Chemoprevention

Question 1

What are the extra hallmarks of cancer?

Answer 1

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

Question 2

How can cancer evade growth suppressors? (Example)

Answer 2

Loss of Rb suppressor

Question 3

Example of how cancer avoids immune destruction?

Answer 3

Infiltrate tumour-promoting inflammatory cells

Question 4

Example of how cancer enables replicative immortality?

Answer 4

Turns on telomerase

Question 5

Example of how there is tumour-promoting inflammation?

Answer 5

COX over-expression

Question 6

Example of how cancer cells activate invasion and metastasis?

Answer 6

Inactivate E-cadherin

Question 7

Example of how cancer cells induce angiogenesis?

Answer 7

Produce VEGF

Question 8

Example of how cancer cells have genome instability and mutation?

Answer 8

Increased mutation rate

Question 9

Example of how cancer resists cell death?

Answer 9

Produces insulin-like growth factor (IGF) survival factors

Question 10

Example of how cancer cells deregulate cellular genetics?

Answer 10

Increase glycolysis

Question 11

Example of how cancer cells sustain proliferative signalling?

Answer 11

Activate Ras oncogenes

Question 12

What are some avoidable risk factors of cancer?

Answer 12

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

Question 13

Define chemoprevention

Answer 13

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

Question 14

What a features of an ideal chemoprevetive agent?

Answer 14

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

Question 15

What are blocking agents?

Answer 15

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

Question 16

Give some examples of how blocking agents work

Answer 16

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

Question 17

What are suppressing agents?

Answer 17

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

Question 18

How can suppressing agents work?

Answer 18

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

Question 19

How can signal transduction be modulated by suppressing agents?

Answer 19

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

Question 20

List the six hallmarks of cancer

Answer 20

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

Question 21

What is primary chemoprevention?

Answer 21

Prevention in high risk individuals without any disease

Question 22

What is secondary chemoprevention?

Answer 22

Patients with pre-invasive dysplasia or paraneoplastic lesions

Question 23

What is tertiary chemoprevention?

Answer 23

Prevention in already successfully treated cancer patients - stop recurrence

Question 24

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

Answer 24

Acceptability of toxicity increases

Subject numbers required to achieve a significant outcome decreases

Question 25

What are the challenges of trialling chemoprevention

Answer 25

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

Question 26

Why are substitutive biomarkers useful for chemoprevention trials?

Answer 26

Allow for smaller trials | Quicker assessment of efficacy without waiting for tumours

Question 27

List the differences between chemoprevention and chemotherapy trial characteristics

Answer 27

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

Question 28

Why are genetic polymorphisms important?

Answer 28

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

Question 29

How can genetic polymorphisms have an effect?

Answer 29

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

Question 30

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

Answer 30

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

Question 31

What is the rationale behind dietary-derived agents?

Answer 31

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

Question 32

Describe the agent development process

Answer 32

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

Question 33

What happens in chemical rodent models?

Answer 33

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

Question 34

What happens in mutant or genetically engineered animal models?

Answer 34

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

Question 35

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

Answer 35

Colon cancer in a rat induced by azoxymethane

Question 36

Why is uptake of tamoxifen low?

Answer 36

Serious ADRs including - endometrial cancer (acts as a partial oestrogen agonist) - thromboembolic events

Question 37

What are some alternatives to tamoxifen with fewer adverse effects?

Answer 37

Raloxifene - fewer endometrial cancers, PEs, DVTs and almost as effective at preventing cancer Anastrozole - lower risk of developing endometrial cancer

Question 38

What does celecoxib do?

Answer 38

Prevents action of COX-2 enzymes causing inflammation and neoplasia

Question 39

What can celecoxib be used for?

Answer 39

As tertiary prevention | -shown to reduce the detection of advanced adenomas on follow-up colonoscopy

Question 40

Problems with celecoxib?

Answer 40

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

Question 41

What is aspirin thought to protect against?

Answer 41

Colorectal cancer

Question 42

Why is there currently a lack of consensus on aspirin?

Answer 42

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

Question 43

Why was beta-carotene unsuccessful?

Answer 43

Increased lung cancer in heavy smokers

Question 44

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

Answer 44

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