Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

LIFE207 > Selective Toxicity > Flashcards

Selective Toxicity Flashcards

1
Q

Antibiotic

A

A substance produced by a microorganism that in low concentrations inhibits the growth of another microbe.
Majority are based on naturally occurring compounds (i.e. penicillin).
May be semi-synthetic or synthetic.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

Types of bacteria

A

Gram negative (cocci/spherical or bacilli/rod-shaped):
- Outer membrane
- Periplasmic space
- Peptidoglycan layer
- Cell membrane
- Stains pink/red

Gram positive (cocci or bacilli):
- No outer membrane
- Thicker layer of peptidoglycan
- Cell membrane
- Stains purple

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

Antimicrobial susceptibility testing (AST)

A

Determines which antibiotics a pathogen is susceptible to (i.e. which antibiotic will inhibit growth)
Used to select appropriate antibiotic treatment

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

Breakpoint

A

Concentration of antibiotic which defines if a species of bacteria is susceptible or resistant to the antibiotic.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

Examples of gram negative bacteria

A

Cocci:
- Neisseria

Bacilli:
- Enterobacteriaceae family
- Escherichia coli
- Klebsiella pneumoniae
- Haemophilus
- Salmonella

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

Examples of gram positive bacteria

A

Cocci:
- Staphylococcus
- Staphylococcus aureas (methicilin-sensitive
(MSSA) and methicilin-resistant (MRSA))
- Coagulase negative (CoNS)
- Streptococcus

Bacilli:
- Listeria
- Clostridium
- Cornyebacterium
- Bacillus

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

Bacteriostatic agent and examples

A

Reversibly inhibits growth
Examples:
- Macrolides
- Sulfonamides
- Tetracyclines
- Oxazolidanones

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Bactericidal agent and examples

A

Causes irreversible lethal action on bacteria
Examples:
- Beta-lactams
- Aminoglycosides
- Glycopeptides
- Quinalones
- Rifamycins

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

Minimum inhibitory concentration (MIC)

A

The lowest visible dilution that inhibits growth of bacteria (first solution that appears clear).

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

MIC - gradient disk test

A
  • Culture taken from patient (e.g. blood, urine, sputum)
  • Culture with the greatest zone of inhibition means that drug has the greatest efficacy
  • Culture with no zone of inhibition is resistant to the drug
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

Bacterial targets and examples

A
  • Cell wall
    • Beta-lactams
    • Glycopeptides
  • Alteration of cell membranes
    • Polymyxins
    • Lipopeptides
  • Ribosomes (protein synthesis)
    • Aminoglycosides
    • Tetracyclines
    • Macrolides
    • Oxazolidinones
  • Biochemical pathways (interference)
    • Sulfonamides
  • RNA synthesis
    • Rifamycins
  • DNA synthesis
    • Fluoroquinolones
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

Targets of antibacterial agents and examples

A
  • Inhibit cell wall production
    • Penicillin binding proteins
    • Cephalosporins
    • Glycopeptides
  • Inhibit protein synthesis
    • Bind 30s or 50s ribosomal units
    • Chloramphenicol, tetracyline, aminoglycosides
  • Block biosynthetic pathways
    • Interfere with folate metabolism sulphonamides
  • Disrupt bacterial membranes
    • Polymyxins
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

What is an ideal antibiotic? (10)

A
  • Appropriate spectrum of activity for the clinical setting (i.e. gram positive, gram negative)
  • No toxicity to the host, well tolerated
  • Low tendency for development of resistance
  • Doesn’t induce hypersensitivities in the host
  • Rapid and extensive tissue distribution (quicker response)
  • Relatively long half-life
  • Free of interactions with other drugs
  • Convenient for administration
  • Relatively cheap
  • Chemically stable
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

Cell wall biosynthesis

A
  • Building block partially constructed in cytoplasm
  • Transported across cell membrane and completed
  • Bacitracin blocks carrier lipid from going back
  • Constructed from 2 sugars (NAM, NAG) and peptide chain
  • Linked to growing cell wall by enzyme (transglycosidation, stopped by vancomycin)
  • Final crosslinking reaction catalysed by transpeptidase enzymes (stopped by beta-lactams)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

Beta-lactam antibiotics examples

A
  • Penicillins
  • Cephalosporins
  • Carbapenems
  • Monobactams
  • Clavulanic acid
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

Mechanism of action for penicillin to transpeptidase (3)

A
  • Penicillin covalently links to enzyme’s active site via ester link
  • Penicillin acts as steric shield to prevent access of substrate/water to active site
  • Results in irreversible inhibition
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

Disadvantages of beta-lactams

A
  • Generally well tolerated
  • Penicillins associated with hypersensitivity which can limit use
  • High doses of carbapenems associated with risk of seizures
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

How do glycopeptides inhibit cell wall synthesis in bacteria? Give examples of glycopeptides

A
  • Bind directly to D-Ala-D-Ala terminus of peptidoglycan pentapeptide chain
  • Prevents cross-linking by transpeptidase
  • Only active against gram-positive bacteria (too large to penetrate gram-negative bacteria’s outer membrane
  • Examples: Vancomycin and teicoplanin
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

Therapeutic drug monitoring (TDM)

A

Minimises toxicity without compromising efficacy for some drugs with a narrow therapeutic index

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

How do polymyxins target the outer bacterial cell membrane? (4)

A
  • Interact with phosholipids in cell membrane
  • Specifically binds to lipopolysaccharides (LPS) in outer membrane of gram negative bacteria
  • Targets gram negative only
  • Only used as a last resort and can cause significant renal toxicity
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

What are the bacterial targets of antibiotics for protein synthesis? (3)

A
  • Chloramphenicol, macrolides and oxazolidanones, pleuromutilin: Bind to 50S subunit
  • Aminoglycosides: Bind to 30S subunit, induce misreading of genetic code, interferes with initiation complex
  • Tetracyclines: Bind to 30S subunit, block binding of tRNAs
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

Chloramphenicol targets (3)

A
  • Prevents peptide bond formation between new amino acid and peptide chain
  • Bacteriostatic
  • Broad spectrum, mainly used to treat eye infections and sometimes ear infections
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

What are the disadvantages of using chloramphenicol? (3)

A
  • Rare but fatal toxic effect in newborns (Grey-baby syndrome)
  • Caused by liver’s inability to glucoronidate the drug effectively in baby whose metabolising enzymes are developing
  • Prevented by correct dosing and therapeutic drug monitoring (not recommended for newborns < 2 weeks)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
24
Q

Macrolide targets and examples of macrolides (3)

A
  • Block polypeptide exit tunnel, thus stopping polypeptide chain from growing
  • Erythromycin, clarithromycin, azithromycin
  • Narrow spectrum and mostly bacteriostatic
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
Q

Oxazolidinone targets and an example (4)

A
  • Inhibit formation of initiation complex (larger ribosomal complex)
  • E.g. Linezolid
  • Gram positive activity - active against MRSA and VRE (gram positive bacteria)
  • Tolerability issues with bone marrow suppression
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
26
Q

Pleuromutilin targets and examples (4)

A
  • Novel drug (new drug never approved or marketed in US)
  • Binds to A and P site on 50S subunit, prevents binding of tRNA
  • E.g. Lefamulin (recently approved for treatment of community acquired pneumonia)
  • Activity against S.pneumoniae and S.aureus inc. MRSA
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
27
Q

Aminoglycoside targets and examples

A
  • Induce misreading of genetic code, interferes with codon:anticodon pairing
  • E.g. Gentamicin (commonly used), amikicin, trobramycin, neomycin and streptomycin
  • Broad spectrum, used mainly to treat gram negative bacteria
  • Bactericidal effect
  • Narrow therapeutic index (neurotoxic and otoxic)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
28
Q

Tetracycline target and examples

A
  • Blocks initiation by inhibiting tRNA, binding to the A site on the ribosome
  • E.g. Tetracycline, minocycline, doxycycline
  • Broad spectrum but used less due to bacterial resistance
  • Usually bacteriostatic
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
29
Q

Disadvantages of tetracycline

A
  • Chelator of metal ions: binds to calcium, magensium, iron and aluminium
  • Binds and forms non-absorbable salt which deposits in bones and teeth
  • Must be avoided in children <8 years (bones are growing) and pregnant women)
  • Patients warned not to drink milk or yoghurt due to formation of calcium salt and inactivation of tetracycline
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
30
Q

Bacterial folate synthesis

A
  • Bacteria synthesise their own folic acid whereas mammals aquire folate from diet
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
31
Q

What is synergy?

A

Combination of compounds increases efficacy of one or both compounds than compounds alone.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
32
Q

Fluoroquinolones targets (DNA synthesis) and examples

A
  • Inhibit two enzymes essential for DNA synthesis: DNA gyrase (gram negative) and Topoisomerase IV (gram positive)
  • Human cells lack DNA topoismerases
  • E.g. Ciprofloxacin, levofloxacin, moxifloxacin
  • Bactericidal effect
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
33
Q

Rifamycin target (RNA synthesis) and examples

A
  • Inhibit bacterial DNA-dependent RNA mechanism
  • Halts initiation of mRNA transcription and translation of polypeptides
  • E.g. rifampicin
  • Bactericidal activity against gram positive and mycobacteria (used more in TB)
  • Induces cytochrome P450 enzymes so can increase metabolisms of co-administered drugs which are substrates leading to sub-therapeutic levels
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
34
Q

Antimicrobial resistance

A
  • Inability to kill or inhibit organism with clinically achievable drug concentrations
  • Resistance may be naturally resistant (innate)
  • Resistance may be acquired (mutation or acquisition of foreign DNA)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
35
Q

Factors which may accelerate the development of resistance

A
  • Inadequate levels of antibiotics at the site of infection
  • Duration of treatment too short
  • Overwhelming numbers of organisms
  • Overuse/ misuse of antibiotics
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
36
Q

General mechanisms of of resistance (7)

A
  • Altered permeability
  • Inactivation/ destruction of antibiotic
  • Altered binding site
  • New binding sites
  • Efflux (flowing our of a substance) mechanisms (pumps)
  • Bypass of metabolic pathways
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
37
Q

Classifications of bacterial resistance

A
  • Intrinsic, e.g. gram negative barrier is hard to penetrate due to outer membrane permeability
  • Acquired:
    • Modification of genetic material/acquisition of new genetic material
    • Vertical gene transfer (spontaneous mutations). Once developed, transferred directly to bacterial descendant during DNA replication
    • Horizontal gene transfer (exchange of genes between strains and species)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
38
Q

Horizontal gene transfer (3 types)

A
  • Transformation: naked DNA uptake
  • Transduction: bacterial DNA transferred by virus (e.g. Phage)
  • Conjugation: DNA transferred through cell to cell contact
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
39
Q

Selective pressure in bacteria (susceptibility and resistance)

A
  • With high numbers of bacteria, some will be resistant to antibiotics
  • Low drug concentrations will kill susceptible bacteria but not mutants
  • Resistant members multiply due to preferred conditions
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
40
Q

Multi-drug resistant (MDR) bacteria

A

Resistant to multiple antimicrobial classes (at least one agent in three or more classes). Often found mainly in hospitals and long-term care facilities.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
41
Q

ESKAPE pathogens

A
  • Enterococcus faecium (VRE - vancomycin-resistant enterococcus)
  • Staphylococcus aureus (MRSA - methicillin-resistant A. aureus)
  • Klebsiella pneumoniae (carbapenemase producer)
  • Acinetobacter aeruginosa
  • Pseudomonas aeruginosa
  • Enterobacter species (ESBLs producer)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
42
Q

What is tuberculosis?

A
  • Bacterial infection in the lungs
  • Caused by Mycobacterium tuberculosis. Resistant to antibiotics: slow growth (most antibiotics active against rapidly growing cells) and lipid rich cell wall (impermeable)
  • Most often affects the lungs (can affect other sites)
  • Contagious (spreads through air droplets)
  • Considered leading cause of death from single infections agent (higher than HIV however large percentage of HIV patients die from TB)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
43
Q

TB epidemic data (from 2017)

A
  • 8 countries account for 2/3 s of global number of incidences: China, Indonesia, Philippines, Pakistan, Nigeria, Bangladesh, South Africa
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
44
Q

TB statistics (from 2018)

A
  • 1.5 million people died from TB (inc. 251,000 among HIV patients)
  • Leading killer of people with HIV
  • Major cause of death due to antimicrobial resistance
  • 10 million people fell ill with TB (5.7m men, 3.2m women, 1.1m children)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
45
Q

Discovery of the cause of TB

A
  • In 1882, Robert Koch discovered TB caused by Mycobacterium tuberculosis
  • Lipid rich cell wall containing mycolic acid creates waxy coating (prevents digestion) and low permeability (prevents drug access)
  • Gram positive aerobic bacilli
  • Slow growth rate compared to most bacteria (15-20h for cell division)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
46
Q

TB symptoms

A

Latent TB:
- No symptoms
- 5-10% will develop TB disease
- Risk higher in immunocompromised (e.g. HIV patients)

TB disease:
- Weight loss and loss of appetite
- Night sweats
- Fever
- Fatigue
- Chills
- In lungs: coughing and chest pain

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
47
Q

Aims of TB treatment

A
  • Cure individual patient of TB
  • Minimise risk of death and disability
  • Prevent relapse
  • Decrease transmission to others
  • Prevent development of acquired resistance
  • Treatment must be for at least 6 months
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
48
Q

Management of TB

A

Physical measures:
- Isolate patients with possible TB in private room with negative pressure
- Medical staff wear high-efficiency disposable masks sufficient to filter bacillus
- Continue isolation until sputum spears are negative for 3 consecutive determinations (usually after approx. 2-4 weeks of treatment)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
49
Q

Anti TB targets

A
  • Isoniazid: Inhibits synthesis of mycolic acid
  • Ethambutol: Inhibits cell wall synthesis
  • Pyrazinamide: Mode of action not fully understood
  • Bedaquiline: Inhibits ATP synthesis
  • Para-aminosalicylic acid (PAS): Disrupts folate metabolism
  • Rifampicin: RNA synthesis inhibitor
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
50
Q

Treatment for Drug-Sensitive TB

A
  • 1st line treatment is combination of 4 drugs: Isoniazid, Rifampicin, Ethambutol, Pyrazinamide
  • Oral
  • Taken daily for at least 6 months
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
51
Q

Isoniazid’s (INH) mode of action

A
  • Inhibition of synthesis of mycolic acid
  • Bactericidal in rapidly dividing mycobacteria
  • Delivered as pro-drug and activated by catalase-peroxidase KatG
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
52
Q

Resistance and disdvantages of INH

A
  • Resistance to INH alone/with other drugs is 2nd most common type (mutations in KatG gene prevents conversion of pro-drug)
  • Hepatotoxicity (more common in older people and alcoholics)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
53
Q

Rifampicin (5)

A
  • Polyketide with a napthoquinone core
  • Mode of action includes inhibition of DNA dependent RNA polymerase in prokaryotic cells
  • One of most active anti TB agents known, also effective against leprosy and most gram positive bacteria
  • Resistance develops rapidly
  • Oral delivery and good distribution is tissues and body fluids like cerebrospinal fluid (CSF)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
54
Q

Pyrazinamide (PZA) (4)

A
  • Highly specific, only active against Mycobacterium tuberculosis
  • Only tuberculostatic at slightly acidic pH
  • Resistance due to impaired uptake and mutations in pyrazinamidase (stops pyrazinoic acid production)
  • Disadvantages: gout, GI upsets, malaise and fever. Liver function should be assessed before treatment.
55
Q

Ethambutol (5)

A
  • Only affects mycobacteria
  • Interrupts cell wall synthesis
  • Inhibits arabinosyl transferase (disrupts arabinogalactan synthesis) so prevents formation of complex in cell wall leading to increased permeability
  • Resistance mediated by mutations altering target gene
  • Resistance emerges rapidly if drug used alone
56
Q

MDR-TB

A
  • Caused by strains resistant to at least both isoniazid and rifampicin
  • Much longer duration of treatment required (e.g. 20 months)
  • Grouping of anti-TB drugs:
    • Group 1: 1st line oral agents
    • Group 2: Parenteral (inc. aminoglycosides such as streptomycin and amikacin)
    • Group 3: Fluoroquinolones (e.g. levofloxacin, moxifloxacin)
    • Group 4: Oral bacteriostatic (e.g. ethionamide, cycloserine, para-aminosalicylic acid)
    • Group 5: Limited data on efficacy or long term safety inc. new agents (e.g. bedaquiline, delamanid, linezolid)
57
Q

XDR-TB

A
  • Resistant to at least 4 of the core anti-TB drugs
  • Resistant to most powerful (isoniazid and rifampicin) aswell as any of fluoroquinolones and at least 1 of Group 2 parenteral 2nd line agents (e.g. aminoglycosides)
  • Occur in patients already receiving TB treatment but inadequately
  • Can be directly transferred from patient with XDR-TB
  • In 2014, nearly 50% people with XDR-TB die within 2 years and 85% within 5 years
58
Q

Bedaquiline

A
  • Inhibits ATP synthetase
  • Active against resistant isolates
  • Accelerated approval by FDA in 2012 despite imbalance in mortality (10/79 in treated patients vs 2/81 in placebo group)
  • Use limited to patients with MDR-TB
59
Q

Differences between fungi and bacteria

A

Fungi:
- Eukaryotic and mostly multicellular
- Has organelles (mitochondria, ER, 80S ribosomes)
- In cell membrane, sterols present (ergosterol: cholesterol in mammalian membranes)
- Cell wall made of chitin
- Are mainly obligate aerobes (require oxygen to survive) or facultative anaerobes i.e. yeast (can survive with or without oxygen, with being best)
- 5-50 microns in diameter

Bacteria:
- Prokaryotic and unicellular
- No organelles (70S ribosomes)
- Sterols absent
- Cell wall made of peptidoglycans
- Are obligate aerobes or facultative anerobes
- 1-5 microns in diameter

60
Q

Examples of fungal infections (aka mycoses)

A
  • Superficial infections e.g. nails, skin and scalp
    • Tinea pedis (athlete’s foot)
    • Candidiasis (yeast infection)
  • Systemic deeper fungal infections: Life-threatening in immunocompromised patients and can spread to other organs
    • Aspergillosis (caused by breathing in spores of mold Aspergillus)
61
Q

Types of fungi

A
  • Candida albicans
    • Most widespread cause of fungal infections
    • Yeast appears white when cultured
  • Aspergillus fumigatus
    • Produces airborne spores
    • Inhaled daily but causes problems with weakened immune system
  • Cryptococcus (-neoformans and -gatti)
    • Invasive fungi which can cause infection in immunosuppressed individuals
62
Q

Why has the development of antifungals lagged behind that of antibacterial agents?

A
  • Grow slower and more difficult to quantify than bacteria: Complicates in vitro and in vivo evaluation of antifungals.
  • Often in multi-cellular forms (eukaryotes): Difficult to develop drugs which only target fungal cells and not human cells.
63
Q

Why have there been increased incidences of fungal infections?

A
  • Irresponsible use of antibiotics
    • Fungal infections cannot be treated by antibiotics
    • Antibiotics are sometimes wrongly prescribed for fungal infections
    • Incomplete course of antibiotics
    • Upset of microbiome by long term use of antibiotics, makes it easier for fungi to grow
  • Large occurrence in HIV population due to lowered immune system
64
Q

Fungal targets (4)

A
  • Inhibition of cell wall formation
  • Inhibition of mitosis
  • Cell membrane disruption
  • Interference with DNA synthesis
65
Q

Drugs that affect the fungal cell wall and membrane and their actions

A
  • Polyenes bind to ergosterol in cell membrane
  • Azoles inhibit ergosterol synthesis
  • Terbinafine inhibits lanosterol and ergosterol synthesis
  • Echinocandins inhibit synthesis of cell wall
66
Q

Azoles mechanism

A
  • Inhibit fungal CYP450 3A enzyme which blocks demethylation of lanosterol to ergosterol
  • Disrupts cell membrane’s structure and function and inhibits growth
  • Broad spectrum inc. Candida and Cryptococcus neoformans
  • DISADVANTAGE: Similar in structure in human CYP450 3A
67
Q

Azoles examples

A
  • Ketoconazole
    • Orally active and first azole to treat systemic infections.
    • High affinity to human CYP450 which can limit use. Rare but possible fatal liver toxicity.
  • Fluconazole
    • Given orally or intravenously
    • Conc. in CSF so drug of choice for fungal meningitis
    • Less affinity to human CYP450 so preferable for use on skin lesions in HIV patients on multiple therapy
  • Itraconazole
    • Given orally or intravenously (in formulation with beta-cyclodextrin)
    • Used in more severe infection
68
Q

Terbinafine mechanism

A
  • Inhibits ergosterol synthesis via inhibition of fungal squalene epoxidase
  • Structural analogue of squalene causing accumulation of this unsaturated hydrocarbon and decrease in ergosterol in the cell membrane
  • Accumulation of toxic amounts of squalene result in death of fungal cell
69
Q

Terbinafine use

A
  • Used topically for superficial infections (e.g. athlete’s foot)
  • Orally active, tablets used for onychomycosis (fungal nail infection). Drug selectively accumulates in nails.
  • Treatment timeframe over growth of nail (approx. 6 months)
  • Relatively well tolerated
70
Q

Polyene mechanism

A
  • Amphotericin B (type of polyene)
    • High affinity for ergosterol, binds irreversibly
    • Cell permeability increased by the pore, with loss of cell content which leads to death
71
Q

Amphotericin B’s use and tolerability

A
  • Broadest spectrum of action inc. aspergillus, candida albicans and cryptococcus neoformans
  • Used to treat fungal membranes
  • Generally IV
  • Tolerability issues with nephrotoxicity (kidney damage)
    • Whilst selective for ergosterol, mammalian cells can be affected
    • Lipid-complexed (liposomal) amphotericin B formulations have reducdd incidence of renal toxicity
72
Q

Echinocandins mechanism and examples

A
  • Selectively target cell wall synthesis by inhibition of beta-D-glucan synthase
  • Caspofungin, micafungan and anidulafungin
  • Used for treatment of invasive candidiasis, particularly in critically ill and neutropenic (lacking white blood cells) patients
73
Q

Flucytosine mechanism

A
  • Fluorinated pyrimidine analogue of cytosine
  • Enters fungal cells via a cytosine-specific permease (not found in mammalian cells)
  • Converted to 5-fluorouracil in fungal cytoplasm
  • 5-fluorouracil converted to 2 active false nucleotides:
    • 5-fluorouridine triphosphate (inhibits RNA processing)
    • 5-fluorodeoxyuridine monophosphate (inhibits thymidylate synthetase, thus DNA synthesis)
74
Q

Use of flucytosine

A
  • Monotherapy with flucytosine is now limited due to resistance development (some due to mutations which affect cellular uptake)
  • Treated in combination with amphotericin B which increases uptake
  • Combination is treatment of choice for cryptococcal meningitis
75
Q

Griseofulvin mechanism

A
  • Inhibits fungal cell mitosis and nuclear acid synthesis
  • First isolated from Penicillium griseofulvum
  • Binds to tubulin (building block of microtubules, essential part of mitotic spindle)
  • This inhibits mitotic spindle formation, inhibits fungal cell division
  • Fungistatic (inhibits growth, doesn’t kill)
  • Active against superificial infections e.g. dermatophytes
  • Used for nail infections
76
Q

What are viruses?

A
  • Non-living particle made up of nucleic acid (either RNA or DNA) enclosed in a protein coat (capsid)
  • Dependent on a living host
  • Attaches to cell to infect host
  • Dependent on host cell to reproduce
  • No cell membrane or wall (instead has an envelope with proteins attached)
  • No organelles
  • Microscopic (much smaller than bacteria)
77
Q

Types of viruses

A

DNA viruses
- Single stranded
- Double stranded
- Replicate in host cell nuclei

RNA viruses
- Single stranded
- + sense
- - sense
- Double stranded
- Generally replicate in cytoplasm
- More prone to mutation

78
Q

What is a viral infection? Give examples

A
  • Rapid increase in the amount of a harmful virus in the body
  • Use host cell to make additional copies of themselves
  • Express polypeptide binding sites on envelope or capsid which bind to host surface receptors
  • Each virus type attaches to different cells
    • E.g. HIV: CD4+ T-Cells, Glandular fever virus: B-lymphocyte complement C3d receptor
79
Q

Examples of pathogenic viruses

A

DNA viruses and diseases:
- Pox: smallpox
- Herpes: chickenpox, shingles, cold sores, glandular fever
- Adeno: sore throat, conjunctivitis
- Papilloma: warts

RNA viruses and diseases:
- Orthomyxo: influenza
- Paramyxo: measles, mumps, resp. tract infections
- Picorna: cold, meningitis, poliomyelitis
- Retro: acquired immunodeficiency syndrome
- Rubella, rhabdo, arena: German measles, rabies, meningitis
- Filovirus: ebola, haemorrhagic fever

80
Q

Viral life cycle stages

A
  • Attachment: specific binding to host cell surface receptors
  • Viral entry: endocytosis, membrane fusion
  • Uncoating: viral capsid removed releasing viral nucleic acids (eclipse phase)
  • Replication of viral components using host-cell machinery
  • Assembly of viral components into complete viral particles
  • Release: lysis or budding, releasing viral particles to infect new host cells
81
Q

Main infection disease targets of antiviral therapeutics

A

DNA viruses
- Hepatitis B virus (HBV) infections
- Human cytomegalovirus infections
- Herpes-Simplex Viruses (HSV) – oral and genital herpes
- Human papillomavirus infections
- Varicella Zoster Virus – Chickenpox and Shingles

RNA viruses
- Hepatitis C virus (HCV) infections
- Respiratory syncytial virus infections
- Influenza virus infections

Retrovirus
- HIV infections

82
Q

Synthetic nucleoside analogues

A
  • All developed as pro drugs
  • Taken up by cells phosphorylated to active form (generally triphosphate) which can inhibit:
    • DNA polymerase
    • Reverse transcriptase
    • RNA polymerase
  • Or incorporated into growing DNA leadig to abnormal proteins or breakage
83
Q

Activity of Acyclovir (nucleoside analogue)

A
  • Used in treatment of herpes virus (HSV and VSV)
  • Inhibits viral DNA polymerase by acting as an analogue to deoxyguanosine triphosphate (dGTP)
  • Competitively inhibits viral DNA polymerase by incorporation into DNA resulting in chain termination
  • Higher affinity for viral DNA polymerase than for cellular DNA polymerase
84
Q

Interferons

A
  • Host cytokines produced by immune system in response to challenge (e.g. virus)
  • Function by inducing intracellular signals resulting inhibition of:
    • Viral penetration
    • Viral translation, transcription and protein processing
    • Viral maturation
    • Viral release
  • Antiviral interferon agents have been developed which promote production and release of interferons
  • Used to treat chronic hepatitis B & C, AIDS-related Kaposi’s sarcoma, herpes and CMV
85
Q

Neuraminidase inhibitors

A
  • Specific to influenza
  • Influenza virus contains enzyme neuraminidase (essential for replication)
  • Neuraminidase inhibitors prevent release of new virions (infective form of virus outside of host cell) and their spread from cell to cell
  • E.g. Oseltamivir (Tamiflu) and Zanamivir (Relenza)
86
Q

SARS-Covid-2

A
  • Severe acute respiratory syndrome coronavirus 2
  • RNA virus - single stranded + sense
  • Thought to attach to cells via angiotensin-converting enzyme 2 (ACE2) receptor
87
Q

What are retrovirals?

A
  • RNA viruses which synthesise DNA from an RNA template
88
Q

What is HIV?

A
  • Most well known RNA retrovirus
  • Interacts with host’s immune cells specifically through binding to T-helper cells (CD4+ T lymphocytes)
    • Reduces CD4 count
  • 2 forms of HIV:
    • HIV-1, can lead to development of acquired immunodeficiency syndrome (AIDS)
    • HIV-2, causes immune suppression but is less virulent
89
Q

HIV lifecycle (7 steps)

A
  • 10^10 new virions can be released per day
  • Replication process is highly error prone
    1. Fusion of HIV to host cell surface
    2. HIV RNA, reverse transciptase, integrase and other viral proteins enter host cell
    3. Viral DNA formed by reverse transcriptase
    4. Viral DNA transported across nucleus and integrates into host DNA
    5. New viral RNA used as genomic RNA and to make viral proteins
    6. New viral RNA and proteins move to cell surface and new, immature HIV forms
    7. Virus released. Viral protease cleaves new polyproteins to create mature infectious virus
90
Q

Targets for antiretroviral agents

A
  • Co-receptor antagonists (CCR5 or CXCR4 antagonists)
  • Fusion inhibitors
  • Reverse transcriptase inhibitors:
    • Nucleoside reverse transcriptase (NRTIs)
    • Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
  • Integrase strand transfer inhibitors (INSTIs)
  • Protease inhibitors (PIs)
91
Q

NRTIs

A
  • Nucleoside analogues which act as competitive substrates inhibitors
  • Phosphorylated to be active
  • Competitively inhibit nucleotide binding to reverse transcriptase and become incorporated into growing DNA
  • This terminates DNA chain
  • First approved in 1987 was Zidovudine (ZDV formerly AZT, Retrovir)
  • Selects for drug resistance
  • Associated with bone marrow suppression
  • A number of approved NRTIs inc.:
    • Didanosine (ddI), zalcitabine (ddC), stavudine (d4T), lamivudine (3TC)
92
Q

NNRTIs

A
  • Bind to reverse transcriptase at different sites to NRTIs (don’t recquire phosphorylation to be active and aren’t incorporated into DNA)
  • Directly bind non-competitively to reverse transcriptase and inactivate it
  • E.g. Nevirapine, Delavirdine and Efavirenz
  • Most are inducers, substrates or inhibitors or liver cytochrome P450 enzymes
  • Common unwanted side effects are rash and hepatoxicity
93
Q

PIs

A
  • Assembly of virions depends of HIV-1 protease which cleaves the polypeptide products of HIV mRNA into functional parts
  • PIs competitively inhibit HIV-1 protease
  • Prevents maturation of virions capable of infecting other cells
  • First approves in 1995 was Saquinavir
  • E.g. Ritonavir, indinavir, nelfinavir, lopinavir
  • Often used in combination with NRTIs
  • Most are substrates of CYP450 3A4 and are effluxed by P-glycoprotein
  • Care must be taken to avoid drug-drug interaction
  • Ritonavir is actually a CYP450 3A4 inhibitor and sometimes given in combinationto boost concentrations
94
Q

Fusion and integrase inhibitors

A

Fusion inhibitor:
- Enfurvitide: binds gp41 inhibiting viral entry
- Maraviroc: binds CCR-5 on surface of CD4 cells and inhibits interaction with gp120

Integrase inhibitor (raltegravir):
- Reversibly binds HIV integrase
- Inhibits HIV genome integration into host cell chromosome
- Generally reserved for cases resistant to other anti-retroviral therapy (ART)

95
Q

Combination ART (cART)

A
  • Introduced in 1995
  • Typically 3-4 drug combination:
    • 2 NRTIs with either an NNRTI or 1 or 2 protease inhibitors
  • Utilises synergy of different viral targets
  • Compliance is an issue, drug involves daily multiple dosing regimens
  • Co-formulation has reduced number of pills and improved patient adherence
  • In the 1990s, ART for HIV inc. up to 20 pills daily taken at different intervals throughout the day
  • Today, as little as 1 pill per day taken, delivering multiple drugs
96
Q

Goals of cART

A
  1. Control of viral replication
  2. Prevention/delay of progressive immunodeficiency
  3. Delayed progression to AIDS (prolonged survival)
  4. Decreased selection of resistant virus
97
Q

HIV drug resistance

A
  • HIV-1 replication prone to mutation which drives drug resistance
  • 2 types of drug resistance:
    • Treatment emergent
    • Transmitted (i.e. drug resistant virus transmitted)
  • Drivers of suboptimal levels inc.
    • Poor compliance
    • Food effects
    • Drug-drug interaction (DDI)
98
Q

How to minimise viral resistance

A
  • Don’t prescribe antiretrovirals (ARVs) in absence of adherence counselling and support
  • Never prescribe monotherapy (single drug treatment) or dual therapy
  • Ensure optimal serum drug concentrations (avoid drug interactions and diagnose and manage malabsorption)
  • If ARV medications discontinued, stop all drugs at same time
99
Q

UNAIDS Programme

A
  • Joint United Nations programme of HIV/AIDS
  • Launched following targets to be achieved by 2020:
    • 90% of all people living with HIV know their HIV status
    • 90% of all people diagnosed with HIV infefction will receive sustained ART
    • 90% of all people receiving ART will have viral suppression
100
Q

What is cancer?

A
  • Due to genetic change causing cells to proliferate (multiply) in an unregulated fashion
  • Invades surrounding tissues (e.g. by secretion of proteolytic enzymes)
  • Grows new blood cells
  • Metastasizes to secondary sites (development of secondary malignant growth)
  • Differentiates abnormally leading to loss of function
  • Displays altered cell surface components e.g. antigens, enzymes and oncogenes (can transform cells into tumour cells in certain circumstances)
101
Q

What makes cancer cells?

A

2 main categories of genetic change:
- Activation of proto-oncogenes to oncogenes
- Inactivation of tumour suppressor genes

Key changes to the cellular system which can cause uncontrolled proliferation include:
- Growth factors
- Cell cycle transducers (convert one form of energy into another)
- Apoptosis (death of cells) machinery
- Telomerase (enzymes that adds DNA to ends of chromosomes to prevent them shortening and and becoming damaged as cells divide) expression
- Changes to local blood supply

102
Q

Types of cancer and areas affected

A

Over 200 different types, major categories include:
- Carcinoma
- Sarcoma
- Leukaemias
- Lymphomas

Can impact multiple different tissues around the body:
- CNS, brain, eye
- Head and neck
- Endocrine (glands)
- Breast
- Blood (leukaemia, lymphoma, Hodgkin’s and non-Hodgkin’s lymphoma, multiple myeloma)
- Genitourinary (bladder, kidney, prostate, testicular)
- Gynecologic (uterine, cervical, ovarian, vaginal, vulvar)
- Skin (melanoma)
- Sarcoma (soft tissue, osteosarcoma)
- Gastrointestinal (colon, rectal, anal, stomach, intestinal, esophageal)
- Hepatobiliary (pancreas, liver, biliary)
- Lung

103
Q

Carcinoma

A
  • Cancer of epithelial cells (line surfaces)
  • Most common, accounts for 80-90% of all cancers
  • 2 major sub-types:
    • Squamous cell: form protective lining of cavities e.g. squamous cell skin cancinoma
    • Adenocarcinoma: Adenomatous cells produce fluids or mucous. Secrete into ducts or cavities they line e.g. lung, pancreatic, colorectal cancers
104
Q

Sarcoma

A
  • Cancer of connective tissue
  • Most common type of bone cancer is osteosarcoma
  • Connective tissue found in: muscle, fat, blood vessels, lymph vessels and fibrous tissue (tendons and ligaments)

Sarcoma types:
- Angiosarcoma (malignant neoplasm in vessel walls)
- Osteosarcoma (tumour in bone)
- Ewing’s sarcoma (bone)
- Chondrosarcoma (cartilage)
- Gastrointestinal stromal tumour (Mesenchymal neoplasms of the gastrointestinal tract)
- Liposarcoma (fat cells)
- Fibrosarcoma (fibrous connective tissue)
- Hemangioendothelioma (vascular neoplasms)

105
Q

Haematopoeitic (cancer of immune system)

A

Leukaemias: cancer of circulating white blood cells (leukocytes) or stem cells of bone marrow
- Do not form solid tumours
- Large numbers of leukaemia cells build up and crowd out normal blood cells

Lymphomas: cancer of lymphatic organs
- T or B lymphocytes
- 2 main types: Hodgkin and non-Hodgkin lymphoma

106
Q

Differences between normal and cancer cells (9)

A

Normal cells:
- Receive/send signals to other cells
- 23 pairs of chromosomes
- Receive signals from plasma membrane leading to cell division or cell cycle arrest
- Maximum of 50-100 cell divisions
- Normal metabolic demands on glycolysis and Krebs cycle
- Apoptosis removes defunct/redundant cells
- Growth is contact inhibited
- Cells anchored to ECM (extracellular matrix)
- Low secretion of angiogenic factors

Cancer cells:
- Incorrectly process signals; amplification of normal signals
- Mutated genes and chromosomal rearrangements
- May uncouple cell division from signals from plasma membrane; loss of cell division control
- Cells become immortalised
- High metabolic demands in hypoxic (low oxygen level) environment
- Apoptosis is blocked, leading to inappropriate cell accumulation
- Loss of contact-inhibition, proliferation therefore uncontrolled
- Cells secrete proteases to break down ECM, allowing migration
- High secretion of angiogenic factors

107
Q

Treatment of cancer

A

Chemotherapy often used with other types of therapy:
- Surgery
- Radiation
- Immunotherapy

108
Q

Determinants of drug response (7)

A
  • Growth fraction (fraction of cells actively dividing)
  • Doubling time (Time for tumour to double in size)
  • Total tumour mass (bulky tumours often not curable with drug)
  • Tumour heterogeneity (variation within tumours may affect overall drug efficacy)
  • Cell cycle (response to certain cell-phase-specific drugs depends on the % of cells in a sensitive phase during the time of exposure
  • Drug resistance (via different biochemical mechanisms)
  • Host factors (general health status and genotype of the patient)
109
Q

Anticancer agents (5)

A

No universal classification but following groups:
- Cytotoxic
- Hormonal
- Immune-oncology
- Targeted
- Monoclonal antibody

110
Q

Examples of cytotoxic anti-cancer agents

A
  • Alkylating e.g. nitrogen mustards, alkyl sulfonate
  • Platinum e.g. cisplatin, carboplatin, oxaliplatin
  • Antimetabolites e.g. methotrexate
  • Microtubule damaging e.g. vincristine, vinblastine, paclitaxel, docetaxel
  • Topoisomerase inhibitors e.g. etoposide, topotecan, ironotecan
  • Antibiotics e.g. actinomycin D, doxorubicin, daunorubicin
  • Miscellaneous e.g. hydroxyurea
111
Q

Cell cycle specificity of drugs

A

Cell cycle specific: kill only actively dividing cells
- G1: vinblastine
- S: doxorubicin, daunorubicin
- G2: bleomycin, etoposide
- M: vincristine, paclitaxel

Cell-cycle non-specific: kill resting as well as dividing cells
- Alkylating agents e.g. nitrosoureas (bind covalently to DNA)
- Cisplatin (DNA chelator/crosslinker)
- Some of the antibiotics

112
Q

Vinca alkaloids

A
  • E.g. vincristine, vinblastine
  • Cell-cycle specific agents
  • Block cells in mitosis by binding to tubulin
  • Tubulin dimers are unable to aggregate to form microtubules
  • Drug resistance:
    • Decreased drug accumulation
    • Alterations in tubulin strcuture
113
Q

Alkylating agents

A
  • E.g. cyclophosphamide
  • Bifunctional alkylating agents which cause intra-strand linking and cross-linking. This interferes with transcription and DNA replication
  • Cell-cycle non-specific, however rapidly dividing cells are most susceptible to effects
  • Drug resistance
    • Increased ability to repair DNA lesions
    • Decreased permeability to agent
114
Q

Anti-metabolites

A
  • Folate antagonists e.g. methotrexate
    • Potent inhibitor of dihydrofolate (DHFR)
    • Blocks formation of tetrahydrofolate required for thymidylate
    • Only partially selective and toxic to all rapidly dividing normal cells
    • Drug resistance: decreased drug uptake, DHFR amplification, mutations in DHFR
  • Pyrimidine analogues
    • 5-fluorouracil: acts as thmidylate synthase inhibitor blocking synthesis of pyrimidine
    • Cytarabine: inhibits DNA polymerase
  • Purine analogues e.g. 6-mercaptopurine
115
Q

Hormonal anti-cancer agents

A

In hormone-dependent tumours, hormones with the opposite effect can be used therapeutically e.g. glucocorticoids, estrogens, progestogens

Hormone antagonists:
- Anti-estrogens e.g. tamoxifen: hormone-dependent estrogen receptor positive breast cancers (ER+), prophylaxis
- Aromatase inhibitors e.g. anastrozole: late-stage menopausal breast cancer

116
Q

Immune response to cancer (6)

A
  1. Antigens released from tumour cells
  2. Tumour antigens taken up by macrophages and dendritic cells (transported to lymph node)
  3. T-cells primed and activated to recognise tumour antigen (t-cells which are trafficked to tumours
  4. Activated T-cells infiltrate tumour
  5. T-cells recognise and bind tumour cells
  6. T-cells kill tumour cells - antigens released and further propagate of immune response
117
Q

Immuno-oncology

A

*Designed to stimulate and enhance immune response to tumours
*Immune-modulating antibodies:
* Stimulate immune cells or block immune inhibitory checkpoint pathways
* Eg. checkpoint inhibitors
* Cancer vaccines – activate host immune system against tumour cell
antigens
* Eg. dendritic cell vaccine
*Adoptive T-cell transfer
* Isolation of anti-tumour T cells – manipulation and re-infusion
* CAR-T cell therapy

118
Q

Resistance classification and treatments

A
  • Resistance can be classified as:
    • Primary (tumours that never respond to drugs)
    • Acquired (adaptation or mutation of the tumour cells
      • Results from suboptimal drug doses
  • Resistance is minimised by:
    • Short-term, intensive, intermittent therapy
    • Drug combinations
119
Q

Resistance mechanisms

A

*Drug transport proteins: Reduced drug accumulation/ increased efflux
(methotrexate)
*Insufficient activation of pro-drugs (fluorouracil, mercaptopurine)
* Rapid repair of drug-induced lesions (alkylating agents)
*Overexpression of target enzyme (methotrexate)
* Mutations in genes leading to resistance target molecules

120
Q

Efflux

A
  • Results from increased expression of energy-dependent transport
    proteins such as P-glycoprotein (P-gp)
  • P-gp normally protects cells against environmental toxins, but it can
    also transport drugs out of cells.
  • Overexpression of P-gp and
    other transporters results in
    “multidrug resistance” (MDR)
121
Q

Pharmacogenomics definition

A

Study of genetic basis for the differences between individuals in responses to drugs

122
Q

Variability in drug response (2 types)

A

Variability in drug concentration at
the site of action:
- Pharmacokinetic variation
- Absorption
- Distribution
- Metabolism
- Excretion

Variability in individual response
to the drug:
- Pharmacodynamic variation
- E.g. differences in expression of drug targets

123
Q

Factors that may cause variability

A
  • Liver function
  • Renal function
  • Drug-drug interactions
  • Compliance
  • Gender
  • Environment
  • Lifestyle
  • Age
  • Somatic genetic variability (gene changes in somatic cells that aren’t part of the germline)
  • Host/germline genetic variability (result of gene changes in reproductive cells passed to offspring)
  • Comorbidity (simultaneous presence of two or more diseases in a patient)
124
Q

Germline and somatic mutations

A

Germline mutations – happen in every cell in the body
* Hereditary
* ~10% of cancer comes under this categrory

Somatic mutations – characteristic for tumour cells – heterogeneous
* Nonheritable
* 90-95% of cancer comes under this category

125
Q

Polymorphisms

A
  • Changes to gene sequence
  • Single nucleotide polymorphisms (SNPs) are the most common type of genetic variation
  • Effect depends on position in the gene
  • If change to letter in nucleotide has no effect on the nucleotide then protein sequence remains the same (e.g. AAC to AAT)
126
Q

Examples of polymorphisms

A

Pharmacokinetics (Absorption, distribution, metabolism, excretion):
- Drug metabolism (e.g. CYPs, NAT etc)
* Drug transporters (e.g. P-gp, MRP2 etc)
* Protein binding (e.g. α1-acid glycoprotein
in plasma)

Pharmacodynamics:
Drug targets: Genetic variation in the drug target may help or hinder drug binding and therefore response (e.g. G-protein-coupled receptors GPCRs)

127
Q

Use of pharmacogenetics in oncology (study of tumours)

A

To investigate the relationship between genetic polymorphism and…
- Drug-related toxicity
- Developing targeted treatments
- Survival rates for chemotherapeutic treatment

128
Q

6-Mercaptopurine (6-MP)

A
  • Purine analogue used to treat leukemia
  • Interindividual toxicity due to genetic polymorphism of 6-MP
    metabolising enzymes
  • Primarily metabolized by thiopurine S-methyltransferase (TPMT)
  • Activity of TPMT varies within population as a result of
    germline polymorphisms
  • TPMT-activity can be divided into 3 major phenotypic subgroups:
    • 90% - 2 functional alleles (normal activity) – H/H
    • 10% - heterozygous (intermediate activity) – L/H
    • 0.3-0.5% - 2 non-functional alleles (little to no TPMT activity) – L/L
129
Q

TMPT activity phenotypes

A

L/H: Thioguanine nucleotides accumulate. Associated with a
higher risk of toxicity

L/L: Individuals accumulate excessive thioguanine nucleotides and are predisposed to severe toxicity reactions (e.g. rapid
and potentially life-threatening myelo-suppression)

130
Q

BRCA mutation

A
  • Breast cancer gene (BRCA1 and BRCA2) associated with risk of developing breast cancer
  • Tumour supressor genes, repair DNA breaks
  • Germline hereditary mutation
  • 5-10% breast cancer cases attributed to BRCA1 and BRCA2
131
Q

PARP inhibitors

A
  • Poly(ADP-ribose) polymerase inhibitors (PARP inhibitors) are lethal for BRCA-deficient cells
  • PARP inhibition promotes progression of single-strand DNA breaks to double strand
    breaks
  • Olaparib (Lynparza) demonstrates preferential effect towards cancers arising in
    BRCA1/2 germ-line mutation carriers
132
Q

BRAF mutation

A
  • Oncogene-targeted therapy
  • B-Raf (encoded by BRAF gene) is a Raf serine-threonine kinase involved in growth signalling
  • Mutated B-Raf is found in some cancer cells e.g. V600E in metastatic melanomas
  • Vemurafenib is a B-Raf inhibitor that targets tumours carrying the V600E B-Raf mutation
133
Q

Iressa (gefitinib)

A
  • EGFR tyrosine kinase inhibitor
  • Treatment for non-small cell lung cancer (NSCLC)
  • Phase II studies showed positive anti-tumour activity
  • Phase III studies failed to show a statistically significant survival
    benefit over standard of care
  • Further analysis demonstrated presence of EGFR mutation was the strongest predictor of favourable outcome
  • Iressa now approved for use in patients with locally advanced or NSCLC with activating mutations of EGFR tyrosine kinase

LIFE207 (4 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2025 Bold Learning Solutions. Terms and Conditions