
Q

Outline examples of the primary prevention of cancer.

A
  1. Low-dose aspirin for the primary prevention of colorectal cancer in adults aged 50-59 with a greater than or equal to 10% 10-year cardiovascular disease risk
  2. Tamoxifen in healthy women at high risk of breast cancer
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13
Q

How does inhibition of PARP-1 increase double strand DNA damage?

A

Prevents recruitment of repair factors to repair single stranded breaks

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14
Q

What repair factors are used to repair single stranded breaks?

A
  1. pol B
  2. XRCC 1
  3. PNK 1
  4. LigIII
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15
Q

How does cancer cell death occur when cancer cells are BRCA-deficient?

A

Deficient HR pathway –> DSBs are not repaired –> cancer cell death

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16
Q

State examples of carcinogenic hormones and the cancers they are associated with.

A

Oestrogen - breast cancer

Testosterone - prostate cancer

17
Q

State the classes of endocrine therapies used for treatment of breast cancer and give examples for each.

A
  1. Antioestrogen: tamoxifen
  2. Aromatase inhibitors: anastrozole, letrozole, exemestane, vorozole, formestane
  3. Progestogens: megestrol
  4. LHRH agonists: goserelin
18
Q

Why are aromatase inhibitors preferred for treatment of breast cancer in post-menopausal women?

A

Reliant on aromatase enzyme to produce estrogen - may not work as well in pre-menopause because still producing ovarian relating estrogen

19
Q

What are the advantages of using surrogate endpoint biomarkers in chemoprevention?

A

Would allow:

  1. Smaller trials
  2. Quicker assessment of efficacy without waiting for tumours
20
Q

What are the disadvantages of using surrogate endpoint biomarkers in chemoprevention?

A
  1. Requires a detailed understanding of the cancer process in any given tissue
  2. Requires a detailed understanding of the mechanism of action of the chemopreventive agent
21
Q

Outline the characteristics of a chemopreventive trial.

A
  1. Sample size: thousands
  2. Duration: years
  3. Toxicity: accept only minimal toxicity
  4. Dosage: minimize dose, emphasise safety
  5. Power: continual monitoring of risk relationship - need for efficacy biomarkers
22
Q

Outline the characteristics of a chemotherapy trial.

A
  1. Duration: months
  2. Sample size: tens/hundreds
  3. Toxicity: accept moderate toxicity
  4. Dosage: maximise dose, emphasise efficacy
  5. Power: easy to calculate
23
Q

What is the rationale for using dietary-derived agents in chemoprevention?

A
  1. Need agents where there is pre-existing evidence of safety
  2. Often consumed in diet regularly - considered relatively safe
  3. Multi-targeted: can interfere with many pathways involved in carcinogenesis
24
Q

State some examples of preventive phytochemicals.

A
  1. Curcumin
  2. EGCG
  3. Sulforaphane - broccoli
  4. Resveratrol - grapes
25
Q

What cancer chemopreventive processes are looked for in in-vitro tests?

A
  1. Inhibition of pre-malignant or tumour cell growth
  2. Induction of apoptosis
  3. Induction of senescence
  4. Induction of cell cycle arrest
  5. Induction of autophagy
  6. Inhibition of Phase I metabolism
  7. Induction of phase II metabolism
  8. Antioxidant activity
  9. Antimutagenesis
  10. Decreased numbers or proliferation of cancer or premalignant stem cells
  11. Modulation of biochemical events relating to chemoprevention: inhibition of COX-2, protein kinases, other signalling cascades, transcription factor activation, activation of AMPK
26
Q

State the properties of cancer cells.

A
  1. Loss of contact inhibition
  2. Increase in growth factor secretion
  3. Loss of tumour suppressor genes
  4. Increase in oncogene expression
  5. Abnormal heterogenous cells
  6. Frequent mitoses
27
Q

State the properties of normal cells.

A
  1. Few mitoses
  2. Oncogene expression is rare
  3. Intermittent or coordinated growth factor secretion
  4. Presence of tumour suppressor genes
28
Q

How does leukaemic transformation occur in CML?

A
  1. abl oncogene on 9 adjacent to breakpoint cluster gene on 22
  2. Fusion leads to transcription of a protein and leukaemic transformation
29
Q

Which chromosome is expressed in 95% of CML patients?

A

Philadelphia chromosome

30
Q

Describe the 2 main types of rodent models that can be used in carcinogenesis.

A
  1. Chemical models:
    Tumours in rodents induced by chemical carcinogens, tumour development rapid, localisation and nature of tumour dependent on dose, strain or rodent, etc
  2. Mutant/genetically engineered models:
    Rodents which carry mutations in genes implicated in the initiation or progression of cancer or where the gene can be knocked out/mutated
31
Q

Outline the mechanism of action of tamoxifen in chemoprevention.

A
  1. SERM
  2. Primary action in breast tissue is as an antioestrogen
  3. Partial agonist properties in other tissues
32
Q

Outline the importance of genetic polymorphisms.

A
  1. Influences host response to endogenous/exogenous carcinogenic factors
  2. Drug metabolising enzymes
  3. Repair enzymes - ability to repair DNA
  4. Receptors, kinases, transcription factors - cell signalling
33
Q

List the problems associated with use of chemopreventive agents.

A
  1. Bioavailability
  2. Cell-type specificity
  3. Cancer subtypes
  4. Concentration effect - high vs. low
  5. Primary targets
34
Q

State the factors stimulated by PGH2.

A
  1. TXA2 synthases
  2. PG synthase:
    - PGF2a
    - PGI2
    - PGE2 –> inflammation and neoplasia
    - PGD2
35
Q

What is the mechanism by which coxibs have been associated with increased cardiovascular risk?

A
  1. Endothelial prostacyclin (COX-2) inhibits platelet aggregation, causes vasodilation, inhibits vascular proliferation
  2. Thromboxane (COX-1) causes platelet aggregation, vasoconstriction and triggers vascular proliferation
  3. Coxibs cause imbalance

Biology of Cancer (11 decks)

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