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Year 3 Sem 2 > 3. Medicines Design > Flashcards

3. Medicines Design Flashcards

1
Q

Describe stages of Carcinoma of the prostate

A
  1. Normal prostatic epithelium
  2. Low-grade prostactic intraepithelial neoplasia
  3. High-grade prostactic intraepithelial neoplasia
  4. Metastatic prostate cancer
  5. Androgen-independent cancer
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2
Q

Statistics about Prostate (JUST READ)

A
  • 1 in 8 in the UK will get prostate cancer at some point in their lives
  • Your risk increases with age (over 50 yrs old)
  • Family history and genes
  • Black men are more likely to get prostate cancer than other men
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3
Q

What are the options for treatment of Prostate Cancer?

A
  1. Watchful waiting
    - slow-growing tumours in frail men
  2. Active surveillance
    - small tumour confined to prostate
  3. Surgery
    - frequently used but major side-effects
  4. Chemotherapy
    - hormone-dependent tumours
  5. Chemotherapy
    - hormone-independent tumours
  6. High-intensity focussed ultrasound (HIFU)
    - de-bulking
  7. External beam radiotherapy
    - small tumours confined to prostate
  8. Permanent seed brachytherapy
    - tumours confined to prostate
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4
Q

How does Testosterone promote proliferation?

A
  • Testosterone (T) binds to the androgen receptor (AR)
  • This causes a conformational change in the AR
  • This complex translocates to the nucleus, where it signals for proliferation
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5
Q

Name drugs that bind to androgen receptor

A

Flutamide
- Bacteriostatic, later found to have anti-androgenic activity. Now little used for prostate cancer. Hepatotoxic

Nilutamide
- Developed from flutamide, Less hepatotoxic

Bicalutamide
- Binding mode to AR known, introduced 1995. Widely used

Enzalutamide
- Approved in 2012. Now supplanting bicalutamide. Rare CNS toxicity

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6
Q

How does Bicalutamide act at androgen receptor

A
  • Bicalutamide (Bic) binds to the androgen receptor (AR) but does not cause conformatonal change
  • Testosterone is blocked from binding
  • The Bic-AR complex is internalised but cannot translocate to the nucleus
  • Bicalutamide has some agonist activity, especially at mutant AR
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7
Q

How does Enzalutamide act at androgen receptor?

A
  • Enzalutamide (Enz) binds to the androgen receptor (AR) but does not cause conformational change
  • Testosterone is blocked from binding
  • The Enz-AR complex is internalised but cannot translocate to the nucleus
  • Enzalutamide has no agonist activity
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8
Q

How does Testosterone bind to androgen receptor?

How does Bicalutamide bind to androgen receptor?

A

Testosterone binds through…

  • H-bonds
  • Hydrophobic interactions

Bicalutamide binds through…

  • H-bond to Arg752, Asn705
  • ‘does not’ H-bond to Thr877
  • hydrophobic side-pocket
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9
Q

Describe biosynthesis of testosterone

A
  1. Cholesterol
    —> Pregnenolone
    —> Progesterone by 3beta-HSD (hydroxysteroid dehydrogenase)
    —> 17a-OH-Progesterone by 17a-Hydroxylase
    —> Androstenedione by 17,20 Lyase
    —> Testosterone by 17b-HSD (hydroxysteroid dehydrogenase)
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10
Q

What are the drugs that inhibit CYP17A1?

A

Ketoconazole
- non-specific inhibitor of CYPs, Antifungal

Abiraterone
- selective inhibitor of CYP17A1

Abiraterone acetate
- prodrug of abiraterone

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11
Q

How does Prosgesterone bind to CYP17A1?

A

C=O forms H-bond to Asn202

Hydrocarbon part of steroid binds to hydrophobic hydrophobic side-chains

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12
Q

Anti-androgens Summary (JUST READ)

A
  • Many early prostate cancers require testosterone to grow
    : Androgen-dependent
  • Advanced prostate cancers lose this dependence
    : Androgen-independent
  • Androgen-dependent cancers can be treated by blocking the androgen receptor
    : Flutamide, Nilutamide, Bicalutamide, Enzalutamide
  • Binding to AR through H-bonds & hydrophobic interactions and in side-pocket
  • Androgen-dependent cancers can be treated by inhibiting the biosynthesis of Testosterone in the testes and in the adrenals
    : inhibition of CYP17A1
    : Ketoconazole, Abiraterone, Abiraterone acetate
  • Binding to CYP17A1 through ligation to Fe, H-bonds & hydrophobic interactions; complementarity of shape; prodrug
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13
Q

20 Amino Acids Summary (JUST READ)

A

Alanine (Ala)
- Small, Non-polar, No H-bonds, Neutral, Chemically unreactive

Arginine (Arg)
- Medium, Polar, H-bond donor, Basic[cation], weak electrophile/nucleophile

Asparagine (Asn)
- Small, Polar, H-bond donor & acceptor, Neutral, Chemically unreactive

Aspartic acid (Asp)
- Small, Polar, H-bond acceptor, Acidic[anion], Nucleophile

Cysteine (Cys)
- Small, Non-polar, No H-bonds, Weak acid, Powerful nucleophile, reducing agent, forms radicals readily
- Disulfide bridges in proteins
: the only covalent link in tertiary structure of proteins

Glutamine (Gln)
- Medium, Polar, H-bond donor & acceptor, Neutral, Chemically unreactive

Glutamic acid (Glu)
- Medium, Polar, H-bond acceptor, Acidic[anion], Nucleophile

Glycine (Gly)
- Small, Non-polar, No H-bonds, Neutral, Chemically unreactive

Histidine (His)
- Large, Polar, H-bond donor & acceptor, Weak base[cation], Nucleophile

Isoleucine (Ile)
- Medium, Non-polar, No- H-bonds, Neutral, Chemically unreactive

Leucine (Leu)
- Medium, Non-polar, No H-bonds, Neutral, Chemically unreactive

Lysine (Lys)
- Large, Polar, H-bond donor, Basic[cation], Nucleophile

Methionine (Met)
- Medium, Non-polar, No H-bonds, Neutral, Weak nucleophile

Phenylalanine (Phe)
- Large, Non-polar, No H-bonds, Neutral, Chemically unreactive, Aromatic (pi-stacking)

Proline (Pro)
- Medium, Non-polar, No H-bonds, Neutral, Chemically unreactive, Cyclic (secondary amine)

Serine (Ser)
- Small, Polar, H-bond donor & acceptor, Neutral, Nucleophile

Phosphoserine
- Medium, Polar, H-bond acceptor, Acidic, Anion

Threonine (Thr)
- Medium, Polar, H-bond donor & acceptor, Neutral, Nucleophile

Phosphothreonine
- Medium, Polar, H-bond acceptor, Acidic, Anion

Tryptophan (Trp)
- Large, Non-polar, H-bond donor, Neutral, Chemically unreactive, Aromatic

Tyrosine (Tyr)
- Large, Polar, H-bond donor, Weak acid, Nucleophile, Aromatic

Phosphotyrosine
- Medium, Polar, H-bond acceptor, Acidic, Anion

Valine (Val)
- Medium, Non-polar, No H-bonds, Neutral, Chemically unreactive

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14
Q

Describe Antimetabolites

A
  • Antimetabolites kill (cancer) cells by inhibiting a critical cellular process
  • Antimetabolites are usually inhibitors of enzymes
  • Biosynthesis of DNA is essential to proliferation of tumour cells
    : therefore, most antimetabolites are inhibitors of critical enzymes involved in DNA biosynthesis
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15
Q

What are the 4 main groups of antimetabolite drugs?

A

Folate ‘antagonists’
- e.g Methotrexate, non-classical lipophilic antifolates, pemetrexed, raltitrexed

Pyrimidine ‘antagonists’
- e.g 5-Fluorouracil (5-FU), fluorodeoxyuridine (FdURD), azacytidine

Purine ‘antagonists’
- e.g 6-Mercaptopurine, thioguanine, tiazofurin

Sugar-modified nucleosides
- e.g Cytarabine (Ara-C), fludarabine, gemicitibine

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16
Q

Describe analogues of folate antagonists regarding its action of antimetabolites

A

Analogue of dihydrofolate
- binds to DHFR (dihydrofolate reductase) at folate-binding site

Very potent competitive inhibitor of DHFR

Too polar for passive diffusion into cells
- taken up through reduced folate carrier (RFC)

Must be polyglutamylated to be retained in cells

Often used in high-dose regimen, with leucovorin (folate) rescue of normal cells

Widely used drug against many cancer types

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17
Q

Describe actions of lipophilic antifolates

A
  • Enter cells by passive diffusion

: don’t need RFC (Reduced Folate Carrier)

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18
Q

What does Azacytidine do?

A
  • Weak inhibitor of TS (Thymidylate Synthase)
  • Phosphorylated to form azacytidine triphosphate, then incorporated into RNA
  • Mimics C in RNA but unstable and decomposes, causing damage to RNA
  • Inhibits DNA methyltransferases (epigenetic effects)
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19
Q

Describe inhibition of biosynthesis of purine nucleosides

A
  • TAD (from Tiazofurin) inhibits by binding at NAD+ binding site
  • Thio-IMP (from 6-MP) and Thio-GMP (from 6-TG) inhibit by binding at purine-binding site
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20
Q

Give an examples of Sugar-modified nucleoside

A

Cytarabien (Ara-C)

  • Converted to triphosphate
  • Triphosphate inhibits DNA polymerases as analogue of dCTP
  • Some incorporation into DNA, making DNA non-functional

Fludarabine

  • Converted to triphosphate
  • Triphoshate inhibits DNA polymerases as analogue of dATP

Gemcitabine

  • Converted very efficiently to triphoshate F2dCTP
  • Triphosphate F2dCTP inhibits DNA polymerases as analogue of dCTP
  • 100x more potent than Ara-C

REMEMBER

  • dCTP is a feedback inhibitor of dCK, so depletion of dCTP actiavtes dCK
  • Activation of dCK increases formation of F2dCMP from gemcitabine
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21
Q

What are Microtubules and how is it regarded with cancer therapy?

A
  • responsible for maintaining the structure of the cell and for seperating the sets of chromosomes during mitosis
  • interfering with the formation and remodelling of microtubules inhibits mitosis and, therefore, proliferation of cancer cells
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22
Q

Describe structure of Microtubules

A
  • Microtubules are assemblies of tubulin dimers

- Each tubulin dimer has one alpha and one beta subunit

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23
Q

How does Mitotic spindle poison interfere with Microtubules?

A
  • Microtubules are in dynamic equilibrium with individual tubulin dimers
  • Mitotic spindle poisons interfere with this dynamic equilibrium
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24
Q

What are Vinca Alkaloids?

A
  • Vinblastine binds to + end of microtubule, capping it and preventing new tubulin dimers from adding
  • Vinca alkaloids bind strongly to individual tubulin dimers, causing conformational change and preventing binding to microtubules
  • Individual complexes of vinca alkaloid and tubulin dimers condense into paracrystalline aggregates
  • Le Chatelier’s Principle applies
    : microtubules shrink
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25
Q

Give 3 examples of Vinca Alkaloids

A

Vincristine (R=CHO)

Vinblastine (R=ME)

Vindesine

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26
Q

What are Taxols? And give 2 examples

A
  • Taxols bind to taxol-binding sites on the inside surface of the microtubule, preventing disassembly
  • Inappropriate microtubules remain
  • Concentration of free tubulin dimers decreases
  • The low concentration of free tubulin dimers means that new microtubules cannot be assembled

Paclitaxel (taxol), Docetaxel (taxotere)

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27
Q

What are Colchicine-like drugs?

A
  • Colchicine binds to cholchicine-binding sites on the b-tubulin, disfavouring assembly of protofilaments
  • Colchicine bound at colchicine-binding sites on b-tubulin in microtubules disfavours disassembly of inappropriate microtubules
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28
Q

What is Poly(ADP-ribose) [PAR]

A
  • After DNA and RNA, poly(ADP-ribose) [PAR] is the third nucleic acid in the mammalian cell
  • First observed in 1963; structure determined in 1967
  • Polyanionic polymer built from ADP-ribose units derived from NAD+
  • Usually built onto Glu side-chains in target proteins
  • MW varies with PARP isoform
    : upto 100KDa for PAR built by PARP-1
  • Linear or branched
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29
Q

What is Poly(ADP-ribose)polymerase-1 [PARP-1]?

A
  • Enzyme mainly found in the nuclei of cells
  • Abundant in most cells (ca. 2x10^6 molecules cell^-1)
  • 116 KDA protein
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30
Q

Describe therapeutic application of inhibition of PARP-1 in..
- Potentiation of radiotherapy and cytotoxic chemotherapy of cancer

A
  1. Radiotherapy of cancer causes DNA strand breaks
  2. Electrophilic cytotoxic drugs (e.g mustards) cause DNA damage
  3. Inhibitors of topoisomerase II (e.g doxorubicin) cause DNA single-strand breaks by inhibiting the strand re-joining step
  4. If the tumour cells can repair the DNA before it is required, then cells survive
  5. Inhibition of PARP-1 inhibits DNA repair
  6. Inhibition of PARP-1 potentiates radiotherapy and DNA-targeted chemotherapy
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31
Q

Describe therapeutic application of inhibition of PARP-1 in..
- Reduction of organ damage following ischaemia/reperfusion injury

A
  1. When the supply of blood to an organ is interrupted, the cells become hypoxic
  2. Reperfusion with blood causes rapid resupply of O2 to the hypoxic cells
  3. O2 is an oxidising diradical and damages DNA
  4. PARP-1 is over-activated
  5. Cells are depleted of NAD+ (also important in production of energy)
  6. Cells die
  7. Organ failure
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32
Q

How does PARP-1 recognise DNA?

A
  • through Zn fingers
  • The thiols of three Cys and the imidazole of one His in the DNA-binding domain of PARP-1 bind to a Zn2+, fixing the conformation of the protein
  • The NAD+ binding domain is at the C-terminal of the protein
  • Inhibitor olaparib binds at the NAD+ binding site
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33
Q

Describe DNA-damaging therapies

A

Therapy
1. Radiotherapy
: radiation, bleomycin

  1. Mono-alkylators
    : alkylsulfonates, nitrosoureas, temozolomide
  2. Cross-linkers
    : N-mustards, mitomycin C, platinum drugs
  3. Topoisomerase inhibitors
    : camptothecins, etoposide
  4. Replication inhibitors
    : aphidicolin, hydroxyurea
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34
Q

What drug is Olaparib?

A
  • Inhibits PARP-1, PARP-2, PARP-3
  • Clinical trials as a single agent started 2005
  • Approved for BRCA-mutant ovarian cancer
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35
Q

What drug is Rucaparib?

A
  • Inhibits PARP-1, PARP-2, Tankyrase-1, Tankyrase-2
  • Clinical trials started in 2003, in combination with temozolomide
  • Approved for BRCA-mutant ovarian cancer
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36
Q

What drug is Veliparib?

A
  • Inhibits PARP-1, PARP-2, not PAPR-3, Tankyrases
  • Phase 1-3 clinical trials, in combination and as single agent
  • Approval expected in 2018/2019
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37
Q

Describe Epidermal Growth Factor Receptor (EGFR)

A

Classical tyrosine kinase receptor
- EGF or TGFa binds to the extracellular domain of EGFR

  • Ligand-EGFR complex forms an asymmetric dimer
  • Signalling cascades trigger proliferation, migration, adheision
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38
Q

Describe EGFR in cancer

A
  • EGFR is implicated in the development and progression of cancer in two main ways
    : Overexpression of EGFR
    : Activating mutation in extracellular or intracellular domains
  • Mutations in the extracellular domain can lead to constitutive (EGF-independent) activity of EGFR and are frequently found in flioblastoma
  • Mutations in the kinase domain are found in a subset of non small-cell lung cancers (NSCLCs)
  • Most common kinase domain mutation is L858R (40% mutations)
  • These mutations are driver mutations (i.e they confer a growth advantage on the cells and so drive cancer)
  • The particular mutation occuring in an individual tumour is important as it can determine the sensitivity of the tumour to different drugs
  • Selecting drugs based on tumour mutation status is an example of personalised medicine in cancer
  • Targeted cancer therapy places a huge selective pressure on the target to evolve, and resistance mutations often emerge. Thus we move from first line therapies, which target the initial state, to second line therapies, which target the new mutant etc.
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39
Q

Describe the two conformations of the EGFR kinase domain

A
  1. Active conformation
    - bound to AMP-PNP
  2. Inactive conformation
    - bound to Lapatinib

EGFR kinase domain is found in two conformations
- active and inactive

Inactive conformation has two hallmarks found in many inactive kinase structures

  • alphaC helix moved away from kinase body (aC out)
  • New helix at beginning of region of kinase known as the activation loop

Physiologically, asymmetric dimerisation promotes the active conformation by stabilising aC helix ‘in’

40
Q

Descrobe stabilisation of the inactive conformation of EGFR kinase domain

A
  • The inactive conformation of EGFR is stabilised by a hydrophobic cluster
  • In the active conformation, the sidechain of Leu858 is solvent exposed
  • Two of the hydrophobic residues form active hydrophobic spine with conserved Phe and His
  • Mutating Leu858 to Arg destabilises this cluster and promotes active conformation
41
Q

What are the limitations of the structural evidence of EGFR?

A
  • EGFR is a crystallographic dimer (dimerised in crystals), so is normally observed in the active conformation in crystal structure
  • EGFR is only observed in the inactive conformation
    : in the presence of the inhibitor lapatinib
    : in the presence of the V948R mutation (which disturbs dimer interface)
  • Crystallography gives us atomic resolution information on the arrangement of the protein in the crystal, but gives no information on conformational heterogeneity or interconversion
42
Q

Why is Gefitinib 100x more potent in cells carrying the L858R mutation?

A
  • Binding data shows that Gefitinib binds more tightly to the L757R mutant than WT
43
Q

What is Gatekeeper mutations? give an example regarding EGFR and how it happens

A
  • Targeted cancer therapy places a huge selective pressure on the target to evolve, and resistance mutations often emerge
  • Eventually patients develop resistance to Gefitinib, usually through a mutation of a structurally conserved residue called the ‘gatekeeper’ to a bulkier residue
  • In EGFR, the gatekeeper residue is Thr790 and the T790M mutation is the most common resistance mutation
  • Once T790M mutation occurs, patients must move from gefitinib to a second line therapy
44
Q

Give 3 examples of common radionuclides and their half-life?

A

11 6 C beta+
- 20.3mins

18 9 F beta+
- 110mins

99m 43 Tc gamma
- 6hrs

32 15 P beta-
- 14.3 days

35 16 S beta-
- 86.5 days

226 88 Ra alpha
- 1600yrs

235 92 U alpha
- 7 x 10^8 yrs

45
Q

Describe the following radiation

- alpha

A
  • 4 2 He2+
  • Weakly penetrating
  • Short path length
  • Brachytherapy
46
Q

Describe the following radiation

- Beta- (minus)

A
  • e-
  • Penetration mm-cm
  • Radiotracers in e.g biodistribution & drug metabolism studies
47
Q

Describe the following radiation

- gamma

A
  • Photon (hv)
  • Highly penetrating
  • Imaging, radiotracers, radiotherapy
48
Q

Describe the following radiation

- beta+

A
  • positron e+
  • Annihilation with e- gives 2xgamma
  • 2 x gamma detected for imaging
49
Q

Describe the following radiation

- p+

A
  • proton
  • Short/medium path length
  • External beam therapy
50
Q

Describe the following radiation

- n

A
  • Neutron
  • short/medium path length
  • BNCT
51
Q

What are the units used to quantify radiation in terms of effect?

A

Units of radioactivity
- 1.0 Bq = 1.0 disintegration per sound

Units of radiation - Dose
- 1.0 Gy = 1.0 J Kg-1

Units of radiation - Relative Biological Dose

  • RBD = dose x RBE
  • RBE = Relative Biological Effectiveness
52
Q

What is Geiger counter?

A
  • instrument used for detecting and measuring ionising radiation
  • it detects ionising radiation such as alpha particles, beta particles, and gamma rays using the ionisation effect produced in Geiger-Muller tube.
53
Q

What is Scintillation counter?

A
  • an instrument for detecting and measuring ionizing radiation by using the excitation effect of incident radiation on a scintillator material, and detecting the resultant light pulses.
  • Sample and scintillant molecules in the same solution
  • beta-particle from radioactive molecule strikes scintillant molecule, transferring energy
  • Energy re-emitted by scintillant molecule as flash of light
  • Flash of light detected by photomultiplier tubes
54
Q

What is Autoradiography?

A
  • image on an x-ray film or nuclear emulsion produced by the pattern of decay emissions from a distribution of a radioactive substance
  • The film or emulsion is apposed to the labeled tissue section to obtain the autoradiograph
55
Q

What is What is gamma-imiaging/SPECT?

A
  • imaging technique using gamma rays

- requires delivery of a gamma-emitting radioisotope into the patient, normally through injection into the bloodstream

56
Q

What is Positron Emission Tomography?

A
  • nuclear medicine functional imaging technique that is used to observe metabolic processes in the body as an aid to the diagnosis of disease
  • The system detects pairs of gamma rays emitted indirectly by a positron emitting radioligand, most commonly fluorine-18, which is introduced into the body on a biologically active molecule called radioactive tracer
57
Q

Describe ‘Nucleotide Excision Repair (NER)

A
  1. DNA is damaged
  2. Damage is recognised by a protein called XPC, which is stably bound to another protein called R23
  3. The binding of the XPC-R23 is followed by the binding of several other proteins (XPA, RPA, TFIIH, XPG) Of these, XPA and RPA are believed to facilitate specific recognition of base damage. TFIIH consists of six subunits and contains two DNA helicase activities (XPB and XPD) that unwind the DNA duplex. This local denaturation generates a bubble in the DNA, the ends of which comprise junctions between duplex and single-stranded DNA
  4. The subsequent binding of the ERCC1-XPF heterodimeric subcomplex generates a completely assembled NER multiprotein complex
  5. XPG is a duplex/single-stranded DNA endonuclease that cuts the damaged strand at such junctions 3’ to the site of base damage. Conversely, the ERCC1-XPF heterodimeric protein is a duplex/single-stranded DNA endonucleases that cuts the damaged strand at such junctions 5’ to the site of base damage
  6. This fragment is removed from the genome, and a new section is synthesised including the damaged base
  7. Collectively, these biochemical events return the damaged DNA to its native chemistry and configuration
58
Q

Describe Base Excision Repair (BER)

A

Step 1
- First the N-glycosidic bond of the damaged base is cleaved by a DNA glycosylase leaving an abasic site in the DNA

Step 2
- The sugar-phosphate backbone of the abasic site is then cleaved by a bi-functional glycosylase and/or an AP-endonuclease. If necessary the 3’ strand break end is converted to hydroxyl allowing DNA polymerases to reinsert new bases

Step 3
- Synthesis of a single base is referred to as short patch (SP) BER and synthesis of several bases is referred to as long patch (LP) BER

Step 4-5
- The 5’ single strand end of the single strand break intermediate is then processed to allow for ligation by DNA ligases

59
Q

What is an AP(abasic) site?

A
  • also known as abasic site
  • AP site (apurini/apyrimidinic site) is a location in DNA that has neither a purine nor a pyrimidine base, either spontaneously or due to DNA damage
60
Q

What is DNA methylation?

A
  • process by which methyl groups are added to the DNA molecule
  • Methylation can change the activity of a DNA segment without changing the sequence.
  • When located in a gene promoter, DNA methylation typically acts to repress gene transcription.
61
Q

Describe DNA minor groove binders

A
  • Covalent (PBD’s, CPI’s, Mitomycin C) and Non-covalent (Distamycin, Netropsin)
  • Flat (Planner) poly-aromatic structures
  • Many have natural twist to fit minor groove
  • Alkylation centre a base of minor groove
  • Secondary non-covalent interactions important in covalent binding
  • Non-covalent compound have been modified with DNA alkylation moieties (mustards, epoxides) to give experimental covalent compounds
  • Many covalent compound have been linked to give dimeric cross-linkers (inter- and intra-strand.
62
Q

How do Cyclopropapyrroloindoles (CPI) based Anti-tumour antibiotics work?

A
  • Ethano bridges cause DNA over-winding and lead to dose limiting toxicity and delayed death
63
Q

Describe Targeted DNA alkylation

A
  • Use of pro-drugs to restrict damage to specific tumour location
  • Size: based on tumour cell increased permittivity (addition of PEG chains)
  • Hypoxia based targeting
  • DNA specific structural targets
  • Antibody based targeting
64
Q

What are Bleomycin and Phleomycins?

A
  • Bleomycin is a mixture of cytotoxic glycopeptide antibiotics isolated from a strain of Streptomyces verticillus and is freely soluble in water
  • Bleomycins are a group of related basic glycopeptides which differ in the terminal amine substituent of the common structural unit, Bleomycin acid. The main components of Bleomycin for injection are Bleomycins A2 and B2
65
Q

How is Bleomycin clinically used?

A
  • Bleomycins are used clinically in combination chemotherapy against lymphomas, squamous-cell carcinomas and germ-cell tumours
66
Q

What is the side effect of Bleomycin?

A
  • The side effects of the bleomycins are dose-dependent and involve lung inflammation that often proceeds to lung fibrosis
67
Q

Which transition metals and other substances can Bleomycins bind to?

A
  • Bleomycins bind transition metals Fe(II) or Cu(I) and oxygen, in the presence of a one-electron reductant, can catalyse formation of single-stranded (ss) and double-stranded (ds) DNA lesions
68
Q

Facts about Bleomycins

A
  • In vitro studies indicate that a single molecule of bleomycin is sufficient to generate lesions on both strands of DNA, the proposed source of cytotoxicity
  • Studies on a large number of bleomycin analogues, made possible by total synthesis of bleomycin, have indicated that the whole molecule is much greater than the sum of its parts
    : the linker between the metal and the bithiazole DNA-binding domain anad the flexibility of the bithiazole moiety itself are essential for efficient dsDNA cleavage.
  • The cellular response to bleomycin treatment are ccomplex and are cell-line and genotype-dependent.
    Extended cell-cycle arrest, apoptosis and mitotic cell death are most common outcomes of bleomycin treatment
  • Bleomycins are hydrophillic molecules that are unable to cross cell membranes by free diffusion. Studies with modified analogues indicate that the positively charged tail of bleomycin might play a key role in cellular uptake
69
Q

Describe Bleomycin’s structure regarding its 3 regions

A
  • Metal-binding region
  • Linker region
  • Bithiazole tail
70
Q

Describe DNA Double Strand Break (DSB) Repair

A
  • Several pathways ensure the repair of DSBs in eukaryotic cells.
  • Recombination is the only inherently error-free pathway to accomplish this and it involves a complex series of events which are now beginning to be understood in eukaryotes.
  • Other pathways like Non-Homologous End Joining (NHEJ) and Break-Induced Replication (BIR) are error-prone. leading to mutations and loss of heterology
  • These DSB repair pathways are conserved in all eukaryotes.

Recent work with transgenic mice has also provided conclusive evidence that recombinational repair is active and important in mammalian cells.

71
Q

How does Platinum anti-cancer drugs work?

A
  • Platinum-based drugs are effective against cancer because at their centre is a platinum atom joined to two ammonia molecules and two chloride ions.
  • The compound is negatively charged, but when it enters the cancer cell it becomes positively charged because the chloride ions are replaced by water molecules.
72
Q

How does Platinum enter cells and how does tumour resistance occur?

A
  1. Platinum might enter cells using either transporters
    : a significant one being the copper transporter CTR1
    : or by passive diffusion.
  • Loss of CTR1 results in less platinum entering cells and, consequently, drug resistance
  • Once inside cells, cisplatin is activated by the addition of water molecules to form a chemically reactive aqua species. This is faciliated by the relatively low chloride concentration that are found within cells
    2. In the cytoplasm, the activated aqua species preferentially reacts with species containing high sulphur levels by virtue of their containing many cysteine or methionine amino acids. These species include tripoptide glutathine or metallothioneins. In some platinum-resistant cancer cells, glutathione and metallothionein levels are relatively high, so activated platinum is effectively mopped up in the cytoplasm before DNA binding can occur, therefore causing resistance
    3. Finally, active export of platinum from the cells through the copper exporters ATP7A and ATP7B as well as through the glutathione S-conjugate export GS-X pump can contribute to platinum drug resistance
73
Q

What are the additional cause of tumour resistance to Cisplastin and Carboplatin mediated after DNA binding?

A

1) loss of DNa mismatch repair
2) Bypassing of adducts by polymerase beta and n
3) Through down regulation of apoptotic pathways

74
Q

What are the strategies to Circumvent Cisplatin and Carboplatin Resistance?

A

Resistance can be tackled by
- increasing levels of platinum reaching tumours thereby in greater killing

  • combining existing platinum drugs with molecularly targeted drugs
  • using novel platinum drugs such as oxaliplatin that are capable of circumventing cisplatin-mediated resistance mechanisms
  • using other drugs either alone or in combination which exploit particular cisplatin-mediated resistance mechanisms
75
Q

How does Angiogenesis inhibitors work?

A

These targeted drugs block the growth of new blood vessels to tumours
- Avastin (bevacizumab) for example, if a monoclonal antibody that binds with vascular endothelial growth factor (VEGF) which tumour cells release to stimulate blood-vessel growth.

  • The binding of the drug to the growth factor prevents VEGF from interacting with its receptors on the endothelial cells that line blood vessels.
  • Activation of these receptors normally leads to endothelial-cell growth and the formation of new blood vessels to the tumour
  • Preventing this growth also inhibits metastasis and may improve sensitivity to cytotoxic drugs
76
Q

Describe targetting DNA topoisomerase II in cancer chemotherapy

A
  • Topoisomerase II (TOP2) is the target of several important classes of anticancer drugs, including the anthracycline doxorubicin
  • most clinically active drugs that target TOP2 kill cells by trapping an enzyme intermediate termed the covalent complex
  • TOP2-mediated DNA damaged is repaired by multiple pathways. This DNA damage includes DNA strand breaks and proteins that are covalently bound to DNA. Repair of TOP2-mediated damage requires double-strand break repair pathways and other pathways that are specific for the removal of protein-DNA adducts
  • Anthracycline use is limited by cardiotoxicity although the mechanism of the cardiotoxicity is poorly understood
  • An important side effect of targeting TOP2 with TOP2 poisons is the formation of secondary malignancies that arise from drug-induced translocations
  • Catalytic inhibition of TOP2 could also be a useful anti-cancer strategy. New compounds are being developed to test this possibility.
77
Q

Describe how Transcription can be targeted by DNA-intercalating drugs

A
  • Doorubicin and SN-38 interact with, and stabilise, the topoisomerases (topo)-II-DNA or topo-I-DNA complexes, respectively, to produce produce a ‘cleavable complex’.
  • This results in DNA strand breakage that is associated with the protein-DNA complex
  • Pluramycin binds peripherally to the TATA-binding protein (TBP)-TATA box complex.
  • Alkylation by pluramycin is enhanced by TBP binding to the TATA box, and as result TBP is immobilised on the DNA
78
Q

Describe Telomerase as a target for cancer therapy

A
  • Telomerase is an enzyme that adds DNA sequence repeats (TTAGGG in all vertebrates) to the 3’ end of DNA strands in the telomere regions, which are found at the ends of eukaryotic chromosomes
  • This region of repeated nucleotide called telomeres contains non-coding DNA material and prevents constant loss of important DNA from chromosome ends
  • Examples of DNA sequences that can form G-quadruplexes include telomeres and promoters that contain a polypurine-rich strand
  • Equilibrium between dsDNA structures and the G-quadruplexes is dependent on helicases that unwind the quadruplex and chaperone proteins that are required for its formation
  • G-quadruplexes-interactive drugs can either inhibit helicases or facilitate formation of new quadruplexes or can isolate newly formed G-quadruplexes
79
Q

What are hormones?

A
  • substances that function as chemical messengers in the body
  • they affect the actions of cells and tissues at various locations in the body, often reaching their targets through the bloodstream
80
Q

How are hormones oestrogen and progesterone produced and what do they do?

A
  • produced by the ovaries in premenopausal women and by some other tissues, including fat and skin, in both premenopausal and postmenopausal women and men.
  • Oestrogen promotes development and maintenance of female sex characteristics and the growth of long bones
  • Progesterone plays a role in the menstrual cycle and pregnancy
  • Oestrogen and progesterone also promote the growth of some breast cancers, which are called hormone-sensitive breast cancers
  • Hormone-sensitive breasst cancer cells contain receptors that become activated when hormones bind to them. The activated receptors cause changes in the expression of specific genes, which can stimulate cell and tumour growth
81
Q

What is hormone therapy?

A
  • Hormone therapy slows or stops the growth of hormone-sensitive tumours by blocking the body’s ability to produce hormones or by interfering with effects of hormones on breast cancer cells
  • Tumours that are hormone insensitive do not have hormone receptors and do not respond to hormone therapy
82
Q

How do you determine whether breast cancer cells contain hormone receptors? (hormone-sensitive) and how do you call different types of breast cancer?

A
  • Biopsy is performed and the sample tested
  • If the tumour cells contain Oestrogen receptors, the cancer is called
    : Oestrogen Receptor Positive (ER positive)
    : Oestrogen sensitive
    : Oestrogen Responsive
  • Similarly, if the tumour cells contain progesterone receptors, the cancer is called
    : Progesterone receptor positive (PR or PgR positive)
  • Approximately 80% of breast cancers are ER positive. Most of these ER-positive breast cancers are also PR positive
  • Breast tumours that contain oestrogen and/or progesterone receptors are sometimes called
    : Hormone Receptor Positive (HR positive)
83
Q

How do you call Breast cancer cells that lack oestrogen/progesterone receptors?

A
  • Oestrogen Receptor Negative (ER-negative)
  • These tumours are oestrogen insensitive, meaning that they do not use oestrogen to grow
  • Breast tumours that lack progesterone receptors are called Progesterone Receptor Negative (PR or PgR negative)
  • Breast tumours that lack both Oestrogen and Progesterone receptors are sometimes called
    : Hormone Receptor Negative (HR negative)

For this reason, when a women taking HRT is diagnosed with HR-positive breast cancer, she is normally asked to stop HRT (or oral contraceptives) therapy.

84
Q

Describe Protein receptors in Breast cancer and which drug is used in this case?

A
  • Some breast cancers have high numbers of receptors for the protein HER2 (Human Epidermal Growth Factor 2)
  • They are called HER2 positive breast cancers
  • About 1 in 7 women (15%) with early breast cancer have HER2 positive cancer.
  • A drug called trastuzumab (Herceptin) is an effective treatment for this type of breast cancer
85
Q

What is a triple negative breast cancer?

A
  • If the cancer does not have receptors for either HER2 or the hormones Oestrogen and Progesterone, it is called triple negative breast cancer
  • It affects around 13% of women with breast cancer and is more common in younger women
86
Q

What are the 3 types of Hormone therapy used for breast cancer?

A

Several strategies are used to treat hormone-sensitive breast cancer

  1. Blocking Ovarian function
  2. Blocking Oestrogen production
  3. Blocking Oestrogen’s effects
87
Q

Describe the following hormone therapy

- Blocking ovarian function

A
  • Because the ovaries are the main source of Oestrogen in premenopausal women, Oestrogen levels in these women can be reduced by eliminating or suppressing ovarian function.
  • Blocking ovarian function is called ovarian ablation
  • Ovarian ablation can be done surgically in an operation to remove the ovaries (called oophorectomy) or by treatment with radiation. This type of ovarian ablation is usually permanent.
  • Alternatively, ovarian function can be suppressed temporarily by treatment with drugs called Gonadotropin-releasing hormone (GnRH) agonists, which are also known as luteinizing hormone-releasing hormone (LH-RH) agonists.
  • These medicines interfere with signals from the pituitary gland that stimulate the ovaries to produce oestrogen
  • An example of ovarian suppression agent is Goserelin (Zoladex)
88
Q

Describe the following hormone therapy

- Blokcing Oestrogen Production

A

Drugs called Aromatase inhibitors are used to block the activity of an enzyme called aromatase, which the body uses to make oestrogen in the ovaries and in other tissues.

Aromatase inhibitors are used primarily in postmenopausal women because the ovaries in premenopausal women produce too much aromatase for the inhibitors to block effectively.

However these drugs can be used in premenopausal women if they are given together with a drug that suppresses ovarian function

  • Examples are Anastrozole (Arimidex) and Letrozole (Femara) both of which temporarily inactivate aromatase
  • Exemestane (Aromasin) permanently inactivates aromatase
89
Q

How does Aromatase produce Oestrogen?

A
  • by aromatizing androgens
  • Aromatase is the only known enzyme in vertebrates capable of catalysing the aromatization of a six-membered ring
  • Aromatase converts androstenedione to oestrogen and testosterone to oestradiol
90
Q

Describe the following hormone therapy

- Blocking Oestrogen’s effects

A
  • Several types of drugs interfere with oestrogen’s ability to stimulate the growth of breast cancer cells

Selective Oestrogen Receptor Modulators (SERM)

  • bind to oestrogen receptors, preventing oestrogen from binding
  • examples are Tamoxifen (Nolvadex) and Toremifene (Fareston)

Other antioestrogen drugs
- Fulvestrant (Faslodex) binds to oestrogen receptor and functions as an oestrogen antagonist

91
Q

How is Hormone therapies used to treat breast cancer?

A

There are three main ways that hormone therapy is used to treat hormone-sensitive breast cancer

  1. Adjuvant therapy for early-stage breast cancer
  2. Treatment of advanced or metastatic breast cancer
  3. Neoadjuvant treatment of breast cancer
92
Q

Describe Adjuvant therapy for early-stage breast cancer

A
  • Tamoxifen is approved for adjuvant hormone treatment of premenopausal and postmenopausal women with ER-positive early-stage breast cancer, and the aromatase inhibitors anastrozole and letrozole are approved for this use in postmenopausal women
  • A third aromatase inhibitor, exemestane, is approved for adjuvant treatment of early stage breast cancer in postmenopausal women who have not received tamoxifen previously
93
Q

Describe Treatment of advanced or metastatic breast cancer

A
  • Several types of hormone therapy are approved to treat metastatic or recurrent hormone-sensitive breast cancer.
  • Hormone therapy is also a treatment option for ER positive breast cancer that has come back in the breast, chest wall, or nearly lymph nodes after treatment
  • Tamoxifen and Toremifene are approved to treat metastatic breast cancer.
  • The anti-oestrogen fulvestrant is approved for postmenopausal women with metastatic ER-positive breast that has spread after treatment with other antioestrogens.
  • The aromomatase inhibitors Anastrozole and Letrozole are approved for use in postmenopausal women as initial therapy for metastatic or locally advanced hormone-sensitive breast cancer
94
Q

Describe Neoadjuvant treatment of breast cancer

A
  • Use of hormone therapy to treat breast cancer before surgery has been studied in clinical trials
  • Goal of neoadjuvant therapy is to reduce the size of a breast tumour to allow breast-conserving surgery
95
Q

Can hormone therapy be used to prevent breast cancer?

A
  • yes, but most breast canccers are ER positive, and clinical trials have tested whether hormone therapy can be used to prevent breast cancer in women who are at increased risk of developing the disease

A large US randomized clinical trial called the “Breast Cancer Prevention Trial” found that tamoxifen, taken for 5 years, reduced the risk of developing invasive breast cancer by about 50% in postmenopausal women who were at increased risk. Long-term follow-up of another randomised trial, the “International Breast Cancer Intervention Study I”, found that 5 years of tamoxifen treatment reduces the incidence of breast cancer for at least 20 years.

96
Q

What are the side effects of hormone therapy?

A
  • depends largely on the specific drug or the type of treatment
  • The benefits and harms of taking hormone therapy should be carefully weighed for each woman
  • A common switching strategy used for adjuvant therapy, in which patients take tamoxifen for 2 or 3 years, followed by an aromatase inhibitor for 2 or 3 years, may yield the best balance of benefits and harms of these two types of hormone therapy

Hot flahses, night sweats, and vaginal dryness are common side effects of hormone therapy.

Hormone therapy also disrupts the menstrual cycle in ppremenopausal women

97
Q

Can other drugs interfere with hormone therapy?

A
  • Certain drugs, including several commonly prescribed anti-depressants (SSRI) inhibit the enzyme CYP2D6. This enzyme plays a critical role in the use of tamoxifen by the body because it metabolises, tamoxifen into metabolites, that are much more active than tamoxifen itself
  • The possibility that SSRI might, by inhibiting CYP2D6, slow the metabolism of tamoxifen and reduce its effectiveness is a concern given that as many as 1 in 4 breast cancer patients experience clinical depression and will often be treated with SSRIs
  • Might change to weaker inhibitor such as sertraline or no inhibitory activity such as citalopram

Year 3 Sem 2 (12 decks)

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