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MO2 > Anthracyclines and Mitotic Inhibitors > Flashcards

Anthracyclines and Mitotic Inhibitors Flashcards

1
Q

what are anthracyclines?

A

they are antitumour antibiotics

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2
Q

how do anthracyclines work?

A

substances produced by microorganisms that exert their anticancer activity by
interacting with DNA
they all intercalate preferentially into major groove of DNA

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3
Q

what are the main anthracyclines available?

A

– Doxorubicin (+ liposomal)
* main anticancer anthracycline
– Daunorubicin (+ liposomal)
– Idarubicin
– Epirubicin
– Mitoxantrone
– pixantrone

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4
Q

how were daunorubicinis/ docorubicins found?

A

isolated soil samples with a new strain
of Streptomyces peucetiusthat produced an antibiotic with good activity against
murine tumors

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5
Q

what clinical condition should danorubicin not be used in?

A

cardiac- could produce fatal cardiac toxicity

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6
Q

what is doxorubicin?

A

Doxorubicin is a 14-hydroxylated version of daunorubicin, the immediate precursor
of doxorubicin in its biosynthetic pathway

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7
Q

what was better daunorubicin or doxorubicin?

A

docorubicin
– better activity than daunorubicin, particularly against solid tumors
– relatively higher therapeutic index
– cardiotoxicityremaine

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8
Q

how is danorubicin produced?

A

produced by a number of different wild type strains of streptomyces

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9
Q

what is the first step in anti-cancer action?

A

involves sliding between the bases of DNA

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10
Q

what are the general features of the anthracyclines?

A

– polycyclic aromatics
– positively charged groups
* ionised amine
* induces stability
* makes molecule more water soluble
* binds strongly to DNA
– hydrogen bonding sites
* H-bond donors / acceptors
* -OH, NH,C=O

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11
Q

what should intercalators be?

A

planar

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12
Q

is DNA static? why?

A

DNA is not a static structure
* Gaps between the base-pairs open and close
* ‘DNA breathing’
* Intercalation into DNA in the space between two adjacent base pairs becomes
possible

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13
Q

what are DNA strands linked by?

A

DNA strands are linked by hydrogen-bonds
– directional
– non-covalent
– can be disrupted

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14
Q

what must the distance be between the dna strands for an intercalator to fit?

A

the latter must separate by over 0.3 nm

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15
Q

what happens when an intercalator fits between base pairs?

A

– local structural changes to the DNA strand
* unwinding of the double helix
* lengthening of the DNA strand
* Structural modifications lead to functional changes
– inhibition of transcription and replication processes

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16
Q

what is the effect of intercalation?

A
  • More rigid structure
    – viscosity mof DNA increase
    – melting temperature Tm of DNA increases
  • DNA breathing is reduced
  • Hydrogen-bonding in DNA fails at point of intercalation
    as bases/strands separated
  • DNA structure partially unwinds and elongates
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17
Q

what are the modes of intercalation?

A

Parallel Intercalation:
– long axis of drug lies parallel to the base-pair axis
– maximum overlap between drug and DNA bases
– most stable form of intercalation
* Perpendicular Intercalation:
– long axis of drug lies perpendicular to the base-pair axis
– most common form of intercalation

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18
Q

what happens after the intercalation into DNA? what is its origin?

A

ring D of the anthracyclineprotrudes into the major
groove of the double helix, while ring A reaches out into the minor groove
– the anthracyclineis at right angles to the direction of the DNA bases
(perpendicular intercalation)
* The amino sugar, linked to ring A of the anthracycline, interacts with groups in the
minor groove, serving as an anchor that stabilises the anthracycline-DNA complex

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19
Q

what is doxorubicin formulated as? why?

A

Formulated as hydrochloride salt, minimal oral activity

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20
Q

what is docorubicin sensitive to? what is done about this?

A

Photosensitive(aluminium/brownwaxpaperbag

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21
Q

how is docorubicin administered?

A
  • Administered by intravenous infusion
    – rapid flowing vein, fine cannula into vein
    – most often a central line into vein near collarbone
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22
Q

what is docorubicin irritating towards?

A
  • Very irritating to tissue
    – vesicant side-effects
    – leakage into tissue around the vein (extravasation), causes tissue damage
    – gloves must be worn for administration
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23
Q

what does admin of docorubicin via fast flowing vein cause?

A
  • Fast flowing vein causes rapid dilution by blood volume
    – reduces damage to vein walls
    – minimises drug leakage
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24
Q

what does admin of docorubicin via fast flowing vein cause?

A
  • Intramuscular/subcutaneous administration causes severe tissue necrosis
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25
Q

how is docorubicin made up?

A
  • Sterile red-orange lyophilised (freeze-dried) powder in single dose flip-top vials
    – 10, 50 mg vial
    – reconstitute with 0.9% saline to 2 mg / mL doxorubicin hydrochloride
    – stable (7 d at RT, 15 d refrigerated) and protected from exposure to sunlight
    – 2 mg / mL pre-prepared
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26
Q

why are liposomal products beneficial?

A
  • Ubiquitous body distribution
  • Little or no preferential accumulation in some tumor tissues
  • Improved by modifying its mode of delivery –liposomes
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27
Q

what are the liposomoal products?

A
  • Doxorubicin (Caelyx), Daunorubicin (DaunoXome)
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28
Q

how are doxorubicin liposomes formulated?

A

Doxorubicin liposomes formulated with surface-bound methoxypolyethylene
glycol

29
Q

what is the benefit of liposomal formulation of docorubicin?

A

ignificantly reduces toxicity, specifically
the cardiotoxic effects of doxorubicin

30
Q

what is a frequent side effect of liposomal doxorubicin?

A

hand and foot syndrome,
managed by reducing dose and increasing the cycle duration
– leakage from capillaries at extremeties(hands, feet)

31
Q

what is the MOA of docorubicin?

A
  • Initially, intercalation with DNA
  • Intercalation with DNA is non-specific between adjacent base-pairs
  • Then … main effect is on function of topoisomerase II
    – forms stable ternary complex with DNA and topoisomerase II at point of
    intercalation
    – functions as enzyme inhibitor
    – Interferes with DNA processing/repair and, hence, prevents cell division
  • Also, involved in oxidation / reduction reactions
32
Q

what is Topoisomerase II?

A
  • Enzyme responsible for controlling topology of DNA
    – number of times DNA is coiled/folded
33
Q

how is top 2 involved in DNA processing?

A

– important during replication –DNA coils are unwound
– topoisomerase II interacts with DNA to form a binary covalent complex
(DNA-topoisomerase)
* complex may be cleaved by water
– topoisomerase II simultaneously breaks both DNA strands
– the ends of the DNA are separated, and a second DNA duplex is passed
through the break.
– following passage, the cut DNA is re-connected
– increases or decrease the linking number of a DNA loop by 2 units
– forms a tighter (or looser) coil

34
Q

how does doorubicin stabilise the top 2- DNA complex?

A

– forms a rigid ternary complex (DNA-topoisomerase-doxorubicin)
– cannot be cleaved
– inhibits DNA replication
– apoptotic response in cells is attributed to inefficient repair of double
strand breaks
– inhibits cell replication -> cell death

35
Q

how does TOP 2 work- short steps?

A

(1) topoisomerase II-DNA binding
(2) generation of a prestrandpassage cleavage complex
(3) DNA strand passage (ATP driven)
(4) re-ligation of the DNA break
(5) ATP hydrolysis
(6) DNA release and subsequent enzyme recycling

36
Q

how does doxorubicin cause intracellular redox reactions?

A

– redox properties of quinonefunctionallity
– CYP450 reductase catalyses reduction to semiquinoneradicals
– generates free radicals
* superoxide radical O2٠-
* hydroxyl radical OH

37
Q

what are the properties of the radicals generated from doxorubicin reactions?

A

– central role in cardiotoxicity
– react with cell membranes
– damage membrane of cancer cells

38
Q

what does the hydroxyl radical do?

A

One of most destructive chemical species known
Mitochondrial dysfunction
Alters calcium ion transport
Causes DNA base oxidation
Causes DNA strand cleavage
Causes protein oxidation
Causes thiol oxidation
Causes lipid membrane oxidation

39
Q

what are some tissues with protective enzymes that are resistant to doxorubicin?

A
  • antioxidants
  • superoxide dismutase
  • glutathione peroxidase
40
Q

what has low superoxide dismutase and thus is suceptiable to docorubicin?

A
  • tumours (and cardiac tissue) have low superoxide dismutase
  • accumulation of superoxide radical
    – cardiac tissue also has low levels of catalase
  • unable to metabolise H2O2
  • readily processed to hydroxyl radical
    *
41
Q

what should you to do prevent fentons reaction?

A

Administration of dexrazoxane before doxorubicin (a strong iron chelator) removes
the iron from the drug complex

42
Q

what is doxorubicin resistant to? why?

A

drug efflux by P-glycoprotein, also cells rich in protective enzymes

43
Q

what are the pharmacokinetic properties of doxorubicin?

A

– extensively plasma protein bound
– does not cross blood-brain barrier
– metabolism/excretion –hepatic and primarily biliary
– some renal excretion leads to red urine

44
Q

doxorubicin and epirubicin are epimers, what is this?

A

wo isomers differ in configuration at
only one stereogeniccenter

45
Q

what is better tolerated out of docorubicin and epirubicin?

A

Epirubicinis better tolerated than doxorubicin with less nausea and vomiting, myelosuppression, and cardiac toxicity
this is due to the distrubution of docorubicin being signifigantly higher

46
Q

what are the outcome of the metabolism of epirubicin?

A
  • Metabolism of epirubicinis complex to give relatively or totally inactive
    metabolites
  • Transformation of epirubicin into its glucuronide represents the major detoxifying
    pathway.
    – also significant is reduction of the ketone moiety at C-13 to give epirubicinol
47
Q

what are bleomycins?

A
  • Naturally occurring glycoprotein
  • From Streptomyces verticillus
    Clinically used Blenoxaneis a mixture that contains predominantly bleomycins A2 and B2
48
Q

what job does the intercalator do in bleomycins?

A

tabilised by H-bonding
– forms a complex with Fe(II)
– formation of hydroxyl and
superoxide radicals
– cleavage of phosphodiesterbon

49
Q

what does the activity of bleomycins require?

A
  • a metal ion (usually Fe2+ / Fe3+)
  • oxygen
  • one-electron reducing agent
50
Q

what are the 4 signifigant molecular regions in bleomycins?

A
  • C-terminal domain (heterocyclic bithiazole)
    provides the DNA binding affinity, both by
    intercalation and minor groove-binding
    (electrostatics)
  • N-terminus domain (b-hydroxyhistidine, b-
    aminoalanineand pyrimidine) constitutes
    the metal-chelating and oxygen activation
    domain (free-radicals and single/double
    strand breaks)
  • flexible central linker gives the metal-
    chelating domain necessary flexibility to
    cleave both strands without dissociation
    from DNA
  • glycoside region role is unclear, but shown
    to be crucial for the DNA and RNA cleaving
    efficiency (may contribute to drug uptake)
51
Q

how do mitotic inhibitors work?

A

suppress cell division by inhibiting mitosis
* Mitotic spindle -vital for equal partitioning of DNA into daughter cells
* Spindle is composed of protein, tubulin -part of larger intracellular skeleton
* Mitotic inhibitors -disrupt balance between polymerised and depolymerised
microtubules
* Cell cycle specific

52
Q

what are microtubules?

A

polymers of tubulin
integral components of mitotic spindle

53
Q

what is tubulin?

A

Microtubules are composed of the protein
tubulin
* Tubulin forms dimers, which consist of an
a and a b subunit (450 aa monomers)
* Dimers stack together into protofilaments,
which are linear strings

54
Q

how do profilaments bind?

A

bind laterally to form
hollow, cylindrical microtubules

55
Q

what does a microtubule scaffold usually do?

A

normally positions
chromosomes, then collapses as the
replicated chromosomes are pulled apart
during cytokinesis

56
Q

what is the equilibrium process of a tubulin?

A

Binding of a/b-tubulin to guanosine-5’-triphosphate (GTP) promotes assembly
Binding of b-tubulin to guanosine-5’-diphosphate (GDP) promotes disassembly
(hydrolysis of GTP -> GDP)

57
Q

what are the various products in the taxane group?

A

Paclitaxel (Taxol)
Docetaxel (Taxotere)
* Cabazitaxel

58
Q

what is the mode of action of taxanes?

A

– Microtubulin antagonist
* bind tubulin dimers and microtubule filaments reversibly
* induces assembly of tubulin into microtubules, inhibits depolymerisation
to tubulin
* stabilises mitotic spindle by formation of abnormal bundles of
microtubules
* microtubules do not depolymerise leading to disruption of mitosis
* equilibrium is shifted to formation of microtubules
* stabilise microtubules to the extent that mitosis is disrupted
* dysfunctional, cell stopped in metaphase
* cell death

59
Q

how do taxanes interact laterally?

A

Taxolbinds very near the M loop of b-tubulin, which
makes lateral contacts between adjacent
protofilaments
Stabilisesmicrotubules by strengthening lateral
interactions between protofilments
Stabilisesa conformation of M loop that favors lateral
contacts
Counteracts destabilisingeffects of GTP induced
hydrolysis
Microtubule with GTP bound to end β-tubulin is stable
and will continue to grow
Microtubule with GDP molecule to end β-tubulin will
be unstable and will depolymerise

60
Q

how do vinca alkaloids work?

A

Cell-cycle specific –blocks mitosis by metaphase arrest

61
Q

how do vina alkaloids interact with tubulin?

A

– binds to tubulin
– inhibits polymerisation to microtubules
* inhibits development of mitotic spindle
– shifts equilibrium toward microtubledisassembly and shrinkage
– prevents formation of the mitotic spindle
* spindle poisons
– metaphase arrest
– cell division inhibited
– effects only apparent during mitosis

62
Q

where do vinca alkaloids and taxanes bind?

A
  • Vincaalkaloids bind to high-affinity sites
    of b-tubulin at the microtubule (+)-end
    to suppress assembly microtubule
    dynamics
  • Taxolbinds along the interior surface of
    the microtubule, suppressing its dis-
    assembly dynamics
63
Q

what is eribulin used for?

A

As mesylatesalt for metastatic breast cancer and liposarcoma

64
Q

what MOA does eribulin have?

A
  • Has both cytotoxic and non-cytotoxic mechanisms of action
    – antimitotic activities
    – decreased capacity for migration and invasion leads to reduced metastatic capacity
65
Q

is eribulin synthetic?

A

fully synthetic
– macrocyclic ketone
– analogue of marine natural product halichondrinB (sponge genus Halichondria)
– halichondrinB is a potent naturally occurring mitotic inhibitor

66
Q

what is the MOA of eribulin

A

– binds predominantly to a small number of high affinity sites at the plus ends of
existing microtubules
– binding site is distinct from vincadomain
– also creates non-functional aggregates of tubulin blocking microtubule
polymerisation
– apoptosis is induced following prolonged and irreversible mitotic blockade

67
Q

what is the binding site of eribulin shaped by?

A
  • Binding site is shaped by hydrophobic and polar residues
  • “Cage” structure is in contact with the ribose moiety of the guanosine nucleotide
  • Acts as a molecular “lid” to inhibit nucleotide exchange and tubulin-tubulin-
    induced hydrolysis
  • Wraps around the side chain of Tyr224
68
Q

how do mandrake plant extracts work?

A

– Teniposide
– Etoposide
* breakdown of microtublesand prevents polymerisation to produce new ones
* binds enzyme-DNA complex and maintains transiently cleavable form
* generates irreversible DNA strand breaks

69
Q

how do the campotheca tree extracts work?

A

Semi-synthetic versions of extract of bark camptothecin
– Irinotecan(urethane prodrug)
– Topotecan
* Inhibition of topoisomerase I

MO2 (55 decks)

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