Brainscape's Knowledge GenomeTM


Top Flashcards (Certified)
All Flashcards

MO2 > Anthracyclines and Mitotic Inhibitors > Flashcards

Anthracyclines and Mitotic Inhibitors Flashcards

1
Q

what are anthracyclines?

A

they are antitumour antibiotics

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

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

what are the main anthracyclines available?

A

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

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

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

what clinical condition should danorubicin not be used in?

A

cardiac- could produce fatal cardiac toxicity

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

what is doxorubicin?

A

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

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

what was better daunorubicin or doxorubicin?

A

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

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

how is danorubicin produced?

A

produced by a number of different wild type strains of streptomyces

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

what is the first step in anti-cancer action?

A

involves sliding between the bases of DNA

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

what should intercalators be?

A

planar

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

what are DNA strands linked by?

A

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

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

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

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

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

what is doxorubicin formulated as? why?

A

Formulated as hydrochloride salt, minimal oral activity

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

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

A

Photosensitive(aluminium/brownwaxpaperbag

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
24
Q

what does admin of docorubicin via fast flowing vein cause?

A
  • Intramuscular/subcutaneous administration causes severe tissue necrosis
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
how is docorubicin made up?
* 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
26
why are liposomal products beneficial?
* Ubiquitous body distribution * Little or no preferential accumulation in some tumor tissues * Improved by modifying its mode of delivery –liposomes
27
what are the liposomoal products?
* Doxorubicin (Caelyx), Daunorubicin (DaunoXome)
28
how are doxorubicin liposomes formulated?
Doxorubicin liposomes formulated with surface-bound methoxypolyethylene glycol
29
what is the benefit of liposomal formulation of docorubicin?
ignificantly reduces toxicity, specifically the cardiotoxic effects of doxorubicin
30
what is a frequent side effect of liposomal doxorubicin?
hand and foot syndrome, managed by reducing dose and increasing the cycle duration – leakage from capillaries at extremeties(hands, feet)
31
what is the MOA of docorubicin?
* 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
what is Topoisomerase II?
* Enzyme responsible for controlling topology of DNA – number of times DNA is coiled/folded
33
how is top 2 involved in DNA processing?
– 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
how does doorubicin stabilise the top 2- DNA complex?
– 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
how does TOP 2 work- short steps?
(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
how does doxorubicin cause intracellular redox reactions?
– redox properties of quinonefunctionallity – CYP450 reductase catalyses reduction to semiquinoneradicals – generates free radicals * superoxide radical O2٠- * hydroxyl radical OH
37
what are the properties of the radicals generated from doxorubicin reactions?
– central role in cardiotoxicity – react with cell membranes – damage membrane of cancer cells
38
what does the hydroxyl radical do?
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
what are some tissues with protective enzymes that are resistant to doxorubicin?
* antioxidants * superoxide dismutase * glutathione peroxidase
40
what has low superoxide dismutase and thus is suceptiable to docorubicin?
* 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
what should you to do prevent fentons reaction?
Administration of dexrazoxane before doxorubicin (a strong iron chelator) removes the iron from the drug complex
42
what is doxorubicin resistant to? why?
drug efflux by P-glycoprotein, also cells rich in protective enzymes
43
what are the pharmacokinetic properties of doxorubicin?
– extensively plasma protein bound – does not cross blood-brain barrier – metabolism/excretion –hepatic and primarily biliary – some renal excretion leads to red urine
44
doxorubicin and epirubicin are epimers, what is this?
wo isomers differ in configuration at only one stereogeniccenter
45
what is better tolerated out of docorubicin and epirubicin?
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
what are the outcome of the metabolism of epirubicin?
* 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
what are bleomycins?
* Naturally occurring glycoprotein * From Streptomyces verticillus Clinically used Blenoxaneis a mixture that contains predominantly bleomycins A2 and B2
48
what job does the intercalator do in bleomycins?
tabilised by H-bonding – forms a complex with Fe(II) – formation of hydroxyl and superoxide radicals – cleavage of phosphodiesterbon
49
what does the activity of bleomycins require?
* a metal ion (usually Fe2+ / Fe3+) * oxygen * one-electron reducing agent
50
what are the 4 signifigant molecular regions in bleomycins?
* 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
how do mitotic inhibitors work?
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
what are microtubules?
polymers of tubulin integral components of mitotic spindle
53
what is tubulin?
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
how do profilaments bind?
bind laterally to form hollow, cylindrical microtubules
55
what does a microtubule scaffold usually do?
normally positions chromosomes, then collapses as the replicated chromosomes are pulled apart during cytokinesis
56
what is the equilibrium process of a tubulin?
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
what are the various products in the taxane group?
Paclitaxel (Taxol) Docetaxel (Taxotere) * Cabazitaxel
58
what is the mode of action of taxanes?
– 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
how do taxanes interact laterally?
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
how do vinca alkaloids work?
Cell-cycle specific –blocks mitosis by metaphase arrest
61
how do vina alkaloids interact with tubulin?
– 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
where do vinca alkaloids and taxanes bind?
* 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
what is eribulin used for?
As mesylatesalt for metastatic breast cancer and liposarcoma
64
what MOA does eribulin have?
* Has both cytotoxic and non-cytotoxic mechanisms of action – antimitotic activities – decreased capacity for migration and invasion leads to reduced metastatic capacity
65
is eribulin synthetic?
fully synthetic – macrocyclic ketone – analogue of marine natural product halichondrinB (sponge genus Halichondria) – halichondrinB is a potent naturally occurring mitotic inhibitor
66
what is the MOA of eribulin
– 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
what is the binding site of eribulin shaped by?
* 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
how do mandrake plant extracts work?
– 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
how do the campotheca tree extracts work?
Semi-synthetic versions of extract of bark camptothecin – Irinotecan(urethane prodrug) – Topotecan * Inhibition of topoisomerase I

MO2 (55 decks)

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