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7361 Hem/Onc Block 1 > DNA Damaging Agents/Cytotoxics > Flashcards

DNA Damaging Agents/Cytotoxics Flashcards

1
Q

__ is a process under the influence of various growth factors by which cells increase in number as a result of cell growth and division

A

cell proliferation

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2
Q

__ is the phenomena by which normal cells cease to divide and are refractory to growth factor stimulation

A

senescence

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3
Q

__ is a programmed destruction of cells that keeps cell numbers in check by eliminating senescent cells or those without useful function

A

apoptosis

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4
Q

__ are regulators of cellular communication with the outside environment derived from mutation of normal proto-oncogenes which induce cancer when stimulated or amplified

A

oncogenes

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5
Q

__ keep oncogenes in check by halting uncontrolled cell growth and their loss of function results in cell immortality

A

tumor suppressor genes

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6
Q

In general, cancer cells undergoing rapid division are most vulnerable to the __ action of anticancer agents

A

cytotoxic

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7
Q

__ and __ atoms of guanine are particularly susceptible to the formation of a covalent bond with alkylating agents

A

N7, O6

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8
Q

All DNA alkylating agents have toxic effects on both male and female reproductive systems

a. true
b. false

A

a. true

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9
Q

Nitrogen mustards have two of what groups attached?

A

chloroethyl

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10
Q

Nitrogen mustards lead to __ cross links on the DNA molecule.

a. intrastrand
b. interstrand

A

b. interstrand

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11
Q

Mutations in __ can lead to tumor cells that are resistant to alkylating agents

A

p53

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12
Q

Monoalkylation is associated with __

a. nitrogen mustards
b. platinum agents
c. DNA methylating agents

A

c. DNA methylating agents

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13
Q

Mustards are alkylated by __ nitrogen of guaning

A

N7

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14
Q

The __ ion is involved in the N7 alkylation of nitrogen mustards

A

aziridinium

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15
Q

Nitrogen mustards with __ groups have a sufficiently controlled reactivity to attenuate the severity of side effects

A

electron withdrawing

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16
Q

Rapid formation of __ with nitrogen mustards leads to indiscriminant alkylation with DNA, electron-rich SH, OH, and NH groups of amino acids of enzymes, and membrane bound receptors

A

aziridinium ion

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17
Q

Which nitrogen mustard is orally available, but absorption can be erratic?

A

melphalan

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18
Q

Which nitrogen mustard has adequate and reliable oral absorption, though food decreases absorption?

A

chlorambucil

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19
Q

Is melphalan (nitrogen mustard) available for IV administration?

A

yes

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20
Q

Which nitrogen mustard is given as a 30 minute IV infusion?

A

bendamustine

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21
Q

Which nitrogen mustard causes less repairable DNA damage?

A

bendamustine

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22
Q

What reaction has been noted to bendamustine therapy?

A

hypersensitivity/anaphylaxis

pretreat with antihistamines and/or corticosteroids

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23
Q

Which nitrogen mustard is the most widely used?

A

cyclophosphamide

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24
Q

Which nitrogen mustard has less effects on peripheral blood platelet counts and less mucosal damage than other DNA alkylating agents?

A

cyclophosphamide

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25
Q

What is required for cyclophosphamide to have alkylation activity?

A

metabolic activation

this hepatic metabolism contributes to kidney and bladder toxicity

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26
Q

Which cyclophosphamide metabolite is highly nephrotoxic and neurotoxic?

A

chloroacetaldehyde

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27
Q

Which cyclophosphamide metabolite is highly reactive and causes damage to kidneys and bladder?

A

acrolein

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28
Q

Which is the most neurotoxic of the DNA alkylating agents?

A

ifosfamide

due to chloroacetaldehyde

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29
Q

What can help reduce ifosfamide bladder toxicity?

A

adequate hydration

increased chloroacetaldehyde leads to increased bladder toxicity and nephrotoxicity

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30
Q

Which nitrogen mustard is used for Tx of relapsed testicular cancer and some sarcomas?

A

ifosfamide

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31
Q

__ is employed as adjuvant or prophylactic therapy wit ifosfamide and high dose cyclophosphamide

A

Mesna

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32
Q

Delivery of the ___ conjugate to the bladder for excretion causes toxicity due to a variety of mechanisms

A

acrolein-GSH

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33
Q

Busulfan can cause severe and prolonged ___ with recovery taking up to two years

A

pancytopenia

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34
Q

__ toxicity is a risk at high doses of busulfan

A

pulmonary

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35
Q

Busulfan:

One or both of the __ esters can be displaced by the nucleophilic N7 of guanine, leading to monoalkylated and cross-linked DNA

A

methylsulfonate

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36
Q

Nitrosoureas:

___ carbocation can alkylate DNA (O6 guanine) to form an intermediate poised for the formation of cross-linked DNA

A

2-chloroethyl

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37
Q

What DNA repair enzyme can reverse the alkylation of nitrosoureas?

A

MGMT

methyl guanine methyltransferase

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38
Q

__ and __ are highly lipophilic nitrosoureas that cross the blood-brain barrier → used in the treatment of a variety of brain tumors, but can cause CNS toxicity at higher doses

A

carmustine, lomustine

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39
Q

Which is more stable lomustine or carmustine?

A

lomustine

can be dosed orally

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40
Q

Which DNA methylating agent requires metabolic demethylation by CYP1A1 or CYP1A2 to generate MTIC, the precursor to diazomethane (the methylating agent)?

A

dacarbazine

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41
Q

Which DNA methylating agent generates MTIC via simple non-enzymatic hydrolysis?

A

temozolomide

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42
Q

__ expression is associated with resistance to DNA methylating agents (dacarbazine, temozolomide

A

MGMT

43
Q

Women clear __ less effectively than men and have a higher incidence of neutropenia and thrombocytopenia

A

temozolomide

44
Q

__ is a hydrazine-containing molecule that is metabolically converted to diazomethane, which reacts with the O6 of guanine nucleobases

A

procarbazine

45
Q

Which hydrazine DNA methylating agent is metabolically converted to diazomethane?

A

procarbazine

reacts wit the O6 of guanine nucleobases

46
Q

__ expression is associated with resistance to procarbazine.

A

MGMT

47
Q

Like the nitrogen mustards, ___ agents are bifunctional and can accept electrons from two DNA nucleophiles

A

platinum

48
Q

What kind of cross links are most common with platinum agents?

a. interstrand
b. intrastrand

A

b. intrastrand

49
Q

__ agents contain an electron-deficient metal atom that acts as a magnet for electron-rich DNA nucleophiles

A

platinum

50
Q

Platinum agents enter the cell via what transporter?

A

active copper transporter (CTR1)

51
Q

The __ poor intracellular environment facilitates the displacement of __ ligands on cisplatin by water

A

chloride, chloride

52
Q

What form of platinum agents is the active cytotoxic?

A

hydrated

53
Q

Platinum agents must not come into contact with infusion equipment containing __

A

aluminum

54
Q

Which platinum agent is photosensitive?

A

cisplatin

packaged in amber bottles

55
Q

Cisplatin causes significant damage to the __

A

renal tubules

56
Q

What is used to mitigate the renal toxicity of cisplatin?

A

aggressive hydration with chloride containing solutions

establishes chloride diuresis

57
Q

Which platinum agent can cause irreversible ototoxicity?

A

cisplatin

manifested by tinnitus and high frequency hearing loss

58
Q

What is used to reduce the renal toxicity of cisplatin?

A

amifostine

use for reducing ototoxicity is controversial

59
Q

Which platinum agent forms the cytotoxic hydrated intermediate at a slower rate, cisplatin or carboplatin?

A

carboplatin

60
Q

What protein can confer resistance to cisplatin and carboplatin?

A

MMR

61
Q

Which platinum agent is most likely not affected by MMR proteins?

A

oxaliplatin

62
Q

Which platinum agent has a different DNA adduct formed?

A

oxaliplatin

63
Q

Why does oxaliplatin often retain activity in pts who have stopped responding to other platinum agents?

A

less dependent on CTR1

64
Q

Two drug classes that have N7 of guanine as alkylation site?

A

nitrogen mustards

methylsulfonate ester

65
Q

Two drug classes that have O6 of guanine as alkylation site?

A

nitrosoureas

DNA methylating agents

66
Q

3 drug classes that form INTERstrand DNA cross links?

A

nitrogen mustards
methylsulfonate ester
nitrosoureas

67
Q

MGMT can cause resistance to which two drug classes?

A

nitrosoureas

DNA methylating agents

68
Q

Bleomycin hydrate is found in all tissues except which two?

A

lungs

skin

69
Q

What is the cytotoxic agent of bleomycin?

A

bleomycin ferric peroxide

Fe2 complex reacts with molecular oxygen to form bleomycin ferric peroxide complex

70
Q

The bleomycin ferric peroxide abstracts a hydrogen atom from __ to form a DNA radical

A

deoxyribose

The DNA free radical is unstable and its formation initiates a cascade of events that leads to DNA strand breaks

71
Q

Bleomycin causes accumulation of cells with chromosomal aberrations in which phase of the cell cycle?

A

G2

72
Q

5-10% of pts will experience potentially fatal ___ with bleomycin

A

pulmonary fibrosis

can occur as late as several months after therapy has ceased

73
Q

The risk for pulmonary toxicity is enhanced in patients of what age?

A

> 40

related to total dose

74
Q

Topoisomerase inhibitors are most toxic to cells in which phase of DNA replication?

A

S phase

75
Q

How do topoisomerase inhibitors work?

A

bind/stabilize DNA topoisomerase complex and block resealing of strand breaks

76
Q

Which camptothecin topoisomerase I inhibitor has modification at C10?

A

irinotecan

incorporate basic amines that permit salt formation and enhance solubility

77
Q

Which camptothecin topoisomerase I inhibitor has modification at C9?

A

topotecan

incorporate basic amines that permit salt formation and enhance solubility

78
Q

What enzyme converts irinotecan to its active metabolite, SN-38?

A

hepatic carboxyl esterases

79
Q

Conjugation of irinotecan SN-38 by __ at C10 yields an inactive metabolite

A

UGT1A1

80
Q

Polymorphisms in UGT1A1 (irinotecan) is more prevalent in pts of what heritage?

A

Asian

81
Q

What therapy should be initiated immediately with irinotecan diarrhea?

A

vigorous loperamide

82
Q

Irinotecan’s anti cholinesterase activity can be treated with what?

A

atropine

83
Q

Epipodophyllotoxin topoisomerase II inhibitors:

Etoposide and teniposide require what for IV dosing?

A

solubility enhancers

ex. polysorbate, polyoxyethylated castor oil

can cause hypersensitivity rxns

84
Q

What CYP catalyzes O-demethylation of etoposide?

A

3A4

CYP3A4 inducers/inhibitors have significant impacts on metabolism

topoisomerase II inhibitor

85
Q

What metabolite of etoposide may be linked to therapy induced leukemia in children?

A

orthoquinone

86
Q

What etoposide metabolite further oxidizes to a reactive orthoquinone metabolite?

A

catechol

87
Q

Serious side effects have been noted in children with what diseases treated with etoposide?

A

acute lymphoblastic leukemia (ALL)

88
Q

2-12% of pts treated for childhood ALL will develop __ within two years of etoposide therapy

A

acute myeloid leukemia (AML)

89
Q

Therapy induced AML with etoposide is thought to be related to what?

A

drug induced chromosomal translocation

90
Q

Anthracycline topoisomerase II inhibitors generate free radicals that can cause what type of irreversible toxicity?

A

cardiotoxicity

doxorubicin, epirubicin, valrubicin, daunorubicin, idarubicin

91
Q

Aldoketoreductase catalyzes the reduction of which carbon in doxorubicin to produce secondary alcohol metabolite linked to cardio toxicity?

A

C13

92
Q

Anthracyclines such as doxorubicin generate what toxic substance?

A

hydrogen peroxide

form semiquinone radical intermediates that react with oxygen to form superoxide anion radicals which form H2O2

93
Q

Anthracyclines (ex. doxorubicin) are potent binders of what?

A

iron

cardiac tissue has low levels of defensive enzymes to combat oxygen radicals

94
Q

What iron chelating drug is used for cardio protection with doxorubicin?

A

dexrazoxane

95
Q

What is the most important toxicity associated with doxorubicin?

A

cardiomyopathy

96
Q

Which is less cardiotoxic, doxorubicin or mitoxantrone?

A

mitoxantrone

Mitoxantrone has limited ability to form semiquinone radicals and lacks the C13 ketone found in the anthracyclines, thus, it is less cardiotoxic than the anthracycline topoisomerase II inhibitors

97
Q

Conjugated metabolites of what drug lead to blue-green feces and urine and sometimes in the skin and sclera?

A

mitoxantrone

anthracenedione topoisomerase II inhibitor

98
Q

Arsenic trioxide is used for treating which cancer?

A

acute promyelocytic leukemia (APL)

99
Q

What characterizes acute promyelocytic leukemia (APL)?

A

reciprocal translocation of chromosomes 15 and 17

treated with arsenic trioxide

100
Q

Arsenic trioxide induces remission in APL how?

A

destruction of fusion protein, induction of apoptosis in malignant cells

101
Q

Hydroxyurea blocks the catalytic site/action of what enzyme?

A

ribonucleotide reductase

the enzyme that catalyzes the rate limiting step in the biosynthesis of DNA

102
Q

Which drug is used as a radiation sensitizer?

A

hydroxyurea

The inhibition causes cell-cycle arrest at the G1-S interface, the stage at which cells are most sensitive to irradiation, thus hydroxyurea is used as a radiation sensitizer

103
Q

Which stage are cells most sensitive to irradiation?

A

G1-S interface

hydroxyurea inhibits cell cycle arrest at this interface and is used as radiation sensitizer

7361 Hem/Onc Block 1 (9 decks)

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