Topo-microtubule inhibitors Flashcards
which of the following is not a crosslinker?
a) cytarabine
b) cyclophosphamide
c) carboplatin
d) chlorambucil
cytarabine
to block hemorrhagic cystitis, Mesna is coadministered with which drug?
a) methotrexate
b) cyclophosphamide
c) cisplatin
d) mitomycin C
cyclophosphamide
Topoisomerase mechanisms
- DNA must be tightly coiled and packed around nucleosomes to fit in the nucleus
- transcription and translation induce ___
- topoisomerases reduce localized supercoiling and provide access to double stranded DNA by enzymes responsivle for replication, transcription, and repair
wire example in class
- supercoiling
cell cycle checkpoints and common chemotherapies
DNA damaging agents (non-cycle specific) (1)
DNA replication (1)
Sister chromatid separation (2)
- doxorubicin
- irinotecan
- etoposide
- bleomycin
topoisomerase I
- cut ___ strand of double stranded DNA
- relax the remaining strand
- reanneals
1
topoisomerase I inhibitors
- form a ternary drug-enzyme-DNA complex
- inhibition provides a ___ barrier to replication and transcription
- cells in ___ phase are most sensitive to Topo I induced cleavage
- most topo inhibitors share a polycyclic aromatic motif for ___
drug resistance
- P-glycoprotein overexpression
- multidrug resistant protein overexpression
- ___ S transferase over expression
- topoisomerase downregulation or muttion to prevent inhibitor binding
- physical
- S
- intercalation
- glutathione
topoisomerase I inhibitors Camptothecins
- semisynthetic analogs of the natural product camptothecin, a plant alkaloid obtained from Camptotheca acuminata
- all are potent inhibitors of Topo I - closed lactone ring essential for activity
- camptothecin has potent activity, but low solubility and severe/unpredictable toxicity - not used clinically
- ___ (Hycamtin) and ___ (Camtosar) are water soluble and are both used clinically
- topotecan
- irinotecan
Irinotecan (Camptosar)
SN-38 is metabolized by uridine diphosphate glucosyltransferase (UGT1A1)
- 10% of the pop has polymorphism predicting ___ expression of UGT1A1, leading to ___ toxicity
low
increased
topoisomerase I inhibitors primarily halt cells in which phase of the cell cycle?
a) G0/G1
b) S
c) G2
d) M
S
topoisomerase II
relieves torsional strain AND untangles DNA by catalyzing ___ stranded DNA breaks
double
many compounds inhibit Top2
only ones that produce ___ stranded DNA breaks are cancer therapies
double
topoisomerase II inhibitors - doxorubicin
- natural products containing a planar ___ ring linked to an amino sugar
- presence of ___ group at R4 confers different clinical properties
polycyclic
OH
multiple mechanisms of toxicity - Topo II
multiple mechanisms of toxicity
- intercalator
- free radical cause DNA damage
- inhibition of Topo II presumed to be most important therapeutically
free radical damage causes __ since heart tissue has low levels of enzymes that neutralize ___ ___
although activity is greater G2/M they are ___ dependent
- cardiotoxicity, free radicals
- non-cycle
Doxorubicin (Adriamycin)
increased therapeutic index over the original anthracycline, daunorubicin
most widely used (best understood anthracycline)
Toxicity
- ___ - damage to cardiac muscle dependent on cumulative dose
- severe local tissue damage if ___ (leakage out of vessels)
red color adn bad side effects = “red devil”
- cardiotoxicity
- extravasated
Topo II inhibitors - anthracyclines
also in this class:
daunorubicin
- OG anthracycline natural product
- cardiotoxicity
epirubicin
- cardiotoxicity ___ severe than with doxorubicin - ___ elimination
idarubicin
- increased ___ solubility and cellular uptake
liposomal doxorubicin
- PEG-based formulation for __ release
- less, faster
- fat
- extended
drug mediate toxicity: Dexrazoxane (Zinecard)
Cyclic analog of the metal chelating agent EDTA
Enters cell and is converted to the ring-opening chelating agent
- binds to iron, blocks iron-oxygen induced toxicities
cardiotoxicity of doxorubicin believed to be cause by iron-catalyzed ___ ___ formation
Dexrazoxane protects against anthracycline-induced ___
no evidence of interference with antitumor effect
- free radical
- cardiotoxicity
topoisomerase II inhibitors - Etoposide
- semisynthetic derivatives of podophyllotoxin called epipodophyllotoxins - glucose analog incorporated
- inhibits religation of ___ stranded breaks induced by Topo II but does NOT ___
- ___ block-cell cycle specific
- double
- intercalate
- G2
resistance to Topo II inhibitors
Drug resistance
- P-glycoprotein overexpression
- MRP overexpression
- ___ S-transferase overexpression -doxorubinin only
___ or mutation
- ___ DNA damage repair
- glutathione
- downregulation
- increased
a patient has a history of heart disease and poor cardiac function. Which topoisomerase inhibitor should not be prescribed?
a) doxorubicin
b) etoposide
c) irinotecan
doxorubicin
Bleomycin (Blenoxane)
glycopeptide ___ - complex molecule: 2 essential parts
- bis(thiazole) with charged side chain - ___ into DNA (GpT selective)
- imidazole coordinated ___ - iron oxygen species generates DNA ___ ___
- radical intermediates leads to DNA ___ and ___ strand breaks - cleaves at the residue adjacent to guanine on 3’ side
- cytotoxic agent different from other classes previously discussed
- antibiotic
- intercalates
- Fe, free radical
- single, double
Bleomycin (Blenoxane)
- greatest effect on cells in the ___ and ___ phases
toxicity
- ___ toxicity is dose-limiting and cumulative - inflammation progresses to fibrosis
- ___ is minimal - good in combination with suppressive drugs
- inactivated by bleomycin aminohydrolase which is in high concentrations everywhere BUT the ___ and ___
- explains pulmonary and rash SE
- increased levels of ___ in resistant cancers
- G2, M
- pulmonary
- myelosuppression
- skin, lungs
- aminohydrolase
microtubules during cell division
essential part of mitotic ___
responsible for moving chromosomal material into daughter cells during mitosis
spindle
cell cycle checkpoints and common chemos
chromosome segregation (2)
- vincristine
- paclitaxel
spindle assembly checkpoint
- ___ need to be attached to the spindle microtubules
- there needs to be kinetochore ___
kinetochores
tension
vinca alkaloids prevent microtubule ___
taxanes prevent microtubule ___
- assembly
- disassembly
T or F: microtubule destabilizers and stabilizers bind different sites on tubulin
T
microtubule destabilizers (2)
- vinca alkaloids (Vincristine and analogs)
- erubulin
Vinca Alkaloids
- natural products isolated from the periwinkle plant (Catharanthus roseus)
- vinca alkaloids among the first natural products effective in cancer treatment
___ molecules - require a specific ___ to get into cells
excellent substrates for___ transporter
- drugs ___ pumped out of resistant cells
- cross ___ with other large molecule anti-tumor agents
- large, transporter
- P-glycoprotein
- rapidly
- resistant
Vinca Alkaloids
these compounds bind to ___ leading to inhibition of ___ (polymerization) and shortening
- no attachment of microtubules to mitotic spindle
- leads to mitotic ___
microtubules are critical to ___ cell axon function
- peripheral ___
Used in many combinations because of unique MOA
- tubulin, assembly
- arrest
- nerve
- neuropathy
Vinca Alkaloids - Vincristine
extraordinarliy potent compound - dose 1-2 mg/m2
toxicity - extravasation causes severe local ___
- ___ - dose dependent, dose-limiting, and cumulative
- peripheral neuropathy, constipation, occaionally paralytic ileus
- neurologic asesessment prior to each dose
- myelosuppression mild/rarely clinically significant
also in this class: vinblastine (Velban) and vinorelbine (Navelbine)
-neurotoxicity less severe than with vincristine
inflammation
- neurotoxicity
Eribulin
natural product halichondrin B analog
microtubule ___ inhibitor
- binds at microtubule ___ and prevents elongation
- different mechanism than Vinca alkaloids, which inhibits elongation and shortening at the ___ end
lower rate of ___
- polymerization
- ends
- +
- neurotoxicity
microtubule stabilizers
(2)
taxanes (Paclitaxel)
epothilones (Ixabepilone)
Taxanes
- natural products obtained from yew tree
- docetaxel = european yew needles
- paclitaxel = pacific yew bark
drugs are produced semisynthetically
taxanes
bind to tubulin with 2 consequences
- promotion of microtubule assesmbly into stable (non-functoinal) bundles ___ free tubulin and prevents microtubule formation at spindle
- stabilization of existing microtubules blocks ___ (shortening) and segregation of sister chromat
- leads to mitotic ___
Excellent substartes for P-glycoprotein transporter (except cabazitaxel)
- drug rapidly pumped out by resistant cells
- cross-resistant with other large molecule antitumor agents
resistance also attributed to ___ mutations
- decreases
- depolymerization
- arrest
- tubulin
taxanes
paclitaxel (taxol)
- linked to ___ to increase solubility and circulation time of drug
toxicitiy profile
- ___ - dose limiting
- neurotoxicity - neuropathy common, but ___
also in this class
- docetaxel (Taxotere)
- cabazitaxel (Jevtana) - poor binding to MDR and P-glycoprotein mumps. Shows ___ in multi-drug resistant tumors
- albumin
- myelosuppresion
- reversible
- efficacy
Epothilones (Ixabepilone)
- naturally occuring macrolides isolated from myxobacterium fermentation
- Ixabepilone (Ixempra) is a semisynthetic analog of epothilone B
- binds to tubulin and promotes tubulin ___ and microtubule ___
- similar to taxol, but more potent and easier to synthesize
- **not cross-resistant with ___. Poor P-glycoprotein substrate*
toxicity profile essentially identical to taxanes
- neurotoxicity - neuropathy common, but reversible
- polymerization, stabilization
- taxol
which of the following microtubule inhibitors block the polymerization of tubulin
a) paclitaxel
b) vincristine
c) ixabepilone
vincristine
