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CHEMOTHERAPY > Topoisomerase Inhibitors > Flashcards

Topoisomerase Inhibitors Flashcards

1
Q

What is the general function of topoisomerases? What 2 processes do they allow?

A

topoisomerases are nuclear enzymes that relax supercoiled ds DNA to allow DNA replication and RNA transcription

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2
Q

What is the function of topoisomerase I? topoII?

A

topoisomerase I – > releases torsional strain via SINGLE strand nick

topoisomerase II – > releases torsional strain via DOUBLE strand nick

After nicks, swiveling of supercoiled DNA occurs at the nicks followed by re-ligation to relieve torsional strain

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3
Q

Topo inhibitors bind and stabilize DNA/topo cleavable complex – > preventing what?

A

Topo inhibitors bind and stabilize DNA/topo cleavable complex – > preventing RE-LIGATION of DNA STRANDS

Irreversible damage results when advancing DNA replication fork encounters drug-stabilized cleavable complex – > lethal DS DNA breaks and cell death

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4
Q

Name the 2 topoisomerase I inhibitors, what group are they in?

A

Topo I

Camtothecins (Topotecan & Irinotecan)

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5
Q

Name the topo II inhibitors, what groups are they in?

A

Anthracyclines:

  • Daunorubicin
  • Doxorubicin
  • Epirubicin (doxorubicin analog)
  • Idarubicin (daunorubicin analog)

Anthracenediones:
- Mitoxantrone

Epipodophyllotoxins:
- Etoposide, Teniposide

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6
Q

What are 2 types of resistance for the topoisomerase inhibitors (both I and II) ?

A
  1. Topo II (NOT topo I) are substrates for p-glycoprotein and have MDR phenotype
  2. For both topo I/II inhibitors, can see resistance w reduced topoisomerase levels or changes in the enzymes dt mutation
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7
Q

Describe metabolism/elimination of topotecan

How administered?

A

Topotecan - NOT metabolized. Excreted unchanged by kidenys, so dose reduce if renal disease

PO or IV

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8
Q

What is the active metabolite of irinotecan?

A

Irinotecan – > SN-38 (active)

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9
Q

Irinotecan requires esterification by serum/tissue ________ to become activated to SN-38

A

Irinotecan requires esterification by serum/tissue ___carboxylesterases__ to become activated to SN-38

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10
Q

Are topoisomerase I inhibitors cell phase specific?

A

NO but Cells in S-phase are very sensitive bc DNA replication requires topo I activity; topo associated ss breaks are converted to ds breaks

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11
Q

What is most interesting side effect of irinotecan?

A

early onset diarrhea and other atropine-responsive cholinergic signs

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12
Q

Name the doxorubicin analog and the daunorubicin analog

A

Epirubicin is the doxorubicin analog.

Idarubicin is the daunorubicin analog.

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13
Q

Teniposide and etoposide are semisynthetic derivatives of podophyllotoxin, a _______ agent derived from the _______ plant

A

Teniposide and etoposide are semisynthetic derivatives of podophyllotoxin, a __antimitotic_ agent derived from the _mandrake__ plant

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14
Q

DLT of etoposide at high doses: _____

What is another concern? ________

A

etoposide

  1. mucositis at high dose
  2. secondary leukemia
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15
Q

Do etoposide and teniposide act against tubulin?

A

In contrast to the parent podophyllotoxin, the epipodophyllotoxins are INACTIVE against tubulin and are PURE inhibitors of DNA topoisomerase II

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16
Q

Which is more potent, etoposide or teniposide?

A

teniposide is 10x more potent than etoposide

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17
Q

Is etoposide or teniposide a radiosensitizer?

Which requires dose reduction in proportion to creatinine?

A

ETOPOSIDE for both

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18
Q

Which topoisomerase II inhibitors also target free radicals?

A

Anthracyclines, Mitoxantrone

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19
Q

Which topo II inhibitors also target DNA intercalation?

A

Anthracyclines, Mitoxantrone, Ellipticines

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20
Q

Which topo II are considered PURE top II poisons?

A

epipodophyllotoxins (teniposide, etoposide)

**they are NON intercalators!

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21
Q

What organs metabolize the epipodophyllotoxins?

A

Etoposide -hepatic metabolism and 35-40% renal excretion (unchanged)

Teniposide -probable hepatic metabolism

22
Q

Name 2 interesting toxicities of mitoxantrone

A

Cardiac dysfunction, especially after doxorubicin

BLUE tint to nails, sclerae, urine

23
Q

Name 2 mechanisms of resistance of mitoxantrone

A
  1. Cross resistance w many other natural products (vincas, adria) - may be mediated by amplification of P170-glycoprotein (MDR1); others likely involved
  2. Altered cellular pH in tumor cells
24
Q

Name 4 modes of cytotoxicity of mitoxantrone

A

Mitoxantrone:

  1. Topo II inhibition
  2. Avid binding to nucleic acids, inhibiting DNA/RNA synthesis (mode of binding includes intercalation bt opposing DNA strands, w preference for GC pairs)
  3. One electron reduction (more than doxorubicin) but reduced potential for free radical generation
  4. Readily induces apoptosis, like doxorubicin
25
Q

Describe the structure of mitoxantrone (anthracenedione)

A

*lacks the sugar and tetracyclic ring

Is synthetic drug w 3 planar rings

26
Q

Mitoxantrone intercalates into DNA w a preference for which types of pairs?

It also functions as a _________

A
  1. GC pairs

2. Topo II inhibitor

27
Q

What are the mechanisms of toxicity for the doxorubicin-related drugs: (4)

A

Cytotoxic Mechanisms for Doxorubicin-Related Drugs

  1. Topo II inhibition - directly binds, preventing resealing of topo II-induced DNA cleavage
  2. DNA intercalation - intercalates bt base pairs perpendicular to long axis of double helix – > partial unwinding of helix
  3. Free radical formation - Adria may undergo metabolism of its quinone ring to a SEMIQUINONE RADICAL that reacts w oxygen to yield a SUPEROXIDE RADICAL – > oxidative dmg of cell membranes/DNA – > death (=cardiotoxicity)
  4. Affects cell membrane = bind cell membranes which can lead to death
28
Q

How does doxorubicin form a superoxide radical?

A

Doxorubicin can undergo metabolism of quinone ring, forming SEMIQUINONE RADICAL – > which reacts w oxygen – > superoxide radical.

Leads to oxidative damage of cell membranes and DNA – > death

29
Q

Anthracyclines:

What are the products of one-electron reduction?

Two-electron reduction?

A
  1. One-electron reduction to semiquinone free radical – > aerobic production of (1) superoxide anion, (2) hydrogen peroxide (3) hydroxyl radical
  2. Two-electron reduction: (1) aglycone species which can be conjugated for export in bile
30
Q
  1. What drug will increase doxorubicin cardiotoxicity?
  2. What will bind doxorubicin, causing aggregation, and increase doxorubicin clearance?
  3. What types of drugs will sensitize liver to anthracycline toxicity?
A
  1. Paclitaxel - dt delayed adria clearance
  2. Heparin
  3. Drugs that decrease hepatic reduced glutathione pools (acetominophen, CCNU)
31
Q

What happens to Adria if….

  1. Intracellular acidosis
  2. Acidification of extracellular fluid
A
  1. Intracellular acidosis – > enhanced drug accumulation bc un-ionized drug enters, gets protonated, then can’t diffuse out of cell
  2. Acidification of ECF – > drug shift out of cell

NOTE: Tumor masses 1cm + can have acidic ECF, so better to treat microscopic disease!

32
Q

Doxorubicin can directly inhibit which enzyme, which can produce alterations in vascular tone, w/in the heart (and tumors)

A

doxo can directly inhibit NO synthase

33
Q

One-electron reduction (adria) – >

  1. leads to formation of __A____ in presence of ___B____ , An electron is then donated to form superoxide anion, which yields ___C____.
  2. Both A and __D__ cleave H2O2 to produce the ___E____ — > this initiates apoptosis or necrosis secondary to….
  • Oxidative damage to cell memb – > can incite Fas/FasL induced apoptosis
  • Mitochondrial membrane injury – > leads to release of cytochrome c
  • DNA base oxidation
  • Altered calcium sequestration
  • Energy loss
A

One-electron reduction (adria) – >

  1. leads to formation of SEMIQUINONE RADICAL in presence of OXYGEN , An electron is then donated to form superoxide anion, which yields HYDROGEN PEROXIDE.
  2. Both SEMIQUINONE RADICAL and IRON cleave H2O2 to produce the _HYDROXYL RADICAL__ — > this initiates apoptosis or necrosis secondary to….
  • Oxidative damage to cell memb – > can incite Fas/FasL induced apoptosis
  • Mitochondrial membrane injury – > leads to release of cytochrome c
  • DNA base oxidation
  • Altered calcium sequestration
  • Energy loss
34
Q

These 3 molecules act as intracellular protectants to reduce superoxide, H2O2, and lipid hydorperoxides, to WATER w/o formation of hydroxyl/peroxyl radicals

(ADRIA)

A
  1. Superoxide dismutase
  2. Catalase
  3. Glutathione peroxidase
    Glutathione also reacts w radicals and helps glutathione peroxidase
35
Q

Cardiotoxicity of doxorubicin results from these 4 things:

A
  1. Low levels of cardiac CATALASE
  2. High levels of mitochondria/myoglobin that enhance drug activation
  3. Cardiac glutathione peroxidases are very sensitive to free radical attack – > free radicals destroy this enzyme while also stimulating cardiac H2O2 formation
  4. Doxorubicinol = alcohol metabolite of doxorubicin that is produced by TWO-electron reduction of C-13 side chain carbonyl group – > causes toxicity
36
Q

Doxorubicin can directly inhibit which enzyme, which can produce alterations in vascular tone, w/in the heart (and tumors)

A

doxo can directly inhibit NO synthase

37
Q

One-electron reduction (adria) – >

  1. leads to formation of __A____ in presence of ___B____ , An electron is then donated to form superoxide anion, which yields ___C____.
  2. Both A and __D__ cleave H2O2 to produce the ___E____ — > this initiates apoptosis or necrosis secondary to….
  • Oxidative damage to cell memb – > can incite Fas/FasL induced apoptosis
  • Mitochondrial membrane injury – > leads to release of cytochrome c
  • DNA base oxidation
  • Altered calcium sequestration
  • Energy loss
A

One-electron reduction (adria) – >

  1. leads to formation of SEMIQUINONE RADICAL in presence of OXYGEN , An electron is then donated to form superoxide anion, which yields HYDROGEN PEROXIDE.
  2. Both SEMIQUINONE RADICAL and IRON cleave H2O2 to produce the _HYDROXYL RADICAL__ — > this initiates apoptosis or necrosis secondary to….
  • Oxidative damage to cell memb – > can incite Fas/FasL induced apoptosis
  • Mitochondrial membrane injury – > leads to release of cytochrome c
  • DNA base oxidation
  • Altered calcium sequestration
  • Energy loss
38
Q

These 3 molecules act as intracellular protectants to reduce superoxide, H2O2, and lipid hydorperoxides, to WATER w/o formation of hydroxyl/peroxyl radicals

(ADRIA)

A
  1. Superoxide dismutase
  2. Catalase
  3. Glutathione peroxidase
    Glutathione also reacts w radicals and helps glutathione peroxidase
39
Q

Cardiotoxicity of doxorubicin results from these 4 things:

A
  1. Low levels of cardiac CATALASE
  2. High levels of mitochondria/myoglobin that enhance drug activation
  3. Cardiac glutathione peroxidases are very sensitive to free radical attack – > free radicals destroy this enzyme while also stimulating cardiac H2O2 formation
  4. Doxorubicinol = alcohol metabolite of doxorubicin that is produced by TWO-electron reduction of C-13 side chain carbonyl group – > causes toxicity
40
Q

Doxorubicin increases intracellular iron by:

  1. ____
  2. _____
A
  1. Releasing it from ferritin and microsomes

2. Increasing iron uptake into cells by transferrin-mediated process (enhancing intracellular iron availability)

41
Q

The hydroquinone structure of doxo/dauno binds what form of iron?

This leads to what 3 effects:

A

FERRIC IRON (doxo is v potent chelator of other metal ions too)

  1. Oxidative destruction of MEMBRANES
  2. Oxidation of SULFHYDRYL groups
  3. Binding to DNA (differently than intercalation mechanism)
42
Q

Dexrazoxane is an iron chelator that prevents doxorubicin-induced lipid peroxidation and cardiac toxicity.

It is a PRODRUG that undergoes _____ to become active. This is markedly enhanced after uptake into cardiac myocytes, with rapid conversion to active drug.

A

hydrolysis.

43
Q

Two electron reduction leads to formation of ____. These are far less toxic than parent drug. Two electron reduction mainly leads to ______ of anthracyclines.

A

Two electron reduction leads to formation of deoxyaglycone metabolites. These are far less toxic than parent drug. Two electron reduction mainly leads to __inactivation_ of anthracyclines.

44
Q

Cell membrane damage from anthracyclines leads to activation of which pathway? (a phospholipid in the cell membrane)

This leads to formation of _____ (a bioactive lipid) — > activates PKC and leads to ______ membrane permeability — > apoptosis

A

Cell membrane damage from anthracyclines leads to activation of which pathway? SPHINGOMYELIN PATHWAY

This leads to formation of CERAMIDE (a bioactive lipid) — > activates PKC and leads to MITOCHONDRIAL membrane permeability — > apoptosis

45
Q

Cell membrane damage from anthracyclines leads to alterations in which pathway? ______

In the heart, it decreases ____ phosphorylation (critical for cell survival); this is blocked by pretreatment with dexraz

A

Cell membrane damage from anthracyclines leads to alterations in which pathway? PI3K/AKT PATHWAY

In the heart, it decreases AKT/ERK phosphorylation (critical for cell survival); this is blocked by pretreatment with dexraz

46
Q

What is the major pharmacokinetic risk for adria-induced cardiotoxicity? How do you lower the risk?

A

PEAK DRUG CONCENTRATION is major risk.

Prolonged infusion will significantly reduce risk.

47
Q

Are the topo II drugs given IV or PO?

A

All given IV except Idarubicin, which is given PO

48
Q

Anthracyclines induce apoptosis by:

  1. stimulating interaction between ______ & ______ .
  2. This leads to _______ generation (secondary to cell membrane damage) – > increased mitochondrial membrane permeability and activation of proapoptotic _________ and ___________ protein phosphatases. (note: altered mitochondrial membr permeability leads to cytochrome c release which can cause apoptosis AND necrosis)
  3. Causing ______ damage (of cell membrane, mitochondrial membrane, DNA)
  4. Leading to elevated ______.
A

Anthracyclines induce apoptosis by:

  1. stimulating interaction between FAS & FASL .
  2. This leads to CERAMIDE generation (secondary to cell membrane damage) – > increased mitochondrial membrane permeability and activation of proapoptotic _CASPASES__ and __SERINE-THREONINE__ protein phosphatases. (note: altered mitochondrial membr permeability leads to cytochrome c release which can cause apoptosis AND necrosis)
  3. Causing __FREE RADICAL_ damage (of cell membrane, mitochondrial membrane, DNA)
  4. Leading to elevated __p53_.
49
Q

Doxorubicin is metabolized in liver to _____

A

doxorubicinol (which retains some activity) and other metabolites…all excreted in bile

50
Q

5 modes of resistance for anthracyclines

A
  1. P53 mutations (diminish apoptosis, increase doxorubicin resistance)
  2. Enhanced drug efflux (P170 glycoprotein-mediated anthracycline efflux) - also, vincas, actino D, epipodophyllotoxins
  3. Altered topo II activity
  4. Altered free radical biochemistry, sensitivity to apoptosis (via overexpression of bcl-2, p53 mutations…)
  5. Coadministration of heparin (increased doxorubicin clearance)
51
Q

P170-glycoprotein-mediated anthracycline efflux reversed with which 4 drugs?

A

verapamil
cyclosporine A
calmodulin inhibitors
tamoxifen

CHEMOTHERAPY (12 decks)

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