DNA Damaging Agents/Cytotoxics Flashcards by Daniel Allen

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

cell proliferation

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

senescence

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

apoptosis

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

oncogenes

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

tumor suppressor genes

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

cytotoxic

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

N7, O6

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

a. true
b. false

a. true

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Nitrogen mustards have two of what groups attached?

chloroethyl

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

a. intrastrand
b. interstrand

b. interstrand

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

p53

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Monoalkylation is associated with __

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

c. DNA methylating agents

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Mustards are alkylated by __ nitrogen of guaning

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

aziridinium

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

electron withdrawing

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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

aziridinium ion

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

melphalan

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

chlorambucil

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Is melphalan (nitrogen mustard) available for IV administration?

yes

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

bendamustine

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Which nitrogen mustard causes less repairable DNA damage?

bendamustine

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What reaction has been noted to bendamustine therapy?

hypersensitivity/anaphylaxis

pretreat with antihistamines and/or corticosteroids

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Which nitrogen mustard is the most widely used?

cyclophosphamide

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

cyclophosphamide

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What is required for cyclophosphamide to have alkylation activity?

metabolic activation this hepatic metabolism contributes to kidney and bladder toxicity

Which cyclophosphamide metabolite is highly nephrotoxic and neurotoxic?

chloroacetaldehyde

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

acrolein

Which is the most neurotoxic of the DNA alkylating agents?

ifosfamide due to chloroacetaldehyde

What can help reduce ifosfamide bladder toxicity?

adequate hydration increased chloroacetaldehyde leads to increased bladder toxicity and nephrotoxicity

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

ifosfamide

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

Mesna

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

acrolein-GSH

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

pancytopenia

__ toxicity is a risk at high doses of busulfan

pulmonary

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

methylsulfonate

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

2-chloroethyl

What DNA repair enzyme can reverse the alkylation of nitrosoureas?

MGMT methyl guanine methyltransferase

__ 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

carmustine, lomustine

Which is more stable lomustine or carmustine?

lomustine can be dosed orally

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

dacarbazine

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

temozolomide

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

MGMT

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

temozolomide

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

procarbazine

Which hydrazine DNA methylating agent is metabolically converted to diazomethane?

procarbazine reacts wit the O6 of guanine nucleobases

__ expression is associated with resistance to procarbazine.

MGMT

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

platinum

What kind of cross links are most common with platinum agents? a. interstrand b. intrastrand

b. intrastrand

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

platinum

Platinum agents enter the cell via what transporter?

active copper transporter (CTR1)

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

chloride, chloride

What form of platinum agents is the active cytotoxic?

hydrated

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

aluminum

Which platinum agent is photosensitive?

cisplatin packaged in amber bottles

Cisplatin causes significant damage to the __

renal tubules

What is used to mitigate the renal toxicity of cisplatin?

aggressive hydration with chloride containing solutions establishes chloride diuresis

Which platinum agent can cause irreversible ototoxicity?

cisplatin manifested by tinnitus and high frequency hearing loss

What is used to reduce the renal toxicity of cisplatin?

amifostine use for reducing ototoxicity is controversial

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

carboplatin

What protein can confer resistance to cisplatin and carboplatin?

MMR

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

oxaliplatin

Which platinum agent has a different DNA adduct formed?

oxaliplatin

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

less dependent on CTR1

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

nitrogen mustards | methylsulfonate ester

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

nitrosoureas | DNA methylating agents

3 drug classes that form INTERstrand DNA cross links?

nitrogen mustards methylsulfonate ester nitrosoureas

MGMT can cause resistance to which two drug classes?

nitrosoureas | DNA methylating agents

Bleomycin hydrate is found in all tissues except which two?

lungs | skin

What is the cytotoxic agent of bleomycin?

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

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

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

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

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

pulmonary fibrosis can occur as late as several months after therapy has ceased

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

> 40 related to total dose

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

S phase

How do topoisomerase inhibitors work?

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

Which camptothecin topoisomerase I inhibitor has modification at C10?

irinotecan incorporate basic amines that permit salt formation and enhance solubility

Which camptothecin topoisomerase I inhibitor has modification at C9?

topotecan incorporate basic amines that permit salt formation and enhance solubility

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

hepatic carboxyl esterases

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

UGT1A1

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

Asian

What therapy should be initiated immediately with irinotecan diarrhea?

vigorous loperamide

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

atropine

Epipodophyllotoxin topoisomerase II inhibitors: Etoposide and teniposide require what for IV dosing?

solubility enhancers ex. polysorbate, polyoxyethylated castor oil can cause hypersensitivity rxns

What CYP catalyzes O-demethylation of etoposide?

3A4 CYP3A4 inducers/inhibitors have significant impacts on metabolism topoisomerase II inhibitor

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

orthoquinone

What etoposide metabolite further oxidizes to a reactive orthoquinone metabolite?

catechol

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

acute lymphoblastic leukemia (ALL)

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

acute myeloid leukemia (AML)

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

drug induced chromosomal translocation

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

cardiotoxicity doxorubicin, epirubicin, valrubicin, daunorubicin, idarubicin

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

C13

Anthracyclines such as doxorubicin generate what toxic substance?

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

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

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

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

dexrazoxane

What is the most important toxicity associated with doxorubicin?

cardiomyopathy

Which is less cardiotoxic, doxorubicin or mitoxantrone?

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

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

mitoxantrone anthracenedione topoisomerase II inhibitor

Arsenic trioxide is used for treating which cancer?

acute promyelocytic leukemia (APL)

What characterizes acute promyelocytic leukemia (APL)?

reciprocal translocation of chromosomes 15 and 17 treated with arsenic trioxide

Arsenic trioxide induces remission in APL how?

destruction of fusion protein, induction of apoptosis in malignant cells

Hydroxyurea blocks the catalytic site/action of what enzyme?

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

Which drug is used as a radiation sensitizer?

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

Which stage are cells most sensitive to irradiation?

G1-S interface hydroxyurea inhibits cell cycle arrest at this interface and is used as radiation sensitizer