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864 > Topo-microtubule inhibitors > Flashcards

Topo-microtubule inhibitors Flashcards

1
Q

which of the following is not a crosslinker?
a) cytarabine
b) cyclophosphamide
c) carboplatin
d) chlorambucil

A

cytarabine

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2
Q

to block hemorrhagic cystitis, Mesna is coadministered with which drug?
a) methotrexate
b) cyclophosphamide
c) cisplatin
d) mitomycin C

A

cyclophosphamide

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3
Q

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

A
  • supercoiling
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4
Q

cell cycle checkpoints and common chemotherapies

DNA damaging agents (non-cycle specific) (1)

DNA replication (1)

Sister chromatid separation (2)

A
  • doxorubicin
  • irinotecan
  • etoposide
  • bleomycin
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5
Q

topoisomerase I

  • cut ___ strand of double stranded DNA
  • relax the remaining strand
  • reanneals
A

1

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6
Q

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

A
  • physical
  • S
  • intercalation
  • glutathione
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7
Q

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
A
  • topotecan
  • irinotecan
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8
Q

Irinotecan (Camptosar)

SN-38 is metabolized by uridine diphosphate glucosyltransferase (UGT1A1)
- 10% of the pop has polymorphism predicting ___ expression of UGT1A1, leading to ___ toxicity

A

low
increased

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9
Q

topoisomerase I inhibitors primarily halt cells in which phase of the cell cycle?
a) G0/G1
b) S
c) G2
d) M

A

S

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10
Q

topoisomerase II

relieves torsional strain AND untangles DNA by catalyzing ___ stranded DNA breaks

A

double

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11
Q

many compounds inhibit Top2

only ones that produce ___ stranded DNA breaks are cancer therapies

A

double

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12
Q

topoisomerase II inhibitors - doxorubicin

  • natural products containing a planar ___ ring linked to an amino sugar
  • presence of ___ group at R4 confers different clinical properties
A

polycyclic
OH

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13
Q

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

A
  • cardiotoxicity, free radicals
  • non-cycle
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14
Q

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”

A
  • cardiotoxicity
  • extravasated
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15
Q

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

A
  • less, faster
  • fat
  • extended
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16
Q

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

A
  • free radical
  • cardiotoxicity
17
Q

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
A
  • double
  • intercalate
  • G2
18
Q

resistance to Topo II inhibitors

Drug resistance
- P-glycoprotein overexpression
- MRP overexpression
- ___ S-transferase overexpression -doxorubinin only
___ or mutation
- ___ DNA damage repair

A
  • glutathione
  • downregulation
  • increased
19
Q

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

A

doxorubicin

20
Q

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

A
  • antibiotic
  • intercalates
  • Fe, free radical
  • single, double
21
Q

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
A
  • G2, M
  • pulmonary
  • myelosuppression
  • skin, lungs
  • aminohydrolase
22
Q

microtubules during cell division

essential part of mitotic ___
responsible for moving chromosomal material into daughter cells during mitosis

A

spindle

23
Q

cell cycle checkpoints and common chemos

chromosome segregation (2)

A
  • vincristine
  • paclitaxel
24
Q

spindle assembly checkpoint

  • ___ need to be attached to the spindle microtubules
  • there needs to be kinetochore ___
A

kinetochores
tension

25
Q

vinca alkaloids prevent microtubule ___

taxanes prevent microtubule ___

A
  • assembly
  • disassembly
26
Q

T or F: microtubule destabilizers and stabilizers bind different sites on tubulin

A

T

27
Q

microtubule destabilizers (2)

A
  • vinca alkaloids (Vincristine and analogs)
  • erubulin
28
Q

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

A
  • large, transporter
  • P-glycoprotein
  • rapidly
  • resistant
29
Q

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

A
  • tubulin, assembly
  • arrest
  • nerve
  • neuropathy
30
Q

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

A

inflammation
- neurotoxicity

31
Q

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 ___

A
  • polymerization
  • ends
  • +
  • neurotoxicity
32
Q

microtubule stabilizers
(2)

A

taxanes (Paclitaxel)
epothilones (Ixabepilone)

33
Q

Taxanes

  • natural products obtained from yew tree
  • docetaxel = european yew needles
  • paclitaxel = pacific yew bark

drugs are produced semisynthetically

A
34
Q

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

A
  • decreases
  • depolymerization
  • arrest
  • tubulin
35
Q

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

A
  • albumin
  • myelosuppresion
  • reversible
  • efficacy
36
Q

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

A
  • polymerization, stabilization
  • taxol
37
Q

which of the following microtubule inhibitors block the polymerization of tubulin
a) paclitaxel
b) vincristine
c) ixabepilone

A

vincristine

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