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Topoisomerase II Flashcards

1
Q

Which of the following when used in combination with doxorubicin can predispose patients to acute myeloid leukemia?

a. Lomustine
b. Cyclophosphamide
c. Paclitaxel
d. Vincristine

A

B - cyclophosphamide

page 360, 374

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2
Q

Which of the following is the major contributor to cardiac toxicity in patients?

a. increased area under the curve for drug exposure
b. individual dosage
c. peak concentration
d. frequency

A

C - peak concentration

page 369 and 372

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3
Q

Which of the following is TRUE regarding doxorubicin?

a. decreased intracellular pH will cause a decrease in drug influx
b. doxorubicin enters the nucleus via passive diffusion
c. metabolites are passively effluxed from the cells
d. doxorubicin preferentially intercalates at the 5’-TCA

A

D - preferentially intercalates at 5’-TCA-3’

pages 357-359
Explanation: a) low pH is where anthracyclines are most attracted. Therefore, low intracellular pH would cause influx to the cell. Alternatively, low extracellular pH would cause an efflux of the chemotherapy. B) influx to the nucleus is an ATP-dependent process. C) again, this is an active process through MDR-1 proteins

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4
Q

Identify which of the following may be associated with mechanisms of doxorubicin resistance in humans.

i. Reduced DNA topoisomerase II activity
ii. Decreased expression of P170-glycoprotein
iii. Overexpression of bcl-2
iv. Decreased expression of MRP
v. Overexpression of BCRP

a. ii, iv
b. i, ii, iv
c. i, iii, v
d. i, ii, iii, iv, v
e. ii, iii, iv

A

c - (reduced topo II activity, overexpr of BCL-2, over expr of BCRP)

Explanation: p. 367-369

i. A reduction or absence of top II activity has been implicated as a cause of resistance involving the anthracyclines.
ii. A majority of the doxorubicin resistant cell lines developed in the laboratory exhibit increased expression of the P170-glycoprotein, an ATP-dependent exporter of the ABC cassette family
iii. The overexpression of bcl-2 can significantly diminish the toxicity of doxorubicin, as can mutations of p53
iv. Resistant cells can display other ATP-dependent efflux proteins. Members of the MRP subgroup have been associate with doxorubicin resistance.
v. Breast cancer resistance protein (BCRP) is a transmembrane protein and if it has a specific mutation it can transport doxorubicin out of the cell

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5
Q

Identify the most appropriate tissue distribution for mitoxantrone after administration.

a. Liver> bone marrow> heart > lung > kidney
b. Kidney> liver> bone marrow> brain> heart
c. Brain> liver> heart> kidney> bone marrow
d. Heart> kidney> bone marrow> liver> lung

A

a. Liver> bone marrow> heart > lung > kidney

Explanation: p. 376
Like doxorubicin the drug distributes into tissues (liver > BM> heart> lung > kidney) and remains in these tissues for weeks after therapy. Although specific guidelines are not available for dose adjustments in patients with hepatic dysfunction, the terminal half-life may be prolonged to greater than 60 hours in patients with liver impairment.

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6
Q

Identify what is true in regards to doxorubicin and daunorubicin chemotherapy.

a. Extravasation of these drugs does not result in complications
b. Radiation sensitization of normal tissues is common and may occur many years after radiation exposure
c. Patients that have evidence of liver dysfunction have normal clearance of the drug and don’t need dose adjustments
d. The drugs don’t circulate predominately as parent compounds, they are converted to metabolites immediately

A

b - Radiation sensitization of normal tissues is common and may occur many years after radiation exposure

Explanation: p. 357, Table 18.1

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7
Q

What drug can enhance cardiotoxicity when given in combination with doxorubicin?

a. Cyclophosphamide
b. Paclitaxel
c. Dexrazoxane
d. Vincristine
e. Glutathione

A

b - Paclitaxel

pg 356 and 369-70.
If paclitaxel is given prior to doxorubicin administration, it can delay the clearance of doxorubicin. Additionally, the diluent present in paclitaxel is a substrate for P-glycoprotein. Lastly, taxanes may increase the activity of carbonyl reductase 3 and increase production of the alcohol metabolites of doxorubicin (which have greater cardiotoxicity).

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8
Q

What is the active metabolite of dexrazoxane?

a. Quinone methide
b. Dihydroquinone
c. Pixantrone
d. ICFR-198
e. Amsacrine

A

d - ICFR-198

pg 363-4.
Explanation: Dexrazoxane is a prodrug that must undergo hydrolysis to become an effective iron chelator. Conveniently, hydrolysis is markedly enhanced after uptake into cardiac myocytes.

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9
Q

Which of the following are mechanisms of anthracycline-induced cardiotoxicity?

i. Increased calcium sequestration by the sarcoplasmic reticulum
ii. Inhibition of NADH dehydrogenase
iii. Release of iron from ferritin and increased iron uptake
iv. Activation of cardiac mRNAs for troponin
v. Lipid membrane peroxidation

a. i, ii, iii
b. ii, iii, v
c. i, ii, iv
d. iii, v
e. i, iii, iv

A

b - NADH inhib, release of iron, lipid membrane peroxidation

Table 18.3 on pg 373.
Explanation: Doxorubicin inhibits calcium sequestration by the SR and inhibits cardiac mRNAs for troponin. The others are all correct.

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10
Q

Which of the following DNA sequences is most likely to be preferentially bound by daunorubicin?

a. 5’-GCC-3’
b. 5’-GAC-3’
c. 5’-TTC-3’
d. 5’-TGC-3’

A

d. TGC

Rationale: Page 358: preference for GdC-rich regions flanked by A:T base pairs; in other words 5’-(A or T)CG or 5’-(A or T)CG

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11
Q

Which of the following is true regarding dexrazoxane when used in conjunction with doxorubicin?

a. It can reduce risk of myocardial damage but also causes a substantial decrease in the effectiveness of doxorubicin.
b. It has therapeutic applications in decreasing the risk of acute arrhythmias
c. In a patient with a cumulative doxorubicin dose of 150 mg/m2, dexrazoxane should be considered prior to additional doxorubicin treatment.
d. In one human study, dexrazoxane was less effective than a prolonged 48-hour infusion in decreasing myocardial damage.

A

c. In a patient with a cumulative doxorubicin dose of 150 mg/m2, dexrazoxane should be considered prior to additional doxorubicin treatment.

Rationale: although the accepted cumulative dose is 180 mg/m2, in many of the studies looking at cardiotoxicity, the median dose for symptomatic patients was 150 mg/m2, and the other options are clearly false. (a) the studies so far show equivalent anti-tumor activity, response rate, and duration of disease control. (b) it is not expected to decrease risk of acute arrhythmias. (d) it was MORE effective than the infusion.

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12
Q

What is the primary mechanism of action of dexrazoxane’s cardioprotectivity?

a. It is an iron chelator, which withdraws iron from participation in further free radical generation.
b. It enhances excretion of doxorubicin by P-glycoprotein, leading to decreased cellular drug exposure.
c. It facilitates repair of free radical damage by the cardiac myocytes by increasing cellular glutathione retention.
d. It enhances transformation of the active doxorubicinol to the inactive metabolite doxorubicinol aglycone.

A

a. It is an iron chelator, which withdraws iron from participation in further free radical generation.

Rationale: page 363. The others are …just wrong

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13
Q

Which of the following potentiates the formation of doxorubicin-DNA adducts?

a. Elevated intracellular pH.
b. CpG methylation.
c. Activation of the ubiquitin-proteasome system.
d. Chelation of iron prior to doxorubicin administration.

A

b. CpG methylation.

Rationale: page 359.

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14
Q

Which of the following is true regarding Doxorubicin?

a. Doxorubicin is capable of inducing apoptosis via the intrinsic pathway, but not the extrinsic pathway.
b. Rats fed a diet enriched with iron were shown to experienced enhanced cardiac apoptosis and mitochondrial injury after treatment with doxorubicin.
c. Dexrazoxane blocks doxorubicin induced cardiotoxicity by acting as a free radical scavenger.
d. The liver is at increased risk of damage with doxorubicin administration compared to other organs due to poor catalase levels.

A

b. Rats fed a diet enriched with iron were shown to experienced enhanced cardiac apoptosis and mitochondrial injury after treatment with doxorubicin.

Rationale: Doxorubicin can induce apoptosis via multiple mechanisms (both intrinsic and extrinsic pathways are involved). Diet in rats was discussed on 364. Dexrazoxane protects the heart via chelating iron prior to doxorubicin administration, which reduces the amount of iron available for free radical reactions → prevents doxorubicin induced lipid peroxidation. The liver is rich in glutathione (reacts with many radicals) and has relatively high catalase activity which reduces its risk for damage.

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15
Q

What portion of doxorubicin’s chemical structure is responsible for DNA intercalation?

a. Planar ring
b. The side chain
c. D ring
d. Daunosamine ring

A

a. Planar ring

Rationale: page 359

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16
Q

Which of the following are actions of Etoposide?

i. Toposisomerase I inhibition
ii. Topoisomerase II alpha inhibition
iii. Topoisomerase II beta inhibition
iv. DNA intercalation
v. Generation of reactive oxygen species

A. i, ii
B. i, ii, iii
C. ii, iii
D. ii, iii, iv, v

A

C (Topo II alpha inhib, Topo II beta inhib)

Explanation: Etoposide is an epipodophyllotoxin. It binds and blocks activity of Top2alpha and beta. Specifically Top2alpha is responsible for anticancer activity of etoposide. Top2beta could be responsible for secondary malignancies. Doxorubicin and daunorubicin are also Top2 inhibitors but they also perform DNA intercalation and generate reactive oxygen species, which contribute to cytotoxic effects. Top1 inhibitors include the camptothecins (topotecan and irinotecan).

17
Q

Which combination of genes is found in the same chromosome region in humans?

A. EGFR and p53
B. Myc and Topoisomerase 1
C. p53 and Topoisomerase 2aplpha
D. HER2 and Topoisomerase 2alpha

A

D. HER2 and Topoisomerase 2alpha

TOP2alpha and HER2 are both found on chromosome 17q in humans. Co-amplification of these genes may occur leading to the interest in using TOP2 inhibitors again HER2 amplified solid tumors. The more expression of Top2 the more efficacious top2 inhibitors.

18
Q

Which of the following is true regarding Topoisomerase II alpha (Top2alpha)?

A. Top2alpha functions as a monomer
B. Top2alpha primarily induces single strand breaks in DNA
C. Top2alpha concentrations are highest during G1 and S phases of the cell cycle
D. Top2alpha functions as an ATPase

A

D. Top2alpha functions as an ATPase

  • Top2alpha functions as a homodimer
  • Induces double strand breaks (Top1 and Top3 catalyze single strand breaks)
  • Concentrations are highest G2/M, especially in rapidly proliferating cells
  • Top2alpha binds ATP prior to conformational change (open → close) and ATP is hydrolyzed by top2alpha prior to final conformational change (close → open)
19
Q

Which of the following relationships is TRUE regarding the resistance conferred by transmembrane transporters?

a. mitoxantrone > doxorubicin
b. etoposide > doxorubicin
c. mitoxantrone > etoposide
d. etoposide > mitoxantrone
A

D. etoposide > mitoxantrone

page 397 Table 19.3

20
Q

What are the preferential cleavage sites of etoposide?

a. CG sites
b. AT sites
c. TA sites	
d. CpG methylation sites
A

A. CG sites

page 398

21
Q

Which of the following down-regulates topoisomerase IIα?

a. caspase 9
b. Fas
c. p53
d. ERRB1
A

C. p53

page 398

22
Q

Which of the following is true in regards to the clinical pharmacology of etoposide (VP-16).

a. The peak plasma concentration and the area under the curve are proportional to the administered dose (up to 800 mg/m2)
b. Biliary excretion is the major route of elimination
c. The main metabolite that is eliminated in the urine is a quinine
d. Severe myelosuppression occurs when the etoposide plasma levels are continuously higher than 1 ug/mL

A

a. The peak plasma concentration and the area under the curve are proportional to the administered dose (up to 800 mg/m2)

Explanation: p. 401-402

b. Biliary excretion is a minor route of elimination; etoposide is eliminated by both renal and nonrenal mechanisms
c. The main metabolite etoposide glucuronide is eliminated in the urine; O-Demethylation cytochrome P450 3A metabolizes etoposide to a catechol metabolite, which is further oxidized to a quinine
d. Etoposide is largely used in high-dose chemotherapy protocols with stem cell rescue because of its moderate non-hematologic toxicity; Severe myelosuppression occurs when the etoposide plasma levels are continuously higher than 3 ug/mL

23
Q

As part of the Topoisomerase II catalytic cycle, what two exogenous energy sources are required for the catalytic activity to take place during steps 1 to 2 and steps 3 to 4?

a. Calcium and ADP
b. Magnesium and ATP
c. Sodium and RNA
d. Phosphorus and glucose

A

b . Magnesium and ATP
Explanation: p. 394-395 and Figure 19-2
In contrast to Top1, Top2 functions as a homodimeric molecule. Its catalytic activity requires the presences of magnesium as well as ATP as an exogenous energy source. Hence, Top2 acts as a DNA-dependent ATP-ase.

24
Q

Which of the following drugs interact with DNA topoisomerase II?

i. mitoxantrone
ii. actinomycin-D
iii. etoposide
iv. topotecan
v. gemcitabine

a. iii
b. i, iii
c. ii, iv
d. i, v
e. i, iii, iv

A

b. Mito, etoposide

Actinomycin-D and gem don’t have anything to do with topos, and topotecan is topo I not topo II.

25
Q

What is true about podophyllotoxin, the parent compound for etoposide?

a. It is a more potent topoisomerase inhibitor than etoposide; its use is limited by its greater toxicity
b. It has no inherent anti-neoplastic activity, and must be converted to etoposide.
c. It is an anti-tubulin agent that binds at a site different from that occupied by the vinca drugs
d. It appears to have improved efficacy in slow-growing tumors.
A

c. It is an anti-tubulin agent that binds at a site different from that occupied by the vinca drugs

Page 392.

26
Q

Which of the following would be expected to increase sensitivity to etoposide?

a. intra-tumor hypoxia
b. poor tumor vascularity
c. increased expression of p53
d. rapid cellular division
A

d. rapid cellular division
(a) and (b) are conditions that lead to decreased expression of topo2 (top2alpha), which would decrease the target and DECREASE sensitivity/increase resistance. (c) p53 also down-regulates top2

Chemotherapy (13 decks)

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