Chemoprevention Flashcards
What are the extra hallmarks of cancer?
Genome instability
Tumour-promoting inflammation
Avoid immune destruction
Deregulate cellular genetics
How can cancer evade growth suppressors? (Example)
Loss of Rb suppressor
Example of how cancer avoids immune destruction?
Infiltrate tumour-promoting inflammatory cells
Example of how cancer enables replicative immortality?
Turns on telomerase
Example of how there is tumour-promoting inflammation?
COX over-expression
Example of how cancer cells activate invasion and metastasis?
Inactivate E-cadherin
Example of how cancer cells induce angiogenesis?
Produce VEGF
Example of how cancer cells have genome instability and mutation?
Increased mutation rate
Example of how cancer resists cell death?
Produces insulin-like growth factor (IGF) survival factors
Example of how cancer cells deregulate cellular genetics?
Increase glycolysis
Example of how cancer cells sustain proliferative signalling?
Activate Ras oncogenes
What are some avoidable risk factors of cancer?
Tobacco Diet Obesity Alcohol Occupation Radiation - UV and ionising Infections Increase exercise Breast feed (protective) Post-menopausal hormones
Define chemoprevention
Use of natural or synthetic compounds to reverse, suppress, prevent or delay the carcinogenic progression to invasive cancer
What a features of an ideal chemoprevetive agent?
High efficacy No/low toxicity Known mechanism Acceptance by humans Oral formulation Low cost
What are blocking agents?
Compounds that inhibit carcinogenesis by preventing carcinogens from being generated or from reaching or reacting with critical target sites in tissues
Give some examples of how blocking agents work
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
What are suppressing agents?
Compounds that act after carcinogenic exposure by suppressing the expression of neoplasia
How can suppressing agents work?
Alter gene expression
Inhibit cell proliferation and clonality expansion
Induce terminal proliferation - senescence
Induce apoptosis in preneoplastic lesions
Modulate signal transduction
How can signal transduction be modulated by suppressing agents?
Inhibit tyrosine kinase activity
Inhibit the arachidonic acid cascade
Modulate hormone/growth factor activity
Induce gap-junction communication
List the six hallmarks of cancer
Infinite replication Tissue invasion and metastasis Evade apoptosis Self-sufficiency in growth signals Insensitivity to anti-growth signals Sustained angiogenesis
What is primary chemoprevention?
Prevention in high risk individuals without any disease
What is secondary chemoprevention?
Patients with pre-invasive dysplasia or paraneoplastic lesions
What is tertiary chemoprevention?
Prevention in already successfully treated cancer patients - stop recurrence
What happens to acceptability of toxicity as you increase from primary to tertiary chemoprevention?
Acceptability of toxicity increases
Subject numbers required to achieve a significant outcome decreases
What are the challenges of trialling chemoprevention
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
Why are substitutive biomarkers useful for chemoprevention trials?
Allow for smaller trials
Quicker assessment of efficacy without waiting for tumours
List the differences between chemoprevention and chemotherapy trial characteristics
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
Why are genetic polymorphisms important?
Influence the response of the host to endogenous and exogenous carcinogenic factors
How can genetic polymorphisms have an effect?
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
What some other problems with chemopreventive agents when trying to prove their efficacy?
Bioavailability Cell-type specificity Cancer subtypes Concentration effects (high vs low) Primary targets
What is the rationale behind dietary-derived agents?
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
Describe the agent development process
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
What happens in chemical rodent models?
Tumours in rodents are induced by chemical carcinogens
Tumour development is rapid
Localisation and nature of tumour dependent on dose, strain of rodent etc
What happens in mutant or genetically engineered animal models?
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
What is an example of a cancer that is induce by what in chemical rodent models?
Colon cancer in a rat induced by azoxymethane
Why is uptake of tamoxifen low?
Serious ADRs including
- endometrial cancer (acts as a partial oestrogen agonist)
- thromboembolic events
What are some alternatives to tamoxifen with fewer adverse effects?
Raloxifene - fewer endometrial cancers, PEs, DVTs and almost as effective at preventing cancer
Anastrozole - lower risk of developing endometrial cancer
What does celecoxib do?
Prevents action of COX-2 enzymes causing inflammation and neoplasia
What can celecoxib be used for?
As tertiary prevention
-shown to reduce the detection of advanced adenomas on follow-up colonoscopy
Problems with celecoxib?
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
What is aspirin thought to protect against?
Colorectal cancer
Why is there currently a lack of consensus on aspirin?
Risk vs benefit balance - risk of bleeding
Optimal dose for prevention unknown
Mechanism of action unknown
Why was beta-carotene unsuccessful?
Increased lung cancer in heavy smokers
Why might beta-carotene not have done what it was thought to do?
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
