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Biology Of Cancer > Chemoprevention > Flashcards

Chemoprevention Flashcards

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AP® Biology flashcards Biology 101 flashcards
1
Q

What are the extra hallmarks of cancer?

A

Genome instability
Tumour-promoting inflammation
Avoid immune destruction
Deregulate cellular genetics

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2
Q

How can cancer evade growth suppressors? (Example)

A

Loss of Rb suppressor

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3
Q

Example of how cancer avoids immune destruction?

A

Infiltrate tumour-promoting inflammatory cells

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4
Q

Example of how cancer enables replicative immortality?

A

Turns on telomerase

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5
Q

Example of how there is tumour-promoting inflammation?

A

COX over-expression

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6
Q

Example of how cancer cells activate invasion and metastasis?

A

Inactivate E-cadherin

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7
Q

Example of how cancer cells induce angiogenesis?

A

Produce VEGF

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8
Q

Example of how cancer cells have genome instability and mutation?

A

Increased mutation rate

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9
Q

Example of how cancer resists cell death?

A

Produces insulin-like growth factor (IGF) survival factors

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10
Q

Example of how cancer cells deregulate cellular genetics?

A

Increase glycolysis

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11
Q

Example of how cancer cells sustain proliferative signalling?

A

Activate Ras oncogenes

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12
Q

What are some avoidable risk factors of cancer?

A 
Tobacco
Diet
Obesity
Alcohol
Occupation
Radiation - UV and ionising 
Infections 
Increase exercise 
Breast feed (protective)
Post-menopausal hormones
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13
Q

Define chemoprevention

A

Use of natural or synthetic compounds to reverse, suppress, prevent or delay the carcinogenic progression to invasive cancer

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14
Q

What a features of an ideal chemoprevetive agent?

A 
High efficacy
No/low toxicity
Known mechanism
Acceptance by humans
Oral formulation
Low cost
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15
Q

What are blocking agents?

A

Compounds that inhibit carcinogenesis by preventing carcinogens from being generated or from reaching or reacting with critical target sites in tissues

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16
Q

Give some examples of how blocking agents work

A

Antioxidants
Scavenging free radicals
Introduction of phase II drug metabolising enzymes
Inhibition of phase I drug metabolising enzymes
Induction of DNA repair
Blockade of carcinogenic uptake

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17
Q

What are suppressing agents?

A

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

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18
Q

How can suppressing agents work?

A

Alter gene expression
Inhibit cell proliferation and clonality expansion
Induce terminal proliferation - senescence
Induce apoptosis in preneoplastic lesions
Modulate signal transduction

19
Q

How can signal transduction be modulated by suppressing agents?

A

Inhibit tyrosine kinase activity
Inhibit the arachidonic acid cascade
Modulate hormone/growth factor activity
Induce gap-junction communication

20
Q

List the six hallmarks of cancer

A 
Infinite replication
Tissue invasion and metastasis
Evade apoptosis
Self-sufficiency in growth signals
Insensitivity to anti-growth signals
Sustained angiogenesis
21
Q

What is primary chemoprevention?

A

Prevention in high risk individuals without any disease

22
Q

What is secondary chemoprevention?

A

Patients with pre-invasive dysplasia or paraneoplastic lesions

23
Q

What is tertiary chemoprevention?

A

Prevention in already successfully treated cancer patients - stop recurrence

24
Q

What happens to acceptability of toxicity as you increase from primary to tertiary chemoprevention?

A

Acceptability of toxicity increases

Subject numbers required to achieve a significant outcome decreases

25
Q

What are the challenges of trialling chemoprevention

A

Need a larger cohort
Need to wait a long time to see if there is any efficacy
Some agents can inhibit carcinogenesis in one setting, but enhance it in another
Some agents can be beneficial to some individuals but harmful to others

26
Q

Why are substitutive biomarkers useful for chemoprevention trials?

A

Allow for smaller trials

Quicker assessment of efficacy without waiting for tumours

27
Q

List the differences between chemoprevention and chemotherapy trial characteristics

A

Last years in prevention, months in chemotherapy

Sample size is thousands in prevention, tens/hundreds in therapy

Dosage is minimum with emphasis on safety, maximises with emphasis on efficacy in therapy

Toxicity, only minimal is accepted in prevention, moderate accepted in therapy

28
Q

Why are genetic polymorphisms important?

A

Influence the response of the host to endogenous and exogenous carcinogenic factors

29
Q

How can genetic polymorphisms have an effect?

A

Drug-metabolising enzymes can affect susceptibility to carcinogenic effects of cigarette smoke
Drug metabolising can be different, with altered response to chemoprevetive agents which need to be metabolised
Repair enzymes which can repair DNA
Receptors, kinases and transcription factors can affect cell signalling

30
Q

What some other problems with chemopreventive agents when trying to prove their efficacy?

A 
Bioavailability
Cell-type specificity
Cancer subtypes
Concentration effects (high vs low)
Primary targets
31
Q

What is the rationale behind dietary-derived agents?

A

Pre-existing evidence of safety because often consumed
Multi-targeted, can interfere with many pathways in carcinogenesis
Novel agents are not an option in chemoprevention

32
Q

Describe the agent development process

A

Look at chemopreventive activity in vivo, ex vivo and in stem cell models

Efficacy and pharmacokinetics in rodent models

Phase I pilot studies of PK/PD, safety and tolerability with healthy volunteers and window studies in patients

All to see if clinically effective

33
Q

What happens in chemical rodent models?

A

Tumours in rodents are induced by chemical carcinogens
Tumour development is rapid
Localisation and nature of tumour dependent on dose, strain of rodent etc

34
Q

What happens in mutant or genetically engineered animal models?

A

Use rodents which carry mutations in genes implicated in the initiation or progression of canned where the gene can be knocked or mutated
E.g. the multi-intestinal neoplasia mouse

35
Q

What is an example of a cancer that is induce by what in chemical rodent models?

A

Colon cancer in a rat induced by azoxymethane

36
Q

Why is uptake of tamoxifen low?

A

Serious ADRs including

  • endometrial cancer (acts as a partial oestrogen agonist)
  • thromboembolic events
37
Q

What are some alternatives to tamoxifen with fewer adverse effects?

A

Raloxifene - fewer endometrial cancers, PEs, DVTs and almost as effective at preventing cancer

Anastrozole - lower risk of developing endometrial cancer

38
Q

What does celecoxib do?

A

Prevents action of COX-2 enzymes causing inflammation and neoplasia

39
Q

What can celecoxib be used for?

A

As tertiary prevention

-shown to reduce the detection of advanced adenomas on follow-up colonoscopy

40
Q

Problems with celecoxib?

A

CVS risks
-stops endothelial prostacyclin being synthesised due to COX-2 inhibition - EP normally inhibits platelet aggregation, causes vasodilation and elevens vascular proliferation

-thomboxane produced by COX-1 causes platelet aggregation, vasoconstriction and vascular proliferation so get more of this because of imbalance between COX-1/2

41
Q

What is aspirin thought to protect against?

A

Colorectal cancer

42
Q

Why is there currently a lack of consensus on aspirin?

A

Risk vs benefit balance - risk of bleeding
Optimal dose for prevention unknown
Mechanism of action unknown

43
Q

Why was beta-carotene unsuccessful?

A

Increased lung cancer in heavy smokers

44
Q

Why might beta-carotene not have done what it was thought to do?

A

Incorrect dose
Co-carcinogen in presence of tobacco smoke?
May be a different constituent of fruit/veg that is chemopreventive such as folate or α-carotene

Biology Of Cancer (13 decks)

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