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SSC- Biology of Cancer > Chemoprevention > Flashcards

Chemoprevention Flashcards

1
Q

What % of patients with cancer can be cured?

A

Approx 50%

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2
Q

Why is prevention better than cure in terms of treatment?

A

It can be unpleasant, ineffective, and extremely expensive

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3
Q

Who does cancer have a huge impact on?

A
  • Patients
  • Families
  • Society
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4
Q

What are the main modifiable risk factors of cancer?

A
  • Tobacco
  • Bad diet
  • Overweight/obesity
  • Alcohol
  • Occupational exposures
  • Radiation
  • Infections
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5
Q

What has shown the importance of lifestyle and environment in cancer?

A

Immigration studies, showing the decreased incidence of stomach cancer in Japanese populations who immigrated to Hawaii

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6
Q

What recommendations were made in 2007 by the WCRF/AICR expert report to prevent cancer?

A
  • Be as lean as possible without being underweight
  • Be physically active for at least 30 minutes per ady
  • Avoid sugary drinks. Limit consumption of energy-dense foods (particularly processed foods high in sugar, or low in fibre, or high in fat)
  • Limit consumption of red meats and avoid processed meats
  • If consumed at all, limit alcoholic drinks to 2 for men and 1 for women a day
  • Limit consumption of salty foods and food processed with salt
  • Don’t use supplements to protect against cancer
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7
Q

Define chemoprevention

A

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

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8
Q

What characteristics should an ideal chemoprevention agent have?

A
  • High efficacy
  • No or low toxicity
  • Known mechanism
  • Acceptable by humans
  • Oral formulation
  • Low cost
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9
Q

What is the result of chemoprevention agents needing to have no or low toxicity?

A

Novel agents are not an option

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10
Q

Why are novel agents not an option in chemoprevention?

A

Because when you develop a new drug, it can take 20/30 years to find side effects

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11
Q

If novel agents can’t be used for chemotherapy, what can?

A

Repurposed drugs, such as aspirin and metformin, or dietary compounds

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12
Q

When in carciongenesis can cancer be prevented?

A

Anywhere before the cancer becomes malignant - gives a big window for prevention

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13
Q

What are blocking agents?

A

Compounds which inhibit carciogenesis by preventing carcinogens from being created, or from reaching, or reacting with, critical target sites in tissues

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14
Q

What are suppressing agents?

A

Compounds which act after carcinogenic exposure by suppressing the expression of neoplasia

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15
Q

What is true of the mechanism of action of most chemoprotective drugs?

A

They have many mechanims, and so often act as blocking agents and suppressing agents

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16
Q

Give 6 mechanisms of action of blocking agents

A
  • Scavenging free radicals
  • Antioxidant activity
  • Induction of phase II drug metabolising enzymes
  • Inhibition of phase I drug metabolising enzymes
  • Induction of DNA repair
  • Blockage of carcinogen uptake
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17
Q

Give 5 mechanisms of action of suppressin agents

A
  • Alteration in gene expression
  • Inhibition of cell proliferation or clonal expansion
  • Induction of terminal differentiation or senescence
  • Induction of apoptosis in preneoplastic lesions
  • Modulation of signal transduction
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18
Q

How can modulation of signal transduction be achieved?

A
  • Inhibition of arachidonic acid cascade
  • Inhibition of tyrosine kinase activity
  • Induction of phosphatases
  • Modulation of hormone/growth factor activity
  • Induction of ornithine decarboxylase activity
  • Induction of gap junction communication
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19
Q

What is primary chemoprevention?

A

Giving chemoprevention to a healthy patient, or one with a genetic predisposition

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20
Q

Give two examples of primary chemoprevention

A
  • Low dose aspirin to prevent colorectal cancer
  • Tamoxifen to prevent breast cancer
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21
Q

What is secondary chemoprevention?

A

Giving chemoprevention to patients with preinvasive dysplasia or preneoplastic lesions

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22
Q

Give an example of secondary chemoprevention

A

Use of valrubin in bladder cancer in situ

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23
Q

What is tertiary prevention?

A

Using chemopreventive agents to prevent relapse or the development of a new primary cancer

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24
Q

Give an example of tertiary chemoprevention

A

SERMs for prevention of breast cancer recurrence/mets

25
Q

How does the acceptibility of toxicity differ in primary and tertiary chemoprevention?

A

Increased toxicity and side effects acceptable in tertiary

26
Q

What are the challenges of chemoprevention research?

A
  • When researching a treatment, you have a population who are all of interest, and get a result in months. In chemoprevention, need a very large population, only a few of which would get cancer, and it takes decades to see if it works.
  • Hard to get funding, as not sponsered by pharmaceutical companies
27
Q

What can be used to overcome the problem of chemoprevention research taking a very long time?

A

Surrogate endpoints

28
Q

What do surrogate endopoint biomarkers allow?

A
  • Smaller trials
  • Quicker assessment of efficacy without waiting for tumours
29
Q

What do surrogate endopoint biomarkers require?

A
  • A detailed understanding of the cancer process in any given issue
  • Requires a detailed understandin of the mechanism of action of chemopreventive agents
30
Q

What is the difference in dosages between chemotherapy and chemoprevention studies?

A

Chemoprevention has to minimise the dose and maximise the safety. Chemotherapy has to maximise the dose, and emphaise efficacy

31
Q

What problems with chemopreventative agents must be considered before approving for public use?

A
  • Some agents inhibit carcinogenesis in one experimental setting, but enhance the process in another
  • Some agents may be beneficial to some individuals and harmful in others
32
Q

What is the importance of genetic polymorphisms in chemopreventative agents?

A

They influence the response of the host to endogenous or exogenous carcinogenic factors

33
Q

What molecules might have drug polymorphisms that are important to consider in chemoprevention?

A
  • Drug metabolising enzymes
  • Repair enzymes
  • Receptors, kinases, and transcription factors
34
Q

Give two examples of where genetic polymorphisms in drug metabolising enzymes may be important

A
  • Susceptibility to carcinogenic effects of cigarette smoke
  • Altered response to chemopreventive agents which require metabolism
35
Q

What are the potential pharmacokinetic problems to be considered with chemoprevention?

A
  • Bioavailability
  • Cell-type specificity
  • Cancer subtypes
  • Concentration effects
  • Primary targets
36
Q

What is the advantages of using dietary derived agents in chemoprevention?

A
  • Need agents where there is existing evidence of safety
  • Often consumed in the diet regularly, so they are considered to be relatively safe
  • They are multi-targeted in than they can interfere with many pathways involved in carciogenesis
37
Q

What are the steps in the chemopreventative agent development process?

A
  1. Look for chemopreventative activity
  2. Look for efficacy/PK in rodent models
  3. Phase 1 pilot studies, looking at PK, PD, safety, and tolerability
38
Q

What methods can be used to look for chemopreventive activity?

A
  • In vitro
  • Ex vivo
  • Stem cell models
39
Q

What are the types of rodent models in carcinogenesis/chemoprevention?

A
  • Chemical
  • Mutant or genetically engineered models
40
Q

What happens in chemical rodent models of carciogenesis?

A

Tumours in rodents induced by chemical carcinogens

41
Q

Describe tumour development in chemical rodent models of carciogenesis

A
  • Rapid
  • Localisation and nature of tumoru dependant on dose, strain of rodent etc
42
Q

What happens in mutant or genetically engineered rodent models of carciogenesis?

A

Rodents carry mutations in genes implicated in initiation or progression of cancer, or the genes are knocked out or mutated

43
Q

What kind of drug is tamoxifen?

A

A selective oestrogen receptor modulator (SERM)

44
Q

What is the action of tamoxifen?

A
  • Primary action is in breat tissue, as an antioestrogen
  • Partial oestrogen agonist properties in other tissues
45
Q

What effect does tamoxifen have in breast cancer?

A
  • It decreases the growth of human breast cancer cells
  • 40% decrease in new tumours in contralateral breast
46
Q

By how much does tamoxifen reduce the incidence of breast cancer in high risk women?

A

38% (48% decrease in OR+ cancers)

47
Q

What are the serious adverse effects of tamoxifen?

A
  • Endometrial cancer risk
  • Risk of venous thromboembolic events
48
Q

How does raloxifene compare to tamoxifen?

A
  • Nearly as effective in preventing invasive breast cancer
  • Caused half as many uterine malignancies, 20% fewer pulmonary emboli, and 28% fewer deep vein thrombi
49
Q

Why is the inhibition of COX enzymes a target for chemoprevention?

A

Because COX-1 and COX-2 are required in the synthesis of PGH2 from arachidonic acid, which then produced prostaglandins which lead to inflammation neoplasia

50
Q

What drugs target COX-1 in chemoprevention?

A

NSAIDs

51
Q

What drugs target COX-2 in chemoprevention?

A

Coxibs

52
Q

Give two examples of coxibs?

A
  • Celecoxib
  • Rofecoxib
53
Q

What are the adverse effects of coxibs?

A

Cardiovascular risk

54
Q

How do coxibs cause cardiovascular risk?

A

Endothelial prostacyclin (COX-2) inhibits platelet aggregation, causes vasodilation, and prevents vascular proliferation. Thromboxane (COX-1) causes platelet aggregation, vasoconstriction, and vascular proliferation - coxibs cause an imbalance

55
Q

By how much does daily aspirin use for 5 years reduce 20 year colorectal cancer mortality?

A

34%

56
Q

What aspects of aspirin as a chemopreventative agent are unknown?

A
  • Risk vs benefit balane
  • Optimal dose for prevention
  • Mechanism of action
57
Q

What happened with ß-carotene?

A

Epidemiology suggested that it would be a useful chemopreventive agent for lung cancer, however two large clinical trials actually demonstrated an adverse effect in heavy smokers.

58
Q

Why may ß-carotene not have been as successful as epidemiology might have suggested?

A
  • May not have been using the correct dose
  • May have been a co-carcinogen in the presence of tobacco smoke
  • May have been another constituent of fruits/veg that are chemopreventative, not the ß-carotene

SSC- Biology of Cancer (11 decks)

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