Topo I , Topo II & Mircotubule Flashcards
REVEIW: what drug cause hemorrhagic cystitis and is coadministered with Mesna?
- Cyclophosphamide [prodrug]
What is the mechanisms based around the topoisomerase?
- DNA must be supercoiled so the Topos can come in to reduce the supercoiling
What are some ways that supercoiling is induced?
- By transcription and translocation [found in both DNA and RNA]
What are some of the common cell cycle checkpoints that are affected by topos?
- G2: Topo 2 inhibitors
- S: Topo 1 inhibitors
- ALL: Topo 2 intercalators
What is the mechanism of action for topo 1 ?
- Will cut ONE strand of the DNA helping it get relaxed then annealing it back together
What is the mechanism of action for Topo 1 inhibitors?
- Camptothecin covalently binds to Topo 1 & DNA blocking up the replication and transcription; forming a Ternary Drug-Enzyme-DNA complex
- Inhibition block DNA religation
What phase of the cell cycle do topo 1 inhibitors affect?
- S phase cells are the most sensitive
What are some of the general drug resistance mechanisms for Topo 1 inhibitors?
- P-Glycoprotein over-expression
- Muiltdrug Resistant Protein over-expression
- Glutathione S-transferase over-expression
What is the way that Glutathione S-transferase overexpression affects the cells?
- Its a complex that participates in tumorgenic progress = cell survival, cell proliferation and drug resistance
What are the two Camptothecins [Topo 1 inhibitors] that are use?
- Topotecan & Irinotencan
What is important to know about Irinotecan?
- Gets metabolized to SN38 by UGT1A1
- 10% have a polymorphism of low UGT1A1 = increased Irinotecan toxicities
Topoisomerase 1 inhibitors primarily halt cells in what phase of the cell cycle?
- The S Phase
How are does Topo 2 differ from Topo 1?
- Topo 2 will break 2 strand of DNA to relax the supercoiling
What is the mechanism of action for Topo 2?
- 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
What step do most of the topo II inhibitors stop in the Topo 2 cycle?
- The religation step
What are the Anthracyclines for Topo 2 Inhibitors?
- Doxorubicin, Dauorubicin, Epirubicin, Idarubicin
What are some of the toxicites that are related toward Topo 2 Inhibitors?
- Intercalator [blobs DNA = Stop]
- Causes free radical DNA damage
- Topoisomerase downregulation
How do free radicals cause DNA damage within Topo 2 Inhibitors?
- Cardiotoxicities: the heart tissue has low levels of enzymes that neutralize free radicals
What part of the cell cycle is affected by Topo 2 Inhibitors
- Non-cell cycle dependent but have great G2/M activity
What drug can you use to help mediate the toxicity cause by the Topo 2 Inhibitors?
- Dexrazoxane
What is the mechanism of action for Dexrazoxane?
- Enters the cell binding to Iron whcih blocks iron-oxygen toxicities [Doxorubicin cardiotoxicities causes iron free radicals]
What is important to know about Etoposide [Topo 2 Inhibitor]?
MOA? Cell Cycle specific?
- Inhibits the religation of DNA but DOES NOT intercalate
- G2 specific
What are some of the general drug resistance mechanism for Topo 2 Inhibitors>
- Same as Topo 1 Inhibitors
- pGP overexpression., MRP overexpression, Gultathione S-transderace overexpression [Doxorubicin ONLY]
If a patient has a history of heart disease and poor cardiac function, What Topo inhibitor should NOT be given?
- Doxorubicin
Where does Bleomycin have its toxic effects at?
- Pulmonary Toxicity & Myelosuppression
Why does Bleomycin have pulmonary toxicity?
- Bleomycin Aminohydrase will inactivate Bleomycin
- Bleomycin Aminohydrase has a high conc. everywhere but skin and LUNGS
At what parts of the microtubule do a-tubulin and b-tubulin bind too?
- Get polymerized to the + end and depolymerized to the - end
What does dynamic instability mean toward the microtubule?
- Growing then paused then shrinks [causes catastrophe]
In what way are microtubules are used in cell division?
- Mitotic Spindle: helps chromosome be lined up and pulls them apart making the daughter cells
What cell cycle checkpoint does microtubule inhibitors affect?
- Mitosis
Before the mircotubules pull apart the daugther cells, what needs to happen first?
- Spindle assembly checkpoint
- Kinetochore tension: feeling if the otherside is pulling too
What are the two major classes of the Microtubule inhibitors?
- Vinca Alkaloids & Taxanes
In what way do the Vinca Alkaloids work?
- They prevent the assembly of mircotubules leading to mitotic arrest
What will happen in result to the prevention of microtubules as part of the vinca alkaloids?
- Peripheral neurpathy as the funcation of axons depends on mircotubules
What are the Vinca Alkaloids that are used?
- Vincristine
- Vinclastine & Vinorelbine
What is some important toxicites for Vincristine?
- Severe Local Inflammation
- Neurotoxicity
- Mild Myelosuppression
What does Eribulin do and what is important to know about it?
MOA? What it helps?
- MOA: binds at microtubule ends and prevents elongation
- Lower Neurotoxicity
What is the mechanism of action for the Taxanes>
- Binds to tubulin leading to inhibition of depolymerization
What are the Taxanes that are used?
- Paclitaxel & Ixabepilone
What is important to know about paclitaxel toxicites?
- Myelosuppression [dose limiting] & Neurotoxicites [less than vinca]
What is mechanism of action for Ixabepilone and what is important to know about it?
- Binds to tubulin and promotes tubulin polymerization and stabilization
- NOT cross-resistant with taxanes
Which microtubule inhibitor blocks the polymerization of tubulin?
- Vincristine [Vinca Alkaloids]
