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PHRM 864: Therapeutics IV > Topo I , Topo II & Mircotubule > Flashcards

Topo I , Topo II & Mircotubule Flashcards

1
Q

REVEIW: what drug cause hemorrhagic cystitis and is coadministered with Mesna?

A
  • Cyclophosphamide [prodrug]
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2
Q

What is the mechanisms based around the topoisomerase?

A
  • DNA must be supercoiled so the Topos can come in to reduce the supercoiling
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3
Q

What are some ways that supercoiling is induced?

A
  • By transcription and translocation [found in both DNA and RNA]
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4
Q

What are some of the common cell cycle checkpoints that are affected by topos?

A
  • G2: Topo 2 inhibitors
  • S: Topo 1 inhibitors
  • ALL: Topo 2 intercalators
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5
Q

What is the mechanism of action for topo 1 ?

A
  • Will cut ONE strand of the DNA helping it get relaxed then annealing it back together
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6
Q

What is the mechanism of action for Topo 1 inhibitors?

A
  • Camptothecin covalently binds to Topo 1 & DNA blocking up the replication and transcription; forming a Ternary Drug-Enzyme-DNA complex
  • Inhibition block DNA religation
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7
Q

What phase of the cell cycle do topo 1 inhibitors affect?

A
  • S phase cells are the most sensitive
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8
Q

What are some of the general drug resistance mechanisms for Topo 1 inhibitors?

A
  • P-Glycoprotein over-expression
  • Muiltdrug Resistant Protein over-expression
  • Glutathione S-transferase over-expression
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9
Q

What is the way that Glutathione S-transferase overexpression affects the cells?

A
  • Its a complex that participates in tumorgenic progress = cell survival, cell proliferation and drug resistance
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10
Q

What are the two Camptothecins [Topo 1 inhibitors] that are use?

A
  • Topotecan & Irinotencan
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11
Q

What is important to know about Irinotecan?

A
  • Gets metabolized to SN38 by UGT1A1
  • 10% have a polymorphism of low UGT1A1 = increased Irinotecan toxicities
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12
Q

Topoisomerase 1 inhibitors primarily halt cells in what phase of the cell cycle?

A
  • The S Phase
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13
Q

How are does Topo 2 differ from Topo 1?

A
  • Topo 2 will break 2 strand of DNA to relax the supercoiling
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14
Q

What is the mechanism of action for Topo 2?

A
  • ONE strand of DNA is cut; where it then opens up the strand allowing the other strand to freely pass through; then it ligates it back together
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15
Q

What step do most of the topo II inhibitors stop in the Topo 2 cycle?

A
  • The religation step
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16
Q

What are the Anthracyclines for Topo 2 Inhibitors?

A
  • Doxorubicin, Dauorubicin, Epirubicin, Idarubicin
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17
Q

What are some of the toxicites that are related toward Topo 2 Inhibitors?

A
  • Intercalator [blobs DNA = Stop]
  • Causes free radical DNA damage
  • Topoisomerase downregulation
18
Q

How do free radicals cause DNA damage within Topo 2 Inhibitors?

A
  • Cardiotoxicities: the heart tissue has low levels of enzymes that neutralize free radicals
19
Q

What part of the cell cycle is affected by Topo 2 Inhibitors

A
  • Non-cell cycle dependent but have great G2/M activity
20
Q

What drug can you use to help mediate the toxicity cause by the Topo 2 Inhibitors?

A
  • Dexrazoxane
21
Q

What is the mechanism of action for Dexrazoxane?

A
  • Enters the cell binding to Iron whcih blocks iron-oxygen toxicities [Doxorubicin cardiotoxicities causes iron free radicals]
22
Q

What is important to know about Etoposide [Topo 2 Inhibitor]?

MOA? Cell Cycle specific?

A
  • Inhibits the religation of DNA but DOES NOT intercalate
  • G2 specific
23
Q

What are some of the general drug resistance mechanism for Topo 2 Inhibitors>

A
  • Same as Topo 1 Inhibitors
  • pGP overexpression., MRP overexpression, Gultathione S-transderace overexpression [Doxorubicin ONLY]
24
Q

If a patient has a history of heart disease and poor cardiac function, What Topo inhibitor should NOT be given?

A
  • Doxorubicin
25
Q

Where does Bleomycin have its toxic effects at?

A
  • Pulmonary Toxicity & Myelosuppression
26
Q

Why does Bleomycin have pulmonary toxicity?

A
  • Bleomycin Aminohydrase will inactivate Bleomycin
  • Bleomycin Aminohydrase has a high conc. everywhere but skin and LUNGS
27
Q

At what parts of the microtubule do a-tubulin and b-tubulin bind too?

A
  • Get polymerized to the + end and depolymerized to the - end
28
Q

What does dynamic instability mean toward the microtubule?

A
  • Growing then paused then shrinks [causes catastrophe]
29
Q

In what way are microtubules are used in cell division?

A
  • Mitotic Spindle: helps chromosome be lined up and pulls them apart making the daughter cells
30
Q

What cell cycle checkpoint does microtubule inhibitors affect?

A
  • Mitosis
31
Q

Before the mircotubules pull apart the daugther cells, what needs to happen first?

A
  • Spindle assembly checkpoint
  • Kinetochore tension: feeling if the otherside is pulling too
32
Q

What are the two major classes of the Microtubule inhibitors?

A
  • Vinca Alkaloids & Taxanes
33
Q

In what way do the Vinca Alkaloids work?

A
  • They prevent the assembly of mircotubules leading to mitotic arrest
34
Q

What will happen in result to the prevention of microtubules as part of the vinca alkaloids?

A
  • Peripheral neurpathy as the funcation of axons depends on mircotubules
35
Q

What are the Vinca Alkaloids that are used?

A
  • Vincristine
  • Vinclastine & Vinorelbine
36
Q

What is some important toxicites for Vincristine?

A
  • Severe Local Inflammation
  • Neurotoxicity
  • Mild Myelosuppression
37
Q

What does Eribulin do and what is important to know about it?

MOA? What it helps?

A
  • MOA: binds at microtubule ends and prevents elongation
  • Lower Neurotoxicity
38
Q

What is the mechanism of action for the Taxanes>

A
  • Binds to tubulin leading to inhibition of depolymerization
39
Q

What are the Taxanes that are used?

A
  • Paclitaxel & Ixabepilone
40
Q

What is important to know about paclitaxel toxicites?

A
  • Myelosuppression [dose limiting] & Neurotoxicites [less than vinca]
41
Q

What is mechanism of action for Ixabepilone and what is important to know about it?

A
  • Binds to tubulin and promotes tubulin polymerization and stabilization
  • NOT cross-resistant with taxanes
42
Q

Which microtubule inhibitor blocks the polymerization of tubulin?

A
  • Vincristine [Vinca Alkaloids]

PHRM 864: Therapeutics IV (28 decks)

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