Topoisomerase and Spindle Inhbitors Flashcards
What are the Vinca Alkaloids?
- MOA
- Resistance
Vincrinstine and Vinblastine
MOA:
- Blocks Tubulin (alpha-beta) polymerization
- METAPHASE arrest => APOPTOSIS
Resitance:
- P-pg (aka MRP (multidrug reistance pump), BCRP)
- Mutaions in BETA-tubulin
How are the Vinca Alkaloids administered?
- Elimination?
- Toxicity?
- NAME THEM
Administration:
- IV
Elimination:
- Hepatic
Toxicity:
- NEUROTOXICITY - coma if intrathecal
- Leukopenia with vinblastin, NOT vincristine
- Extravasational necrosis (Hair loss, cellulitis too with ex.v.)
names:
VINCRISTINE and VINBLASTINE
Besides the vinca alkaloids, what other drugs cause microtubule defects?
- Name drugs in each of these classes.
- method of administration.
Taxanes:
- Paclitaxel [taxol]
- Docataxel [taxotere]
Vinca Alkaloids:
- Vincristine
- Vinblastine
**IV administration for both classes
Taxanes:
- NAME THEM.
- MOA.
- Administration.
- Resistance.
Paclitaxel [taxol] and Docataxel [taxotere]
MOA:
- Binds to BETA-tubulin and prevents (antagonizes) microtubule DISassembly
Administration:
- IV - less soluble so may be given with Cremaphor (with Paclitaxel) or Polysorbate (with Docetaxel)
- (this can change pharacokinetics)
Resistance:
- Mutation of Beta-Tubulin
- Efflux (p-gp)
What toxicities are common to both types of microtubule inhibiting drugs?
- Name the class of drug and drugs.
- Elimination?
- DIFFERENCES?
Both:
- Peripheral Neurpathy
- Blood Dyscrasias
Vinca Alkaloids (vincristine, vinblastine)
- Vinblastine - Leukopenia
- Vincristine - (no unique qualities?)
Taxols (Paclitaxel, Docataxel)
- Paclitaxel - Hypersensitivity Infusion Reactions
- Docataxel - more severe, short lived, Neutropenia
***All microtubule inhibitors are eliminated hepatically
Are the Microtubule inhibitors cell cycle specific?
- why or why not?
- NAME THEM.
Yes, ALL Target M phase of the cell cycle
Vinca Alkaloids:
- Vincristine and Vinblastin
Taxols:
- Paclitaxel and Docetaxel
Where on microtubules do the vinca alkaloids and Taxols bind?
- Differences in effect.
- NAME THEM.
Vinca Alkaloids - Vincristine, Vinblastine:
- bind at the + end
- prevents addition of alpha-tubulin
EFFECT: - no microtubule formation
Taxanes - Paclitaxel, Docetaxel:
- Binds at a site to stabilize tubulin subunits
EFFECT: - nucleus FULL of microtubules
Peripheral Neuropathy is produced most reliably by what 5 cancer drugs belonging to what 3 classes?
- Mechanism of this side effect.
Vinca Alkaloids and Taxols:
Distal Neuron Affected- Microtubules needed to transport nutrients along axon
(drugs: Vincristine, Vinblastin, Paclitaxel, Docetaxel)
Platinum Alkylating agent:
CISPLATIN - messes up the nucleus
Which of all the microtubule drugs is most associated with glove and stocking syndrome?
Paclitaxel
What Drugs work by inhibiting Topoisomerase I?
Camptothecins
- Irinotecan and its metabolite SN-38
Camptothecins:
- NAME THEM
- MOA
- Administration
Irinotecan [camptosar] Topotecan [hycamtin]
MOA:
- Binds to Topoisomerase I causing Single and Double strand breaks
- ONLY DOUBLE strand breaks are truly effective BUT this only happend when DNA fork encounters the complex of Camptothecin/Topoisomerase I complex
Administration:
- IV (irotecan has a greater 1/2 life)
Are the Camptothecins cell cycle specific?
- if so what phase are they specific for?
Yes, they they are only affective during S phase because they require the replication fork encountering the Topo-1/drug complex
S-phase specific
Names:
- Irotecan
- Topotecan
Which of the camptothecins has a unique toxicity and why is this?
- what patients is this particularly problematic in?
Irinotecan metabolized by phase II glucuronidation
Patients:
- Gilbert Syndrome patients that have SNPs in the UDP-glucuronosyltransferase (UGT) 1 A1 gene
Toxicities of the camptothecins?
- differences among drugs in the class.
- dose limitations.
BOTH:
- Elevated Hepatic Enzymes
- myelosuppression
Topotecan:
- Nuetropenia
Irinotecan:
- DOSE LIMITING DIARRHEA
Etoposides
- Name Them.
- MOA
- Resistance
- Administration
Etoposide and VP-16 [toposar]
MOA:
- Forms complex with Topo-II causing 2x DNA breaks
Resistance:
- Efflux, downregulation of Topo II
Administration:
- Oral
- Renally Excreted